User login
Sharon Worcester is an award-winning medical journalist for MDedge News. She has been with the company since 1996, first as the Southeast Bureau Chief (1996-2009) when the company was known as International Medical News Group, then as a freelance writer (2010-2015) before returning as a reporter in 2015. She previously worked as a daily newspaper reporter covering health and local government. Sharon currently reports primarily on oncology and hematology. She has a BA from Eckerd College and an MA in Mass Communication/Print Journalism from the University of Florida. Connect with her via LinkedIn and follow her on twitter @SW_MedReporter.
Poziotinib provides ‘modest but meaningful’ efficacy in NSCLC subgroup
The overall response rate (ORR) in the 115 patients was 14.8%, according to Xiuning Le, MD, PhD, of MD Anderson Cancer Center in Houston, who reported these results at the AACR virtual meeting I.
The ORR fell short of the greater than 17% required to meet the primary endpoint, but 65% of patients experienced tumor shrinkage, Dr. Le noted.
Overall, 17 patients had a confirmed partial response, 5 had an unconfirmed partial response, and 62 had stable disease, for a disease control rate of 68.7%.
Responses occurred early and were durable, Dr. Le said. The median duration of response was 7.4 months.
Responses were also consistent across subgroups based on the number of prior lines of therapy and prior EGFR tyrosine kinase inhibitor (TKI) therapy.
The median progression-free survival was 4.2 months.
Patients, treatment, and safety
The patients, who were enrolled in the first cohort of the ZENITH20 study, had a median age of 61 years. They had received a median of two prior therapies, with most having received both chemotherapy and immunotherapy.
Poziotinib was given at a once-daily dose of 16 mg for 28-day cycles, with follow-up of 24 months. Dose reductions were allowed for adverse events (AEs).
AEs were on target and consistent with EGFR TKI class effects. The most common AEs were rash, diarrhea, stomatitis, and paronychia.
Grade 3 AEs included rash (28%) and diarrhea (25%). No grade 5 treatment-related AEs occurred.
Dose reductions were common, occurring in 68% of patients. The median relative poziotinib dose intensity was 72%, suggesting that response can be maintained at lower dose levels, Dr. Le said.
Drug interruptions were also common, occurring in 88% of patients. Ten percent of patients discontinued treatment permanently, Dr. Le said, noting that this is consistent with findings in prior large trials of second-generation TKIs.
Implications
The results of this study are of note because EGFR is a known driver of NSCLC, Dr. Le said. She explained that, while effective treatments exist for more common EGFR mutations, such as the classic sensitizing exon 21 mutation L858R and exon 19 deletion, no approved targeted therapies are available for the approximately 10% of lung cancer patients whose tumors harbor EGFR exon 20 insertions.
“Those EGFR exon 20 insertions are not sensitive to most of the approved EGFR inhibitors,” Dr. Le said. She noted that, in one study, the median progression-free survival following treatment with an approved agent was 14 months in patients with classical mutations, compared with 2 months in those with exon 20 insertions.
The difference is attributable to molecular structural differences. Exon 20 insertions create a smaller and more shallow EGFR protein interaction surface, Dr. Le explained. “So some of the approved inhibitors don’t fit well into the oncogenic molecule,” she said.
Poziotinib has a small size and shape that can fit into the binding pocket of exon 20, and that, along with its mechanism of action, made it a promising candidate for this population, Dr. Le said. She referenced a study of 44 patients at MD Anderson Cancer Center in which poziotinib produced an ORR of 43%.
In the current study, “[p]oziotinib has further demonstrated clinical activity in previously treated lung cancer patients with EGFR exon 20 insertions ... with a toxicity profile similar to that of other second-generation TKIs,” she said.
The findings underscore the promise of EGFR exon 20 insertions as targets for therapeutic intervention, said invited discussant Taofeek Owonikoko, MD, PhD, of Winship Cancer Institute of Emory University in Atlanta.
“Poziotinib showed modest but meaningful efficacy,” he said. “However, its safety remains a challenge. It is expected that ongoing modifications in the dosing schedule will make it a more tolerable agent.”
“Future studies to systematically explore differential sensitivity of various exon 20 insertion mutations by location will be informative, as will [elucidation of] mechanisms of resistance to prioritize combinatorial strategies to further enhance the efficacy of this drug,” Dr. Owonikoko added.
Next steps
Analyses of other cohorts in the ZENITH20 trial will be reported at upcoming conferences as the data mature, Dr. Le noted. Cohorts 2-4 include patients with previously treated HER2 exon 20 insertions and treatment-naive patients with EGFR and HER2 exon 20 insertions, respectively.
Additionally, three new cohorts are being added, including one with patients who have EGFR or HER2 exon 20 insertions, one with EGFR patients who failed prior osimertinib treatment, and one with patients who have atypical EGFR or HER2 mutations.
Rather than the once-daily dosing used in cohorts 1-4, twice-daily dosing will be evaluated in these cohorts, Dr. Le said, explaining that the half-life of poziotinib is about 8 hours.
“Recent pharmacological modeling showed that a [twice-daily] regimen would reduce the maximal serum concentration and increase trough, which could lead to optimized drug coverage,” she said. “This may potentially reduce toxicity and improve patient compliance and efficacy.”
ZENITH20 is sponsored by Spectrum Pharmaceuticals Inc. Dr. Le disclosed relationships with Spectrum as well as Eli Lilly, AstraZeneca, EMD Serono, and Boehringer Ingelheim. Dr. Owonikoko disclosed relationships with many companies, not including Spectrum.
SOURCE: Le X et al. AACR 2020, Abstract CT081.
The overall response rate (ORR) in the 115 patients was 14.8%, according to Xiuning Le, MD, PhD, of MD Anderson Cancer Center in Houston, who reported these results at the AACR virtual meeting I.
The ORR fell short of the greater than 17% required to meet the primary endpoint, but 65% of patients experienced tumor shrinkage, Dr. Le noted.
Overall, 17 patients had a confirmed partial response, 5 had an unconfirmed partial response, and 62 had stable disease, for a disease control rate of 68.7%.
Responses occurred early and were durable, Dr. Le said. The median duration of response was 7.4 months.
Responses were also consistent across subgroups based on the number of prior lines of therapy and prior EGFR tyrosine kinase inhibitor (TKI) therapy.
The median progression-free survival was 4.2 months.
Patients, treatment, and safety
The patients, who were enrolled in the first cohort of the ZENITH20 study, had a median age of 61 years. They had received a median of two prior therapies, with most having received both chemotherapy and immunotherapy.
Poziotinib was given at a once-daily dose of 16 mg for 28-day cycles, with follow-up of 24 months. Dose reductions were allowed for adverse events (AEs).
AEs were on target and consistent with EGFR TKI class effects. The most common AEs were rash, diarrhea, stomatitis, and paronychia.
Grade 3 AEs included rash (28%) and diarrhea (25%). No grade 5 treatment-related AEs occurred.
Dose reductions were common, occurring in 68% of patients. The median relative poziotinib dose intensity was 72%, suggesting that response can be maintained at lower dose levels, Dr. Le said.
Drug interruptions were also common, occurring in 88% of patients. Ten percent of patients discontinued treatment permanently, Dr. Le said, noting that this is consistent with findings in prior large trials of second-generation TKIs.
Implications
The results of this study are of note because EGFR is a known driver of NSCLC, Dr. Le said. She explained that, while effective treatments exist for more common EGFR mutations, such as the classic sensitizing exon 21 mutation L858R and exon 19 deletion, no approved targeted therapies are available for the approximately 10% of lung cancer patients whose tumors harbor EGFR exon 20 insertions.
“Those EGFR exon 20 insertions are not sensitive to most of the approved EGFR inhibitors,” Dr. Le said. She noted that, in one study, the median progression-free survival following treatment with an approved agent was 14 months in patients with classical mutations, compared with 2 months in those with exon 20 insertions.
The difference is attributable to molecular structural differences. Exon 20 insertions create a smaller and more shallow EGFR protein interaction surface, Dr. Le explained. “So some of the approved inhibitors don’t fit well into the oncogenic molecule,” she said.
Poziotinib has a small size and shape that can fit into the binding pocket of exon 20, and that, along with its mechanism of action, made it a promising candidate for this population, Dr. Le said. She referenced a study of 44 patients at MD Anderson Cancer Center in which poziotinib produced an ORR of 43%.
In the current study, “[p]oziotinib has further demonstrated clinical activity in previously treated lung cancer patients with EGFR exon 20 insertions ... with a toxicity profile similar to that of other second-generation TKIs,” she said.
The findings underscore the promise of EGFR exon 20 insertions as targets for therapeutic intervention, said invited discussant Taofeek Owonikoko, MD, PhD, of Winship Cancer Institute of Emory University in Atlanta.
“Poziotinib showed modest but meaningful efficacy,” he said. “However, its safety remains a challenge. It is expected that ongoing modifications in the dosing schedule will make it a more tolerable agent.”
“Future studies to systematically explore differential sensitivity of various exon 20 insertion mutations by location will be informative, as will [elucidation of] mechanisms of resistance to prioritize combinatorial strategies to further enhance the efficacy of this drug,” Dr. Owonikoko added.
Next steps
Analyses of other cohorts in the ZENITH20 trial will be reported at upcoming conferences as the data mature, Dr. Le noted. Cohorts 2-4 include patients with previously treated HER2 exon 20 insertions and treatment-naive patients with EGFR and HER2 exon 20 insertions, respectively.
Additionally, three new cohorts are being added, including one with patients who have EGFR or HER2 exon 20 insertions, one with EGFR patients who failed prior osimertinib treatment, and one with patients who have atypical EGFR or HER2 mutations.
Rather than the once-daily dosing used in cohorts 1-4, twice-daily dosing will be evaluated in these cohorts, Dr. Le said, explaining that the half-life of poziotinib is about 8 hours.
“Recent pharmacological modeling showed that a [twice-daily] regimen would reduce the maximal serum concentration and increase trough, which could lead to optimized drug coverage,” she said. “This may potentially reduce toxicity and improve patient compliance and efficacy.”
ZENITH20 is sponsored by Spectrum Pharmaceuticals Inc. Dr. Le disclosed relationships with Spectrum as well as Eli Lilly, AstraZeneca, EMD Serono, and Boehringer Ingelheim. Dr. Owonikoko disclosed relationships with many companies, not including Spectrum.
SOURCE: Le X et al. AACR 2020, Abstract CT081.
The overall response rate (ORR) in the 115 patients was 14.8%, according to Xiuning Le, MD, PhD, of MD Anderson Cancer Center in Houston, who reported these results at the AACR virtual meeting I.
The ORR fell short of the greater than 17% required to meet the primary endpoint, but 65% of patients experienced tumor shrinkage, Dr. Le noted.
Overall, 17 patients had a confirmed partial response, 5 had an unconfirmed partial response, and 62 had stable disease, for a disease control rate of 68.7%.
Responses occurred early and were durable, Dr. Le said. The median duration of response was 7.4 months.
Responses were also consistent across subgroups based on the number of prior lines of therapy and prior EGFR tyrosine kinase inhibitor (TKI) therapy.
The median progression-free survival was 4.2 months.
Patients, treatment, and safety
The patients, who were enrolled in the first cohort of the ZENITH20 study, had a median age of 61 years. They had received a median of two prior therapies, with most having received both chemotherapy and immunotherapy.
Poziotinib was given at a once-daily dose of 16 mg for 28-day cycles, with follow-up of 24 months. Dose reductions were allowed for adverse events (AEs).
AEs were on target and consistent with EGFR TKI class effects. The most common AEs were rash, diarrhea, stomatitis, and paronychia.
Grade 3 AEs included rash (28%) and diarrhea (25%). No grade 5 treatment-related AEs occurred.
Dose reductions were common, occurring in 68% of patients. The median relative poziotinib dose intensity was 72%, suggesting that response can be maintained at lower dose levels, Dr. Le said.
Drug interruptions were also common, occurring in 88% of patients. Ten percent of patients discontinued treatment permanently, Dr. Le said, noting that this is consistent with findings in prior large trials of second-generation TKIs.
Implications
The results of this study are of note because EGFR is a known driver of NSCLC, Dr. Le said. She explained that, while effective treatments exist for more common EGFR mutations, such as the classic sensitizing exon 21 mutation L858R and exon 19 deletion, no approved targeted therapies are available for the approximately 10% of lung cancer patients whose tumors harbor EGFR exon 20 insertions.
“Those EGFR exon 20 insertions are not sensitive to most of the approved EGFR inhibitors,” Dr. Le said. She noted that, in one study, the median progression-free survival following treatment with an approved agent was 14 months in patients with classical mutations, compared with 2 months in those with exon 20 insertions.
The difference is attributable to molecular structural differences. Exon 20 insertions create a smaller and more shallow EGFR protein interaction surface, Dr. Le explained. “So some of the approved inhibitors don’t fit well into the oncogenic molecule,” she said.
Poziotinib has a small size and shape that can fit into the binding pocket of exon 20, and that, along with its mechanism of action, made it a promising candidate for this population, Dr. Le said. She referenced a study of 44 patients at MD Anderson Cancer Center in which poziotinib produced an ORR of 43%.
In the current study, “[p]oziotinib has further demonstrated clinical activity in previously treated lung cancer patients with EGFR exon 20 insertions ... with a toxicity profile similar to that of other second-generation TKIs,” she said.
The findings underscore the promise of EGFR exon 20 insertions as targets for therapeutic intervention, said invited discussant Taofeek Owonikoko, MD, PhD, of Winship Cancer Institute of Emory University in Atlanta.
“Poziotinib showed modest but meaningful efficacy,” he said. “However, its safety remains a challenge. It is expected that ongoing modifications in the dosing schedule will make it a more tolerable agent.”
“Future studies to systematically explore differential sensitivity of various exon 20 insertion mutations by location will be informative, as will [elucidation of] mechanisms of resistance to prioritize combinatorial strategies to further enhance the efficacy of this drug,” Dr. Owonikoko added.
Next steps
Analyses of other cohorts in the ZENITH20 trial will be reported at upcoming conferences as the data mature, Dr. Le noted. Cohorts 2-4 include patients with previously treated HER2 exon 20 insertions and treatment-naive patients with EGFR and HER2 exon 20 insertions, respectively.
Additionally, three new cohorts are being added, including one with patients who have EGFR or HER2 exon 20 insertions, one with EGFR patients who failed prior osimertinib treatment, and one with patients who have atypical EGFR or HER2 mutations.
Rather than the once-daily dosing used in cohorts 1-4, twice-daily dosing will be evaluated in these cohorts, Dr. Le said, explaining that the half-life of poziotinib is about 8 hours.
“Recent pharmacological modeling showed that a [twice-daily] regimen would reduce the maximal serum concentration and increase trough, which could lead to optimized drug coverage,” she said. “This may potentially reduce toxicity and improve patient compliance and efficacy.”
ZENITH20 is sponsored by Spectrum Pharmaceuticals Inc. Dr. Le disclosed relationships with Spectrum as well as Eli Lilly, AstraZeneca, EMD Serono, and Boehringer Ingelheim. Dr. Owonikoko disclosed relationships with many companies, not including Spectrum.
SOURCE: Le X et al. AACR 2020, Abstract CT081.
FROM AACR 2020
ALTERNATE trial: No fulvestrant benefit in locally advanced ER+ HER2– breast cancer
Neither fulvestrant alone nor fulvestrant plus anastrozole improved the endocrine-sensitive disease rate (ESDR) versus anastrozole alone as neoadjuvant endocrine therapy in postmenopausal women with locally advanced estrogen receptor-positive HER2-negative (ER+ HER2–) breast cancer in the phase 3 ALTERNATE trial.
The ESDRs were 22.7% in 431 evaluable patients randomized to receive fulvestrant alone, 20.5% in 434 patients who received fulvestrant + anastrozole, and 18.6% in 434 who received anastrozole alone, Cynthia X. Ma, MD, PhD, reported as part of the American Society of Clinical Oncology virtual scientific program.
, said Dr. Ma, a professor at Washington University in St. Louis.
Study subjects had a median age of 64 years, clinical stage II/III ER+ HER2– breast cancer, and were randomized 1:1:1 between February 2014 and November 2018 to receive 6 months of treatment with 500 mg of intramuscular fulvestrant given every 4 weeks following a loading dose, fulvestrant plus a 1 mg daily oral does of anastrozole, or anastrozole alone prior to breast conserving surgery.
The groups were similar with respect to baseline characteristics, and more than 70% were eligible for breast conserving surgery prior to the start of neoadjuvant therapy, Dr. Ma noted, adding that the treatments were well tolerated.
Grade 3 or 4 adverse events were rare, and the percentage of patients experiencing arthralgia, myalgia, or hot flashes was low and similar across arms, she said.
“Neoadjuvant therapy downstages the tumor and improves the rate of breast conserving surgery,” Dr. Ma said, adding that pathologic tumor size, nodal status, Ki67 level, and ER status of resected tumors after neoadjuvant therapy have been shown to be independent prognostic factors for relapse-free survival.
A modified preoperative endocrine prognostic index (mPEPI) of 0 (defined as pT1-2 pN0 Ki67< 2.7%) or pathologic complete response (pCR) is associated with low risk of recurrence without adjuvant chemotherapy. ESDR, defined as the combined mPEPI 0 rates and pCR rates, was a co-primary endpoint of the ALTERNATE trial.
The rationale for studying fulvestrant with or without anastrozole in this setting came from the FALCON and S0226 trials showing superiority of those treatments versus anastrozole monotherapy as first-line endocrine therapy in the metastatic setting, Dr. Ma explained.
In the ALTERNATE trial, Ki67 was tested centrally on biopsies acquired prior to therapy, at weeks 4 and 12, and at surgery. Those with Ki67 greater than 10% at week 4 (20.7% of patients overall) or at week 12 (an additional 1.3% overall) were triaged to receive neoadjuvant chemotherapy; a similar number of patients in each group met these criteria, Dr. Ma said.
Further, patients with mPEPI score of 0 at surgery, were recommended to continue their assigned endocrine therapy without chemotherapy for 1.5 years followed by anastrozole for a total of 5 years of endocrine therapy. Those with mPEPI scores above zero, received chemotherapy and physician’s choice of endocrine therapy.
Follow-up is planned for 10 years. A second primary endpoint will be the breast cancer–free interval in the adjuvant setting.
Among the 936 patients with week 4 Ki67 of 10% or less who completed NET and surgery, the ESDRs were similar across the arms: 31.7% for fulvestrant alone, 26.3% with fulvestrant plus anastrozole, and 28.0% with anastrozole alone, Dr. Ma said.
Week 4 Ki67 reductions from baseline also were similar across the arms.
Nearly all patients with Ki67 of 10% or less at baseline continued to have Ki67 less than 10% at week 4, and about two-thirds of those with Ki67 over 10% at baseline had Ki67 less than 10% at week 4, she said, noting that these findings were also similar across treatment arms.
These first results from the ALTERNATE trial show that fewer than 2% of patients treated with 6 months of neoadjuvant endocrine therapy progressed, likely as a result of the Ki67 triaging strategy, Dr. Ma said.
“Neoadjuvant chemotherapy outcomes for patients with week 4 Ki67 over 10% will be reported later,” she said. “Genomic and biomarker correlates, as well as, importantly, relapse-free survivals are also awaited.”
An invited discussant, Antonio C. Wolff, MD, professor of oncology at Johns Hopkins University, Baltimore, said that while the co-primary endpoint of ESDR in the study was not met, the results provide “a few important messages.”
First, the study showed that low Ki67 at baseline largely stays low at 4 weeks. High Ki67 at baseline frequently became low at week 4, he said.
“Finally, we must congratulate Dr. Ma and colleagues on showing that research biopsies for integral biomarker testing can happen across the [National Clinical Trials Network] throughout the U.S., including most community sites,” he said, adding “that alone is a major accomplishment.”
Dr. Wolff also noted that the 5-year relapse-free survival data for patients who achieve mPEPI 0 at surgery are “awaited with great interest.”
The ALTERNATE trial is funded by the Alliance Foundation, NCI Biomarker, Imaging and Quality of Life Studies Funding Program, Breast Cancer Research Foundation, Genentech,and AstraZeneca. Dr. Ma reported consulting or advisory roles with a variety of pharmaceutical companies, and research funding from pharmaceutical companies to her institution. Dr. Wolff reported relationships (consulting or advisory roles and research funding) with Ionis, Biomarin, Celldex, and patents or royalties (issued or pending) associated with methylation in breast cancer.
SOURCE: Ma C et al. ASCO 2020: Abstract 504.
Neither fulvestrant alone nor fulvestrant plus anastrozole improved the endocrine-sensitive disease rate (ESDR) versus anastrozole alone as neoadjuvant endocrine therapy in postmenopausal women with locally advanced estrogen receptor-positive HER2-negative (ER+ HER2–) breast cancer in the phase 3 ALTERNATE trial.
The ESDRs were 22.7% in 431 evaluable patients randomized to receive fulvestrant alone, 20.5% in 434 patients who received fulvestrant + anastrozole, and 18.6% in 434 who received anastrozole alone, Cynthia X. Ma, MD, PhD, reported as part of the American Society of Clinical Oncology virtual scientific program.
, said Dr. Ma, a professor at Washington University in St. Louis.
Study subjects had a median age of 64 years, clinical stage II/III ER+ HER2– breast cancer, and were randomized 1:1:1 between February 2014 and November 2018 to receive 6 months of treatment with 500 mg of intramuscular fulvestrant given every 4 weeks following a loading dose, fulvestrant plus a 1 mg daily oral does of anastrozole, or anastrozole alone prior to breast conserving surgery.
The groups were similar with respect to baseline characteristics, and more than 70% were eligible for breast conserving surgery prior to the start of neoadjuvant therapy, Dr. Ma noted, adding that the treatments were well tolerated.
Grade 3 or 4 adverse events were rare, and the percentage of patients experiencing arthralgia, myalgia, or hot flashes was low and similar across arms, she said.
“Neoadjuvant therapy downstages the tumor and improves the rate of breast conserving surgery,” Dr. Ma said, adding that pathologic tumor size, nodal status, Ki67 level, and ER status of resected tumors after neoadjuvant therapy have been shown to be independent prognostic factors for relapse-free survival.
A modified preoperative endocrine prognostic index (mPEPI) of 0 (defined as pT1-2 pN0 Ki67< 2.7%) or pathologic complete response (pCR) is associated with low risk of recurrence without adjuvant chemotherapy. ESDR, defined as the combined mPEPI 0 rates and pCR rates, was a co-primary endpoint of the ALTERNATE trial.
The rationale for studying fulvestrant with or without anastrozole in this setting came from the FALCON and S0226 trials showing superiority of those treatments versus anastrozole monotherapy as first-line endocrine therapy in the metastatic setting, Dr. Ma explained.
In the ALTERNATE trial, Ki67 was tested centrally on biopsies acquired prior to therapy, at weeks 4 and 12, and at surgery. Those with Ki67 greater than 10% at week 4 (20.7% of patients overall) or at week 12 (an additional 1.3% overall) were triaged to receive neoadjuvant chemotherapy; a similar number of patients in each group met these criteria, Dr. Ma said.
Further, patients with mPEPI score of 0 at surgery, were recommended to continue their assigned endocrine therapy without chemotherapy for 1.5 years followed by anastrozole for a total of 5 years of endocrine therapy. Those with mPEPI scores above zero, received chemotherapy and physician’s choice of endocrine therapy.
Follow-up is planned for 10 years. A second primary endpoint will be the breast cancer–free interval in the adjuvant setting.
Among the 936 patients with week 4 Ki67 of 10% or less who completed NET and surgery, the ESDRs were similar across the arms: 31.7% for fulvestrant alone, 26.3% with fulvestrant plus anastrozole, and 28.0% with anastrozole alone, Dr. Ma said.
Week 4 Ki67 reductions from baseline also were similar across the arms.
Nearly all patients with Ki67 of 10% or less at baseline continued to have Ki67 less than 10% at week 4, and about two-thirds of those with Ki67 over 10% at baseline had Ki67 less than 10% at week 4, she said, noting that these findings were also similar across treatment arms.
These first results from the ALTERNATE trial show that fewer than 2% of patients treated with 6 months of neoadjuvant endocrine therapy progressed, likely as a result of the Ki67 triaging strategy, Dr. Ma said.
“Neoadjuvant chemotherapy outcomes for patients with week 4 Ki67 over 10% will be reported later,” she said. “Genomic and biomarker correlates, as well as, importantly, relapse-free survivals are also awaited.”
An invited discussant, Antonio C. Wolff, MD, professor of oncology at Johns Hopkins University, Baltimore, said that while the co-primary endpoint of ESDR in the study was not met, the results provide “a few important messages.”
First, the study showed that low Ki67 at baseline largely stays low at 4 weeks. High Ki67 at baseline frequently became low at week 4, he said.
“Finally, we must congratulate Dr. Ma and colleagues on showing that research biopsies for integral biomarker testing can happen across the [National Clinical Trials Network] throughout the U.S., including most community sites,” he said, adding “that alone is a major accomplishment.”
Dr. Wolff also noted that the 5-year relapse-free survival data for patients who achieve mPEPI 0 at surgery are “awaited with great interest.”
The ALTERNATE trial is funded by the Alliance Foundation, NCI Biomarker, Imaging and Quality of Life Studies Funding Program, Breast Cancer Research Foundation, Genentech,and AstraZeneca. Dr. Ma reported consulting or advisory roles with a variety of pharmaceutical companies, and research funding from pharmaceutical companies to her institution. Dr. Wolff reported relationships (consulting or advisory roles and research funding) with Ionis, Biomarin, Celldex, and patents or royalties (issued or pending) associated with methylation in breast cancer.
SOURCE: Ma C et al. ASCO 2020: Abstract 504.
Neither fulvestrant alone nor fulvestrant plus anastrozole improved the endocrine-sensitive disease rate (ESDR) versus anastrozole alone as neoadjuvant endocrine therapy in postmenopausal women with locally advanced estrogen receptor-positive HER2-negative (ER+ HER2–) breast cancer in the phase 3 ALTERNATE trial.
The ESDRs were 22.7% in 431 evaluable patients randomized to receive fulvestrant alone, 20.5% in 434 patients who received fulvestrant + anastrozole, and 18.6% in 434 who received anastrozole alone, Cynthia X. Ma, MD, PhD, reported as part of the American Society of Clinical Oncology virtual scientific program.
, said Dr. Ma, a professor at Washington University in St. Louis.
Study subjects had a median age of 64 years, clinical stage II/III ER+ HER2– breast cancer, and were randomized 1:1:1 between February 2014 and November 2018 to receive 6 months of treatment with 500 mg of intramuscular fulvestrant given every 4 weeks following a loading dose, fulvestrant plus a 1 mg daily oral does of anastrozole, or anastrozole alone prior to breast conserving surgery.
The groups were similar with respect to baseline characteristics, and more than 70% were eligible for breast conserving surgery prior to the start of neoadjuvant therapy, Dr. Ma noted, adding that the treatments were well tolerated.
Grade 3 or 4 adverse events were rare, and the percentage of patients experiencing arthralgia, myalgia, or hot flashes was low and similar across arms, she said.
“Neoadjuvant therapy downstages the tumor and improves the rate of breast conserving surgery,” Dr. Ma said, adding that pathologic tumor size, nodal status, Ki67 level, and ER status of resected tumors after neoadjuvant therapy have been shown to be independent prognostic factors for relapse-free survival.
A modified preoperative endocrine prognostic index (mPEPI) of 0 (defined as pT1-2 pN0 Ki67< 2.7%) or pathologic complete response (pCR) is associated with low risk of recurrence without adjuvant chemotherapy. ESDR, defined as the combined mPEPI 0 rates and pCR rates, was a co-primary endpoint of the ALTERNATE trial.
The rationale for studying fulvestrant with or without anastrozole in this setting came from the FALCON and S0226 trials showing superiority of those treatments versus anastrozole monotherapy as first-line endocrine therapy in the metastatic setting, Dr. Ma explained.
In the ALTERNATE trial, Ki67 was tested centrally on biopsies acquired prior to therapy, at weeks 4 and 12, and at surgery. Those with Ki67 greater than 10% at week 4 (20.7% of patients overall) or at week 12 (an additional 1.3% overall) were triaged to receive neoadjuvant chemotherapy; a similar number of patients in each group met these criteria, Dr. Ma said.
Further, patients with mPEPI score of 0 at surgery, were recommended to continue their assigned endocrine therapy without chemotherapy for 1.5 years followed by anastrozole for a total of 5 years of endocrine therapy. Those with mPEPI scores above zero, received chemotherapy and physician’s choice of endocrine therapy.
Follow-up is planned for 10 years. A second primary endpoint will be the breast cancer–free interval in the adjuvant setting.
Among the 936 patients with week 4 Ki67 of 10% or less who completed NET and surgery, the ESDRs were similar across the arms: 31.7% for fulvestrant alone, 26.3% with fulvestrant plus anastrozole, and 28.0% with anastrozole alone, Dr. Ma said.
Week 4 Ki67 reductions from baseline also were similar across the arms.
Nearly all patients with Ki67 of 10% or less at baseline continued to have Ki67 less than 10% at week 4, and about two-thirds of those with Ki67 over 10% at baseline had Ki67 less than 10% at week 4, she said, noting that these findings were also similar across treatment arms.
These first results from the ALTERNATE trial show that fewer than 2% of patients treated with 6 months of neoadjuvant endocrine therapy progressed, likely as a result of the Ki67 triaging strategy, Dr. Ma said.
“Neoadjuvant chemotherapy outcomes for patients with week 4 Ki67 over 10% will be reported later,” she said. “Genomic and biomarker correlates, as well as, importantly, relapse-free survivals are also awaited.”
An invited discussant, Antonio C. Wolff, MD, professor of oncology at Johns Hopkins University, Baltimore, said that while the co-primary endpoint of ESDR in the study was not met, the results provide “a few important messages.”
First, the study showed that low Ki67 at baseline largely stays low at 4 weeks. High Ki67 at baseline frequently became low at week 4, he said.
“Finally, we must congratulate Dr. Ma and colleagues on showing that research biopsies for integral biomarker testing can happen across the [National Clinical Trials Network] throughout the U.S., including most community sites,” he said, adding “that alone is a major accomplishment.”
Dr. Wolff also noted that the 5-year relapse-free survival data for patients who achieve mPEPI 0 at surgery are “awaited with great interest.”
The ALTERNATE trial is funded by the Alliance Foundation, NCI Biomarker, Imaging and Quality of Life Studies Funding Program, Breast Cancer Research Foundation, Genentech,and AstraZeneca. Dr. Ma reported consulting or advisory roles with a variety of pharmaceutical companies, and research funding from pharmaceutical companies to her institution. Dr. Wolff reported relationships (consulting or advisory roles and research funding) with Ionis, Biomarin, Celldex, and patents or royalties (issued or pending) associated with methylation in breast cancer.
SOURCE: Ma C et al. ASCO 2020: Abstract 504.
FROM ASCO 2020
LOTUS: Ipatasertib plus paclitaxel may prolong OS in TNBC
according to final results of the phase 2 LOTUS trial.
The median OS was 25.8 months in patients who received ipatasertib plus paclitaxel and 16.9 months in patients who received paclitaxel plus placebo. Although this difference was not statistically significant, it was “clinically meaningful,” according to Rebecca Dent, MD, of the National Cancer Center Singapore. Dr. Dent presented OS data from the LOTUS trial at the European Society of Medical Oncology: Breast Cancer virtual meeting.
Previously reported data showed a progression-free survival benefit in the ipatasertib arm, compared with the placebo arm – 6.2 months and 4.9 months, respectively (Lancet Oncol. 2017 Oct;18[10]:1360-72). An enhanced effect was noted in patients with PIK3CA/AKT1/PTEN–altered tumors, but the OS data were not mature at the time of that primary analysis.
Patients, treatment, and safety
LOTUS participants had measurable locally advanced/metastatic TNBC that was previously untreated with systemic therapy, and they were stratified by prior adjuvant therapy, chemotherapy-free interval, and tumor immunohistochemistry PTEN status.
Patients were randomized 1:1 to receive paclitaxel at a dose of 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle plus either placebo (n = 62) or ipatasertib at a dose of 400 mg on days 1-21 (n = 62).
The safety results didn’t differ between the primary and updated results, Dr. Dent noted.
“What we can say is that the combination is extremely well tolerated, especially when we compare it to other targeted agents targeting this pathway,” she said. “What we do see is noticeable diarrhea ... [and] an increase in sensory neuropathy, which is not entirely unexpected.”
Subsequent systemic anticancer therapy was required in 77% of patients in the ipatasertib arm and 90% of patients in the placebo arm.
OS results
The final OS data show a numerical advantage for patients in the ipatasertib arm compared with the placebo arm. The 1-year OS was 83% in the ipatasertib arm and 68% in the placebo arm. The median OS was 25.8 months and 16.9 months, respectively (stratified hazard ratio, 0.80).
“This is a clinically meaningful improvement of 9 months in overall survival, which is indeed not too dissimilar to what we have seen in patients with PD-L1-positive TNBC who are receiving immune checkpoint inhibition in combination with chemotherapy,” Dr. Dent said.
However, the 95% confidence interval for the stratified OS hazard ratio crossed 1 (0.50-1.28). Therefore, the findings require confirmatory phase 3 trial results, Dr. Dent said.
The OS improvements with ipatasertib were seen “in all biomarker-defined subgroups – PTEN normal or low, PIK3CA/AKT1/PTEN altered or non-altered,” she said. OS benefits were more pronounced in patients with altered PIK3C/AKT1/PTEN status, but the numbers are too small to make definitive conclusions, according to Dr. Dent.
‘Promising’ results, confirmation needed
Invited discussant Suzette Delaloge, MD, head of the breast cancer department at Gustave Roussy, Paris, said the OS findings from LOTUS are “quite promising,” and the safety data are “reassuring.”
The findings are comparable to those of the recently published PAKT trial (J Clin Oncol. 2020 Feb 10;38[5]:423-33), she said, noting that “AKT inhibition in combination with paclitaxel deserves phase 3 development, and this is ongoing in major phase 3 trials.”
Dr. Delaloge also noted that the efficacy may not be limited to PIK3CA/AKT–altered tumors, and given the heterogeneity of TNBC – which may explain the differences seen among various studies – “it is very important that such phase 3 trials ideally involve extensive genomical definitions of tumors so that we understand what it is we are talking about and what is the real effect of the drug.”
“The adequate positioning of AKT inhibition in competition/complementation with other ongoing strategies remains to be defined,” she said. “I think these drugs are ready for translation to early phases.”
Dr. Dent said the results of LOTUS warrant confirmation in the ongoing, randomized phase 3 IPATunity130 trial , in which researchers are evaluating first-line ipatasertib plus paclitaxel for metastatic TNBC. She noted that the small sample sizes and heterogeneity of TNBC among LOTUS participants limited the interpretation of the findings.
In another trial, IPATunity170, researchers are evaluating the first-line role of ipatasertib plus paclitaxel and atezolizumab in locally advanced or metastatic TNBC.
“This is an exciting triplet combination that’s been evaluated already in the phase 1 setting, and now we have a phase 3 study evaluating the triplet,” Dr. Dent said.
The LOTUS trial was funded by Roche/Genentech. Dr. Dent reported receiving honoraria from Roche, Novartis, Lilly, Pfizer, Eisai, Merck, and AstraZeneca. Dr. Delaloge reported personal financial interests in AstraZeneca until 2018 and travel and accommodation support from AstraZeneca, Pfizer, Roche, and Pierre Fabre.
SOURCE: Dent R et al. ESMO Breast Cancer 2020, Abstract 139O
according to final results of the phase 2 LOTUS trial.
The median OS was 25.8 months in patients who received ipatasertib plus paclitaxel and 16.9 months in patients who received paclitaxel plus placebo. Although this difference was not statistically significant, it was “clinically meaningful,” according to Rebecca Dent, MD, of the National Cancer Center Singapore. Dr. Dent presented OS data from the LOTUS trial at the European Society of Medical Oncology: Breast Cancer virtual meeting.
Previously reported data showed a progression-free survival benefit in the ipatasertib arm, compared with the placebo arm – 6.2 months and 4.9 months, respectively (Lancet Oncol. 2017 Oct;18[10]:1360-72). An enhanced effect was noted in patients with PIK3CA/AKT1/PTEN–altered tumors, but the OS data were not mature at the time of that primary analysis.
Patients, treatment, and safety
LOTUS participants had measurable locally advanced/metastatic TNBC that was previously untreated with systemic therapy, and they were stratified by prior adjuvant therapy, chemotherapy-free interval, and tumor immunohistochemistry PTEN status.
Patients were randomized 1:1 to receive paclitaxel at a dose of 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle plus either placebo (n = 62) or ipatasertib at a dose of 400 mg on days 1-21 (n = 62).
The safety results didn’t differ between the primary and updated results, Dr. Dent noted.
“What we can say is that the combination is extremely well tolerated, especially when we compare it to other targeted agents targeting this pathway,” she said. “What we do see is noticeable diarrhea ... [and] an increase in sensory neuropathy, which is not entirely unexpected.”
Subsequent systemic anticancer therapy was required in 77% of patients in the ipatasertib arm and 90% of patients in the placebo arm.
OS results
The final OS data show a numerical advantage for patients in the ipatasertib arm compared with the placebo arm. The 1-year OS was 83% in the ipatasertib arm and 68% in the placebo arm. The median OS was 25.8 months and 16.9 months, respectively (stratified hazard ratio, 0.80).
“This is a clinically meaningful improvement of 9 months in overall survival, which is indeed not too dissimilar to what we have seen in patients with PD-L1-positive TNBC who are receiving immune checkpoint inhibition in combination with chemotherapy,” Dr. Dent said.
However, the 95% confidence interval for the stratified OS hazard ratio crossed 1 (0.50-1.28). Therefore, the findings require confirmatory phase 3 trial results, Dr. Dent said.
The OS improvements with ipatasertib were seen “in all biomarker-defined subgroups – PTEN normal or low, PIK3CA/AKT1/PTEN altered or non-altered,” she said. OS benefits were more pronounced in patients with altered PIK3C/AKT1/PTEN status, but the numbers are too small to make definitive conclusions, according to Dr. Dent.
‘Promising’ results, confirmation needed
Invited discussant Suzette Delaloge, MD, head of the breast cancer department at Gustave Roussy, Paris, said the OS findings from LOTUS are “quite promising,” and the safety data are “reassuring.”
The findings are comparable to those of the recently published PAKT trial (J Clin Oncol. 2020 Feb 10;38[5]:423-33), she said, noting that “AKT inhibition in combination with paclitaxel deserves phase 3 development, and this is ongoing in major phase 3 trials.”
Dr. Delaloge also noted that the efficacy may not be limited to PIK3CA/AKT–altered tumors, and given the heterogeneity of TNBC – which may explain the differences seen among various studies – “it is very important that such phase 3 trials ideally involve extensive genomical definitions of tumors so that we understand what it is we are talking about and what is the real effect of the drug.”
“The adequate positioning of AKT inhibition in competition/complementation with other ongoing strategies remains to be defined,” she said. “I think these drugs are ready for translation to early phases.”
Dr. Dent said the results of LOTUS warrant confirmation in the ongoing, randomized phase 3 IPATunity130 trial , in which researchers are evaluating first-line ipatasertib plus paclitaxel for metastatic TNBC. She noted that the small sample sizes and heterogeneity of TNBC among LOTUS participants limited the interpretation of the findings.
In another trial, IPATunity170, researchers are evaluating the first-line role of ipatasertib plus paclitaxel and atezolizumab in locally advanced or metastatic TNBC.
“This is an exciting triplet combination that’s been evaluated already in the phase 1 setting, and now we have a phase 3 study evaluating the triplet,” Dr. Dent said.
The LOTUS trial was funded by Roche/Genentech. Dr. Dent reported receiving honoraria from Roche, Novartis, Lilly, Pfizer, Eisai, Merck, and AstraZeneca. Dr. Delaloge reported personal financial interests in AstraZeneca until 2018 and travel and accommodation support from AstraZeneca, Pfizer, Roche, and Pierre Fabre.
SOURCE: Dent R et al. ESMO Breast Cancer 2020, Abstract 139O
according to final results of the phase 2 LOTUS trial.
The median OS was 25.8 months in patients who received ipatasertib plus paclitaxel and 16.9 months in patients who received paclitaxel plus placebo. Although this difference was not statistically significant, it was “clinically meaningful,” according to Rebecca Dent, MD, of the National Cancer Center Singapore. Dr. Dent presented OS data from the LOTUS trial at the European Society of Medical Oncology: Breast Cancer virtual meeting.
Previously reported data showed a progression-free survival benefit in the ipatasertib arm, compared with the placebo arm – 6.2 months and 4.9 months, respectively (Lancet Oncol. 2017 Oct;18[10]:1360-72). An enhanced effect was noted in patients with PIK3CA/AKT1/PTEN–altered tumors, but the OS data were not mature at the time of that primary analysis.
Patients, treatment, and safety
LOTUS participants had measurable locally advanced/metastatic TNBC that was previously untreated with systemic therapy, and they were stratified by prior adjuvant therapy, chemotherapy-free interval, and tumor immunohistochemistry PTEN status.
Patients were randomized 1:1 to receive paclitaxel at a dose of 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle plus either placebo (n = 62) or ipatasertib at a dose of 400 mg on days 1-21 (n = 62).
The safety results didn’t differ between the primary and updated results, Dr. Dent noted.
“What we can say is that the combination is extremely well tolerated, especially when we compare it to other targeted agents targeting this pathway,” she said. “What we do see is noticeable diarrhea ... [and] an increase in sensory neuropathy, which is not entirely unexpected.”
Subsequent systemic anticancer therapy was required in 77% of patients in the ipatasertib arm and 90% of patients in the placebo arm.
OS results
The final OS data show a numerical advantage for patients in the ipatasertib arm compared with the placebo arm. The 1-year OS was 83% in the ipatasertib arm and 68% in the placebo arm. The median OS was 25.8 months and 16.9 months, respectively (stratified hazard ratio, 0.80).
“This is a clinically meaningful improvement of 9 months in overall survival, which is indeed not too dissimilar to what we have seen in patients with PD-L1-positive TNBC who are receiving immune checkpoint inhibition in combination with chemotherapy,” Dr. Dent said.
However, the 95% confidence interval for the stratified OS hazard ratio crossed 1 (0.50-1.28). Therefore, the findings require confirmatory phase 3 trial results, Dr. Dent said.
The OS improvements with ipatasertib were seen “in all biomarker-defined subgroups – PTEN normal or low, PIK3CA/AKT1/PTEN altered or non-altered,” she said. OS benefits were more pronounced in patients with altered PIK3C/AKT1/PTEN status, but the numbers are too small to make definitive conclusions, according to Dr. Dent.
‘Promising’ results, confirmation needed
Invited discussant Suzette Delaloge, MD, head of the breast cancer department at Gustave Roussy, Paris, said the OS findings from LOTUS are “quite promising,” and the safety data are “reassuring.”
The findings are comparable to those of the recently published PAKT trial (J Clin Oncol. 2020 Feb 10;38[5]:423-33), she said, noting that “AKT inhibition in combination with paclitaxel deserves phase 3 development, and this is ongoing in major phase 3 trials.”
Dr. Delaloge also noted that the efficacy may not be limited to PIK3CA/AKT–altered tumors, and given the heterogeneity of TNBC – which may explain the differences seen among various studies – “it is very important that such phase 3 trials ideally involve extensive genomical definitions of tumors so that we understand what it is we are talking about and what is the real effect of the drug.”
“The adequate positioning of AKT inhibition in competition/complementation with other ongoing strategies remains to be defined,” she said. “I think these drugs are ready for translation to early phases.”
Dr. Dent said the results of LOTUS warrant confirmation in the ongoing, randomized phase 3 IPATunity130 trial , in which researchers are evaluating first-line ipatasertib plus paclitaxel for metastatic TNBC. She noted that the small sample sizes and heterogeneity of TNBC among LOTUS participants limited the interpretation of the findings.
In another trial, IPATunity170, researchers are evaluating the first-line role of ipatasertib plus paclitaxel and atezolizumab in locally advanced or metastatic TNBC.
“This is an exciting triplet combination that’s been evaluated already in the phase 1 setting, and now we have a phase 3 study evaluating the triplet,” Dr. Dent said.
The LOTUS trial was funded by Roche/Genentech. Dr. Dent reported receiving honoraria from Roche, Novartis, Lilly, Pfizer, Eisai, Merck, and AstraZeneca. Dr. Delaloge reported personal financial interests in AstraZeneca until 2018 and travel and accommodation support from AstraZeneca, Pfizer, Roche, and Pierre Fabre.
SOURCE: Dent R et al. ESMO Breast Cancer 2020, Abstract 139O
FROM ESMO BREAST CANCER 2020
Novel penclomedine shows promise for some AYAs with CNS cancers
according to phase 1/2 clinical trial findings.
The trial included 15 patients, aged 15-39 years, with measurable cancer involving the CNS who were treated with the agent 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN).
Two of these patients were “in their 59th month of survival and doing well” as of April, when the data were presented at the AACR virtual meeting I.
One of the patients with long-term survival benefit had non–small cell lung cancer, and one had astrocytoma, Lee Roy Morgan, MD, PhD, chief executive officer of Dekk-Tec Inc., New Orleans, reported during a poster presentation.
Patients with glioblastoma, however, “did not do well,” said Dr. Morgan, an adjunct professor at Tulane University in New Orleans. He noted that none of the five glioblastoma patients experienced a long-term response.
Safety
Study subjects were treated with the maximum tolerated dose (MTD) of DM-CHOC-PEN as identified in an earlier study. Patients with liver involvement received 75 mg/m2, and those without liver involvement received up to 98.7 mg/m2. Dosing was by 3-hour intravenous administration once every 21 days as lab tests and subject status allowed.
DM-CHOC-PEN was generally well tolerated. One patient experienced grade 2 vasogenic edema, and another experienced seizures. Both were secondary to tumor swelling, and both resolved with tumor regression.
No grade 3 toxicities occurred at the MTD, and “no renal, hematological, hepatic, or pulmonary toxicities were noted using the MTD in this trial,” Dr. Morgan said.
Mechanism
DM-CHOC-PEN is a polychlorinated pyridine with a cholesteryl carbonate attachment that induces lipophilicity, which potentiates the drug’s penetration of the blood-brain barrier and its entry into the brain and brain cancers, Dr. Morgan explained.
He added that DM-CHOC-PEN is a bis-alkylator that binds to DNA’s cytosine/guanine nucleotides. The agent does not require hepatic activation, it crosses the blood-brain barrier intact, and accumulates in CNS tumors but not normal CNS tissue, he said.
Further, it “is not a substrate for [p-glycoprotein] transport; thus, it doesn’t easily get out of the brain,” Dr. Morgan said. He noted that DM-CHOC-PEN can be used with other agents, such as temozolomide and bis-chloroethylnitrosourea, because of the difference in mechanisms of action.
This study was supported by Louisiana state grants, the National Cancer Institute, the National Institute of General Medical Sciences, and the Small Business Innovation Research program. Dr. Morgan reported having no disclosures, but he is chief executive officer of Dekk-Tec Inc., which is developing DM-CHOC-PEN.
SOURCE: Morgan L et al. AACR 2020, Abstract CT181.
according to phase 1/2 clinical trial findings.
The trial included 15 patients, aged 15-39 years, with measurable cancer involving the CNS who were treated with the agent 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN).
Two of these patients were “in their 59th month of survival and doing well” as of April, when the data were presented at the AACR virtual meeting I.
One of the patients with long-term survival benefit had non–small cell lung cancer, and one had astrocytoma, Lee Roy Morgan, MD, PhD, chief executive officer of Dekk-Tec Inc., New Orleans, reported during a poster presentation.
Patients with glioblastoma, however, “did not do well,” said Dr. Morgan, an adjunct professor at Tulane University in New Orleans. He noted that none of the five glioblastoma patients experienced a long-term response.
Safety
Study subjects were treated with the maximum tolerated dose (MTD) of DM-CHOC-PEN as identified in an earlier study. Patients with liver involvement received 75 mg/m2, and those without liver involvement received up to 98.7 mg/m2. Dosing was by 3-hour intravenous administration once every 21 days as lab tests and subject status allowed.
DM-CHOC-PEN was generally well tolerated. One patient experienced grade 2 vasogenic edema, and another experienced seizures. Both were secondary to tumor swelling, and both resolved with tumor regression.
No grade 3 toxicities occurred at the MTD, and “no renal, hematological, hepatic, or pulmonary toxicities were noted using the MTD in this trial,” Dr. Morgan said.
Mechanism
DM-CHOC-PEN is a polychlorinated pyridine with a cholesteryl carbonate attachment that induces lipophilicity, which potentiates the drug’s penetration of the blood-brain barrier and its entry into the brain and brain cancers, Dr. Morgan explained.
He added that DM-CHOC-PEN is a bis-alkylator that binds to DNA’s cytosine/guanine nucleotides. The agent does not require hepatic activation, it crosses the blood-brain barrier intact, and accumulates in CNS tumors but not normal CNS tissue, he said.
Further, it “is not a substrate for [p-glycoprotein] transport; thus, it doesn’t easily get out of the brain,” Dr. Morgan said. He noted that DM-CHOC-PEN can be used with other agents, such as temozolomide and bis-chloroethylnitrosourea, because of the difference in mechanisms of action.
This study was supported by Louisiana state grants, the National Cancer Institute, the National Institute of General Medical Sciences, and the Small Business Innovation Research program. Dr. Morgan reported having no disclosures, but he is chief executive officer of Dekk-Tec Inc., which is developing DM-CHOC-PEN.
SOURCE: Morgan L et al. AACR 2020, Abstract CT181.
according to phase 1/2 clinical trial findings.
The trial included 15 patients, aged 15-39 years, with measurable cancer involving the CNS who were treated with the agent 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN).
Two of these patients were “in their 59th month of survival and doing well” as of April, when the data were presented at the AACR virtual meeting I.
One of the patients with long-term survival benefit had non–small cell lung cancer, and one had astrocytoma, Lee Roy Morgan, MD, PhD, chief executive officer of Dekk-Tec Inc., New Orleans, reported during a poster presentation.
Patients with glioblastoma, however, “did not do well,” said Dr. Morgan, an adjunct professor at Tulane University in New Orleans. He noted that none of the five glioblastoma patients experienced a long-term response.
Safety
Study subjects were treated with the maximum tolerated dose (MTD) of DM-CHOC-PEN as identified in an earlier study. Patients with liver involvement received 75 mg/m2, and those without liver involvement received up to 98.7 mg/m2. Dosing was by 3-hour intravenous administration once every 21 days as lab tests and subject status allowed.
DM-CHOC-PEN was generally well tolerated. One patient experienced grade 2 vasogenic edema, and another experienced seizures. Both were secondary to tumor swelling, and both resolved with tumor regression.
No grade 3 toxicities occurred at the MTD, and “no renal, hematological, hepatic, or pulmonary toxicities were noted using the MTD in this trial,” Dr. Morgan said.
Mechanism
DM-CHOC-PEN is a polychlorinated pyridine with a cholesteryl carbonate attachment that induces lipophilicity, which potentiates the drug’s penetration of the blood-brain barrier and its entry into the brain and brain cancers, Dr. Morgan explained.
He added that DM-CHOC-PEN is a bis-alkylator that binds to DNA’s cytosine/guanine nucleotides. The agent does not require hepatic activation, it crosses the blood-brain barrier intact, and accumulates in CNS tumors but not normal CNS tissue, he said.
Further, it “is not a substrate for [p-glycoprotein] transport; thus, it doesn’t easily get out of the brain,” Dr. Morgan said. He noted that DM-CHOC-PEN can be used with other agents, such as temozolomide and bis-chloroethylnitrosourea, because of the difference in mechanisms of action.
This study was supported by Louisiana state grants, the National Cancer Institute, the National Institute of General Medical Sciences, and the Small Business Innovation Research program. Dr. Morgan reported having no disclosures, but he is chief executive officer of Dekk-Tec Inc., which is developing DM-CHOC-PEN.
SOURCE: Morgan L et al. AACR 2020, Abstract CT181.
FROM AACR 2020
Universal CAR-T therapy produces CRs in relapsed/refractory T-ALL
according to initial findings from an ongoing study.
The first five patients enrolled in this first-in-human study received conditioning and an infusion of the premanufactured CD7-targeted CAR T-cell therapy, TruUCAR GC027.
All five patients achieved a complete remission (CR) or CR with incomplete count recovery (CRi), although one patient had a morphological relapse at 1 month.
Xinxin Wang, PhD, reported these results at the AACR Virtual Meeting I. Dr. Wang is employed by Gracell Biotechnologies in Shanghai, China, which is the company developing TruUCAR GC027.
The CAR T-cell therapy is manufactured using lentivirus and leukopaks from HLA-mismatched healthy donors, according to Dr. Wang. TruUCAR GC027 contains second-generation CAR T cells with genomic disruption of TCR-alpha and CD7 to help prevent graft-versus-host disease and fratricide.
TruUCAR GC027 was previously shown to expand and have antileukemic activity in a murine model, Dr. Wang noted.
Patients and treatment
The five patients in the phase 1 study had a median age of 24 years (range, 19 to 38 years). They had heavily pretreated T-ALL, with a median of 5 prior lines of therapy (range, 1-9). Baseline bone marrow tumor burden ranged from 4% to 80.2% (median, 38.2%).
None of the patients received prior allogeneic hematopoietic stem cell transplant.
All patients received a preconditioning chemotherapy regimen. One patient received TruUCAR GC027 at dose level 1 (6 x 106 cells/kg), three patients received dose level 2 (1 x 107 cells/kg), and one patient received dose level 3 (1.5 x 107 cells/kg) – each as a single infusion.
Expansion, response, and safety
“GC027 expansion, analyzed by flow [cytometry] was observed in most of the patients treated,” Dr. Wang said. “We started to see GC027 in the peripheral blood as early as day 5, with peaks around day 7-14.”
All five patients had a CR or CRi at the first postinfusion evaluation, which occurred at day 14 in four of the five patients. Four patients also achieved minimum residual disease (MRD) negativity by 1 month of follow-up and remained in MRD-negative CR at the February 6, 2020, data cutoff.
One patient achieved MRD-positive CR at day 14 but experienced morphological relapse at 1 month.
In the four patients with MRD-negative CR at 1 month, cellular expansion was observed as early as day 5 and continued for 2 weeks, but the patient who relapsed at day 29 showed no cellular expansion on flow cytometry, Dr. Wang said.
However, by a more sensitive quantitative polymerase chain reaction analysis, cellular expansion was observed in all five patients starting as early as day 1 after infusion, although the patient who relapsed had the shortest duration of expansion.
All patients developed cytokine release syndrome (CRS). Four patients experienced grade 3 CRS, and one experienced grade 4 CRS.
“The CRS was manageable and reversible,” Dr. Wang said, adding that none of the patients experienced neurotoxicity or graft-versus-host disease.
Prolonged cytopenia occurred in four patients, including one grade 1 case, two grade 3 cases, and one grade 4 case. Grade 3 pulmonary infections occurred in three patients, and grade 3 neutropenia occurred in all five patients.
‘Very impressive’ early results
Dr. Wang said the responses observed in this trial are notable because T-ALL constitutes 20%-25% of all adult ALL and 12%-15% of all pediatric ALL. T-ALL is highly aggressive, with event-free and overall survival of less than 25% in the relapsed setting. Dr. Wang noted that, despite the high unmet medical need and lack of treatment options for T-ALL, the development of novel immunotherapies has lagged.
One challenge is that T-ALL and normal T cells share common surface antigens, so targeted therapies for T-ALL will also target normal T cells. Another challenge is the potential contamination by malignant cells in autologous T-cell products, Dr. Wang said, noting that this can be avoided with universal CAR T cells.
Further, CD7 is a good target for T-ALL because it is expressed in more than 95% of T-ALL patients, she added.
“[TruUCAR GC027] demonstrated a very promising early response rate ... and showed a manageable toxicity profile at all three dose levels,” Dr. Wang said in closing, noting that further evaluation is warranted.
Indeed, the results of this next-generation CAR T-cell trial are “very impressive,” said invited discussant Yvonne Y. Chen, PhD, of the University of California, Los Angeles.
There have been concerns that “off-the-shelf” CAR T-cell products like TruUCAR GC027 might be limited by factors such as a reduced level of CAR T-cell persistence and therefore reduced efficacy leading to a need for repeat dosing, Dr. Chen noted. However, Dr. Wang and her colleagues showed a 100% CR/CRi rate with a single dose of CAR T cells and without graft-versus-host disease or neurotoxicity, Dr. Chen emphasized.
“I think it’s also important to note, however, that there’s quite a high incidence rate of grade 3 or higher toxicities, including CRS,” Dr. Chen said. “I suspect this may have something to do with the fairly high dosing levels used in this trial.”
The “big question,” however, is durability of the response, Dr. Chen said. “And this is something that the field will really watch as this trial progresses beyond the 7-month monitoring period ... reported today.”
Dr. Wang is an employee of Gracell Biotechnologies. Dr. Chen is cofounder of Kalthera Therapeutics and a scientific adviser for Gritstone Oncology and Notch Therapeutics.
SOURCE: Wang X et al. AACR 2020, Abstract CT052.
according to initial findings from an ongoing study.
The first five patients enrolled in this first-in-human study received conditioning and an infusion of the premanufactured CD7-targeted CAR T-cell therapy, TruUCAR GC027.
All five patients achieved a complete remission (CR) or CR with incomplete count recovery (CRi), although one patient had a morphological relapse at 1 month.
Xinxin Wang, PhD, reported these results at the AACR Virtual Meeting I. Dr. Wang is employed by Gracell Biotechnologies in Shanghai, China, which is the company developing TruUCAR GC027.
The CAR T-cell therapy is manufactured using lentivirus and leukopaks from HLA-mismatched healthy donors, according to Dr. Wang. TruUCAR GC027 contains second-generation CAR T cells with genomic disruption of TCR-alpha and CD7 to help prevent graft-versus-host disease and fratricide.
TruUCAR GC027 was previously shown to expand and have antileukemic activity in a murine model, Dr. Wang noted.
Patients and treatment
The five patients in the phase 1 study had a median age of 24 years (range, 19 to 38 years). They had heavily pretreated T-ALL, with a median of 5 prior lines of therapy (range, 1-9). Baseline bone marrow tumor burden ranged from 4% to 80.2% (median, 38.2%).
None of the patients received prior allogeneic hematopoietic stem cell transplant.
All patients received a preconditioning chemotherapy regimen. One patient received TruUCAR GC027 at dose level 1 (6 x 106 cells/kg), three patients received dose level 2 (1 x 107 cells/kg), and one patient received dose level 3 (1.5 x 107 cells/kg) – each as a single infusion.
Expansion, response, and safety
“GC027 expansion, analyzed by flow [cytometry] was observed in most of the patients treated,” Dr. Wang said. “We started to see GC027 in the peripheral blood as early as day 5, with peaks around day 7-14.”
All five patients had a CR or CRi at the first postinfusion evaluation, which occurred at day 14 in four of the five patients. Four patients also achieved minimum residual disease (MRD) negativity by 1 month of follow-up and remained in MRD-negative CR at the February 6, 2020, data cutoff.
One patient achieved MRD-positive CR at day 14 but experienced morphological relapse at 1 month.
In the four patients with MRD-negative CR at 1 month, cellular expansion was observed as early as day 5 and continued for 2 weeks, but the patient who relapsed at day 29 showed no cellular expansion on flow cytometry, Dr. Wang said.
However, by a more sensitive quantitative polymerase chain reaction analysis, cellular expansion was observed in all five patients starting as early as day 1 after infusion, although the patient who relapsed had the shortest duration of expansion.
All patients developed cytokine release syndrome (CRS). Four patients experienced grade 3 CRS, and one experienced grade 4 CRS.
“The CRS was manageable and reversible,” Dr. Wang said, adding that none of the patients experienced neurotoxicity or graft-versus-host disease.
Prolonged cytopenia occurred in four patients, including one grade 1 case, two grade 3 cases, and one grade 4 case. Grade 3 pulmonary infections occurred in three patients, and grade 3 neutropenia occurred in all five patients.
‘Very impressive’ early results
Dr. Wang said the responses observed in this trial are notable because T-ALL constitutes 20%-25% of all adult ALL and 12%-15% of all pediatric ALL. T-ALL is highly aggressive, with event-free and overall survival of less than 25% in the relapsed setting. Dr. Wang noted that, despite the high unmet medical need and lack of treatment options for T-ALL, the development of novel immunotherapies has lagged.
One challenge is that T-ALL and normal T cells share common surface antigens, so targeted therapies for T-ALL will also target normal T cells. Another challenge is the potential contamination by malignant cells in autologous T-cell products, Dr. Wang said, noting that this can be avoided with universal CAR T cells.
Further, CD7 is a good target for T-ALL because it is expressed in more than 95% of T-ALL patients, she added.
“[TruUCAR GC027] demonstrated a very promising early response rate ... and showed a manageable toxicity profile at all three dose levels,” Dr. Wang said in closing, noting that further evaluation is warranted.
Indeed, the results of this next-generation CAR T-cell trial are “very impressive,” said invited discussant Yvonne Y. Chen, PhD, of the University of California, Los Angeles.
There have been concerns that “off-the-shelf” CAR T-cell products like TruUCAR GC027 might be limited by factors such as a reduced level of CAR T-cell persistence and therefore reduced efficacy leading to a need for repeat dosing, Dr. Chen noted. However, Dr. Wang and her colleagues showed a 100% CR/CRi rate with a single dose of CAR T cells and without graft-versus-host disease or neurotoxicity, Dr. Chen emphasized.
“I think it’s also important to note, however, that there’s quite a high incidence rate of grade 3 or higher toxicities, including CRS,” Dr. Chen said. “I suspect this may have something to do with the fairly high dosing levels used in this trial.”
The “big question,” however, is durability of the response, Dr. Chen said. “And this is something that the field will really watch as this trial progresses beyond the 7-month monitoring period ... reported today.”
Dr. Wang is an employee of Gracell Biotechnologies. Dr. Chen is cofounder of Kalthera Therapeutics and a scientific adviser for Gritstone Oncology and Notch Therapeutics.
SOURCE: Wang X et al. AACR 2020, Abstract CT052.
according to initial findings from an ongoing study.
The first five patients enrolled in this first-in-human study received conditioning and an infusion of the premanufactured CD7-targeted CAR T-cell therapy, TruUCAR GC027.
All five patients achieved a complete remission (CR) or CR with incomplete count recovery (CRi), although one patient had a morphological relapse at 1 month.
Xinxin Wang, PhD, reported these results at the AACR Virtual Meeting I. Dr. Wang is employed by Gracell Biotechnologies in Shanghai, China, which is the company developing TruUCAR GC027.
The CAR T-cell therapy is manufactured using lentivirus and leukopaks from HLA-mismatched healthy donors, according to Dr. Wang. TruUCAR GC027 contains second-generation CAR T cells with genomic disruption of TCR-alpha and CD7 to help prevent graft-versus-host disease and fratricide.
TruUCAR GC027 was previously shown to expand and have antileukemic activity in a murine model, Dr. Wang noted.
Patients and treatment
The five patients in the phase 1 study had a median age of 24 years (range, 19 to 38 years). They had heavily pretreated T-ALL, with a median of 5 prior lines of therapy (range, 1-9). Baseline bone marrow tumor burden ranged from 4% to 80.2% (median, 38.2%).
None of the patients received prior allogeneic hematopoietic stem cell transplant.
All patients received a preconditioning chemotherapy regimen. One patient received TruUCAR GC027 at dose level 1 (6 x 106 cells/kg), three patients received dose level 2 (1 x 107 cells/kg), and one patient received dose level 3 (1.5 x 107 cells/kg) – each as a single infusion.
Expansion, response, and safety
“GC027 expansion, analyzed by flow [cytometry] was observed in most of the patients treated,” Dr. Wang said. “We started to see GC027 in the peripheral blood as early as day 5, with peaks around day 7-14.”
All five patients had a CR or CRi at the first postinfusion evaluation, which occurred at day 14 in four of the five patients. Four patients also achieved minimum residual disease (MRD) negativity by 1 month of follow-up and remained in MRD-negative CR at the February 6, 2020, data cutoff.
One patient achieved MRD-positive CR at day 14 but experienced morphological relapse at 1 month.
In the four patients with MRD-negative CR at 1 month, cellular expansion was observed as early as day 5 and continued for 2 weeks, but the patient who relapsed at day 29 showed no cellular expansion on flow cytometry, Dr. Wang said.
However, by a more sensitive quantitative polymerase chain reaction analysis, cellular expansion was observed in all five patients starting as early as day 1 after infusion, although the patient who relapsed had the shortest duration of expansion.
All patients developed cytokine release syndrome (CRS). Four patients experienced grade 3 CRS, and one experienced grade 4 CRS.
“The CRS was manageable and reversible,” Dr. Wang said, adding that none of the patients experienced neurotoxicity or graft-versus-host disease.
Prolonged cytopenia occurred in four patients, including one grade 1 case, two grade 3 cases, and one grade 4 case. Grade 3 pulmonary infections occurred in three patients, and grade 3 neutropenia occurred in all five patients.
‘Very impressive’ early results
Dr. Wang said the responses observed in this trial are notable because T-ALL constitutes 20%-25% of all adult ALL and 12%-15% of all pediatric ALL. T-ALL is highly aggressive, with event-free and overall survival of less than 25% in the relapsed setting. Dr. Wang noted that, despite the high unmet medical need and lack of treatment options for T-ALL, the development of novel immunotherapies has lagged.
One challenge is that T-ALL and normal T cells share common surface antigens, so targeted therapies for T-ALL will also target normal T cells. Another challenge is the potential contamination by malignant cells in autologous T-cell products, Dr. Wang said, noting that this can be avoided with universal CAR T cells.
Further, CD7 is a good target for T-ALL because it is expressed in more than 95% of T-ALL patients, she added.
“[TruUCAR GC027] demonstrated a very promising early response rate ... and showed a manageable toxicity profile at all three dose levels,” Dr. Wang said in closing, noting that further evaluation is warranted.
Indeed, the results of this next-generation CAR T-cell trial are “very impressive,” said invited discussant Yvonne Y. Chen, PhD, of the University of California, Los Angeles.
There have been concerns that “off-the-shelf” CAR T-cell products like TruUCAR GC027 might be limited by factors such as a reduced level of CAR T-cell persistence and therefore reduced efficacy leading to a need for repeat dosing, Dr. Chen noted. However, Dr. Wang and her colleagues showed a 100% CR/CRi rate with a single dose of CAR T cells and without graft-versus-host disease or neurotoxicity, Dr. Chen emphasized.
“I think it’s also important to note, however, that there’s quite a high incidence rate of grade 3 or higher toxicities, including CRS,” Dr. Chen said. “I suspect this may have something to do with the fairly high dosing levels used in this trial.”
The “big question,” however, is durability of the response, Dr. Chen said. “And this is something that the field will really watch as this trial progresses beyond the 7-month monitoring period ... reported today.”
Dr. Wang is an employee of Gracell Biotechnologies. Dr. Chen is cofounder of Kalthera Therapeutics and a scientific adviser for Gritstone Oncology and Notch Therapeutics.
SOURCE: Wang X et al. AACR 2020, Abstract CT052.
FROM AACR 2020
MRD surveillance can detect relapse before imaging in early-stage NSCLC
, according to findings from the TRACERx study.
The findings pave the way for clinical trials of MRD-driven treatment escalation, Chris Abbosh, MD, of University College London, reported during a presentation at the AACR virtual meeting I. Data in the presentation were updated from the abstract.
Dr. Abbosh and colleagues used phylogenetic circulating tumor DNA (ctDNA) profiling to assess MRD and predict relapse in patients from the TRACERx study who underwent surgery for stage I-III NSCLC.
“The approach we take is technically termed a ‘tumor-informed, personalized cell-free DNA-enrichment approach,’” Dr. Abbosh explained. “We take out the primary tumor from the patient, we multiregion sample that tumor, and submit each region for deep whole-exome sequencing.”
The researchers prioritize variants for MRD tracking based on clonality/subclonality, high copy number status, and low background sequencing noise. The researchers then construct an anchored-multiplex PCR panel against the positions of interest, which is applied to cell-free DNA in the pre- and postoperative setting.
“We’ve developed an MRD caller to go alongside this chemistry,” Dr. Abbosh said. “The main premise behind the MRD caller is that it can calculate intralibrary error rates to inform the MRD pool.”
Sensitivity and specificity
To validate their approach, Dr. Abbosh and colleagues tested the assay with low DNA input (5 ng, 10 ng) and high DNA input (30 ng, 60 ng). They found the assay to be more sensitive with higher DNA input, and variant fractions were detected down to 0.003%.
The researchers also assessed how sensitivity and specificity scale with an increasing number of variants – 50, 100, or 200 variants. When tracking 200 variants, the assay was powered to detect lower ctDNA fractions than when tracking 50 variants. On the other hand, specificity was higher with 50 variants (99.8%) than with 200 variants (99.4%).
Next, Dr. Abbosh and colleagues analyzed postoperative cell-free DNA collected at 271 time points from 37 NSCLC patients who did not relapse. This included 11 patients who developed proven second primary malignancies.
Of the 271 time points when MRD negativity was expected, MRD was not detected at 269 time points, which translates to 99.3% specificity for the assay.
Shedding, relapse, and disease-free survival
Dr. Abbosh and colleagues also found that non-adenocarcinoma histology is associated with preoperative ctDNA shedding in NSCLC. The researchers analyzed 88 early-stage preoperative samples from NSCLC patients. ctDNA was detected preoperatively in 49% of lung adenocarcinomas and 100% of lung squamous cell carcinomas.
“This finding is important when it comes to interpreting our non–small cell lung cancer relapse data from 53 TRACERx patients,” Dr. Abbosh said.
Of the 53 patients who relapsed, 42 had ctDNA detected prior to surgery and were thus considered shedders, while 11 were nonshedders. ctDNA was detectable at or before relapse in 91% (38/42) of shedders and 64% (7/11) of nonshedders.
The median time from ctDNA detection to clinical relapse was 164 days in shedders and 22 days in nonshedders. The median disease-free survival was 362 days and 640 days, respectively.
“So what these data suggest is that preoperative ctDNA detection status will be a proxy of the potential utility of ctDNA as an MRD biomarker in a clinical setting,” Dr. Abbosh explained.
Standard-of-care imaging findings in the 53 patients who relapsed further demonstrated the utility of ctDNA in this setting, Dr. Abbosh said.
All scans were divided into three categories: those showing unequivocal relapse, those with a new equivocal change (relapse, inflammation, or a nonspecific finding), and those with no evidence of relapse. Each was further categorized by preimaging MRD status.
Relapse occurred in 9 of 10 patients who were MRD positive but had a scan showing no evidence of relapse. Relapse occurred in 15 of 16 patients who were MRD positive and had scans showing new equivocal changes.
Patients with unequivocal evidence of relapse who were MRD negative at or before the scan were more likely to have a second primary cancer than to have NSCLC relapse (52% vs. 48%), which is a reflection of the specificity of the MRD assay to the primary tumor, Dr. Abbosh said.
Implications of the findings
The researchers’ findings are important because establishing an MRD-driven approach to treating early-stage NSCLC would facilitate escalation of standard-of-care treatment only for those patients at high risk for relapse, thereby overcoming a key challenge in conventional adjuvant drug-trial design, Dr. Abbosh said.
“If we take a patient population with high-risk early-stage disease who have undergone potentially curative resection of their cancer and we offer these patients adjuvant chemotherapy or adjuvant chemoradiation therapy, then we can improve 5-year survival outcomes in this population,” Dr. Abbosh said. “This is striking because, if we give the same treatment in the metastatic setting, we only see a progression-free survival benefit of a short number of months.”
This suggests a potential “vulnerability of low-burden residual cancer to systemic treatment following surgery,” he added. “So if we want to improve outcomes further in non–small cell lung cancer, we really need to focus on innovation in the early-stage space.”
Dr. Abbosh said he and colleagues demonstrated that “personalized cell-free DNA enrichment can detect low-frequency variant DNA in an accurate manner.
“We’ve shown that preoperative ctDNA shedding is associated with utility of ctDNA as an MRD biomarker and that MRD surveillance can lead to detection of relapse in advance of standard-of-care-imaging,” he said. “We feel that the field is now ready for MRD-driven adjuvant trials.”
Questions to be answered
Invited discussant Corey J. Langer, MD, of Penn Medicine in Philadelphia, outlined “fundamental questions” raised by the findings.
“We need more information on the staging and demographics of those who were MRD positive versus MRD negative,” he said.
Dr. Langer also asked about the findings for shedders versus nonshedders.
“Does this mean nonshedders fare better? This needs to addressed formally,” he said.
Another question is whether the assay “simply enables us to detect relapse sooner and increase anxiety,” or if the trajectory and outcomes in those who prove MRD positive ahead of radiographic manifestations can actually be altered.
A study comparing standard observation with early immunotherapy or chemoimmunotherapy in patients with MRD-positive radiographically occult relapse or progression – using progression-free and overall survival, along with time without symptoms of disease or relapse – would be useful, Dr. Langer said.
“A hazard ratio of 0.8 or less would be meaningful,” he added. “In this regard, there are trials looking at enhanced adjuvant treatment both in colorectal and breast cancer, and trials planned in advanced non–small cell [lung cancer].”
Dr. Langer also said it would be interesting to know if the assay can be used as an adjunct to diagnosis in frailer patients with inaccessible tumors or equivocal biopsy results or to avoid invasive procedures in patients who are stereotactic radiation candidates.
“The jury is still out on this,” he said.
TRACERx is funded by University College London in collaboration with Cancer Research UK. Dr. Abbosh disclosed relationships with AstraZeneca, Novartis, Roche Diagnostics, Bristol Myers Squibb, Achilles Therapeutics, and Archer Diagnostics. Dr. Langer reported grant/research support and/or scientific advisory work for multiple companies.
SOURCE: Abbosh C et al. AACR 2020, Abstract CT023.
, according to findings from the TRACERx study.
The findings pave the way for clinical trials of MRD-driven treatment escalation, Chris Abbosh, MD, of University College London, reported during a presentation at the AACR virtual meeting I. Data in the presentation were updated from the abstract.
Dr. Abbosh and colleagues used phylogenetic circulating tumor DNA (ctDNA) profiling to assess MRD and predict relapse in patients from the TRACERx study who underwent surgery for stage I-III NSCLC.
“The approach we take is technically termed a ‘tumor-informed, personalized cell-free DNA-enrichment approach,’” Dr. Abbosh explained. “We take out the primary tumor from the patient, we multiregion sample that tumor, and submit each region for deep whole-exome sequencing.”
The researchers prioritize variants for MRD tracking based on clonality/subclonality, high copy number status, and low background sequencing noise. The researchers then construct an anchored-multiplex PCR panel against the positions of interest, which is applied to cell-free DNA in the pre- and postoperative setting.
“We’ve developed an MRD caller to go alongside this chemistry,” Dr. Abbosh said. “The main premise behind the MRD caller is that it can calculate intralibrary error rates to inform the MRD pool.”
Sensitivity and specificity
To validate their approach, Dr. Abbosh and colleagues tested the assay with low DNA input (5 ng, 10 ng) and high DNA input (30 ng, 60 ng). They found the assay to be more sensitive with higher DNA input, and variant fractions were detected down to 0.003%.
The researchers also assessed how sensitivity and specificity scale with an increasing number of variants – 50, 100, or 200 variants. When tracking 200 variants, the assay was powered to detect lower ctDNA fractions than when tracking 50 variants. On the other hand, specificity was higher with 50 variants (99.8%) than with 200 variants (99.4%).
Next, Dr. Abbosh and colleagues analyzed postoperative cell-free DNA collected at 271 time points from 37 NSCLC patients who did not relapse. This included 11 patients who developed proven second primary malignancies.
Of the 271 time points when MRD negativity was expected, MRD was not detected at 269 time points, which translates to 99.3% specificity for the assay.
Shedding, relapse, and disease-free survival
Dr. Abbosh and colleagues also found that non-adenocarcinoma histology is associated with preoperative ctDNA shedding in NSCLC. The researchers analyzed 88 early-stage preoperative samples from NSCLC patients. ctDNA was detected preoperatively in 49% of lung adenocarcinomas and 100% of lung squamous cell carcinomas.
“This finding is important when it comes to interpreting our non–small cell lung cancer relapse data from 53 TRACERx patients,” Dr. Abbosh said.
Of the 53 patients who relapsed, 42 had ctDNA detected prior to surgery and were thus considered shedders, while 11 were nonshedders. ctDNA was detectable at or before relapse in 91% (38/42) of shedders and 64% (7/11) of nonshedders.
The median time from ctDNA detection to clinical relapse was 164 days in shedders and 22 days in nonshedders. The median disease-free survival was 362 days and 640 days, respectively.
“So what these data suggest is that preoperative ctDNA detection status will be a proxy of the potential utility of ctDNA as an MRD biomarker in a clinical setting,” Dr. Abbosh explained.
Standard-of-care imaging findings in the 53 patients who relapsed further demonstrated the utility of ctDNA in this setting, Dr. Abbosh said.
All scans were divided into three categories: those showing unequivocal relapse, those with a new equivocal change (relapse, inflammation, or a nonspecific finding), and those with no evidence of relapse. Each was further categorized by preimaging MRD status.
Relapse occurred in 9 of 10 patients who were MRD positive but had a scan showing no evidence of relapse. Relapse occurred in 15 of 16 patients who were MRD positive and had scans showing new equivocal changes.
Patients with unequivocal evidence of relapse who were MRD negative at or before the scan were more likely to have a second primary cancer than to have NSCLC relapse (52% vs. 48%), which is a reflection of the specificity of the MRD assay to the primary tumor, Dr. Abbosh said.
Implications of the findings
The researchers’ findings are important because establishing an MRD-driven approach to treating early-stage NSCLC would facilitate escalation of standard-of-care treatment only for those patients at high risk for relapse, thereby overcoming a key challenge in conventional adjuvant drug-trial design, Dr. Abbosh said.
“If we take a patient population with high-risk early-stage disease who have undergone potentially curative resection of their cancer and we offer these patients adjuvant chemotherapy or adjuvant chemoradiation therapy, then we can improve 5-year survival outcomes in this population,” Dr. Abbosh said. “This is striking because, if we give the same treatment in the metastatic setting, we only see a progression-free survival benefit of a short number of months.”
This suggests a potential “vulnerability of low-burden residual cancer to systemic treatment following surgery,” he added. “So if we want to improve outcomes further in non–small cell lung cancer, we really need to focus on innovation in the early-stage space.”
Dr. Abbosh said he and colleagues demonstrated that “personalized cell-free DNA enrichment can detect low-frequency variant DNA in an accurate manner.
“We’ve shown that preoperative ctDNA shedding is associated with utility of ctDNA as an MRD biomarker and that MRD surveillance can lead to detection of relapse in advance of standard-of-care-imaging,” he said. “We feel that the field is now ready for MRD-driven adjuvant trials.”
Questions to be answered
Invited discussant Corey J. Langer, MD, of Penn Medicine in Philadelphia, outlined “fundamental questions” raised by the findings.
“We need more information on the staging and demographics of those who were MRD positive versus MRD negative,” he said.
Dr. Langer also asked about the findings for shedders versus nonshedders.
“Does this mean nonshedders fare better? This needs to addressed formally,” he said.
Another question is whether the assay “simply enables us to detect relapse sooner and increase anxiety,” or if the trajectory and outcomes in those who prove MRD positive ahead of radiographic manifestations can actually be altered.
A study comparing standard observation with early immunotherapy or chemoimmunotherapy in patients with MRD-positive radiographically occult relapse or progression – using progression-free and overall survival, along with time without symptoms of disease or relapse – would be useful, Dr. Langer said.
“A hazard ratio of 0.8 or less would be meaningful,” he added. “In this regard, there are trials looking at enhanced adjuvant treatment both in colorectal and breast cancer, and trials planned in advanced non–small cell [lung cancer].”
Dr. Langer also said it would be interesting to know if the assay can be used as an adjunct to diagnosis in frailer patients with inaccessible tumors or equivocal biopsy results or to avoid invasive procedures in patients who are stereotactic radiation candidates.
“The jury is still out on this,” he said.
TRACERx is funded by University College London in collaboration with Cancer Research UK. Dr. Abbosh disclosed relationships with AstraZeneca, Novartis, Roche Diagnostics, Bristol Myers Squibb, Achilles Therapeutics, and Archer Diagnostics. Dr. Langer reported grant/research support and/or scientific advisory work for multiple companies.
SOURCE: Abbosh C et al. AACR 2020, Abstract CT023.
, according to findings from the TRACERx study.
The findings pave the way for clinical trials of MRD-driven treatment escalation, Chris Abbosh, MD, of University College London, reported during a presentation at the AACR virtual meeting I. Data in the presentation were updated from the abstract.
Dr. Abbosh and colleagues used phylogenetic circulating tumor DNA (ctDNA) profiling to assess MRD and predict relapse in patients from the TRACERx study who underwent surgery for stage I-III NSCLC.
“The approach we take is technically termed a ‘tumor-informed, personalized cell-free DNA-enrichment approach,’” Dr. Abbosh explained. “We take out the primary tumor from the patient, we multiregion sample that tumor, and submit each region for deep whole-exome sequencing.”
The researchers prioritize variants for MRD tracking based on clonality/subclonality, high copy number status, and low background sequencing noise. The researchers then construct an anchored-multiplex PCR panel against the positions of interest, which is applied to cell-free DNA in the pre- and postoperative setting.
“We’ve developed an MRD caller to go alongside this chemistry,” Dr. Abbosh said. “The main premise behind the MRD caller is that it can calculate intralibrary error rates to inform the MRD pool.”
Sensitivity and specificity
To validate their approach, Dr. Abbosh and colleagues tested the assay with low DNA input (5 ng, 10 ng) and high DNA input (30 ng, 60 ng). They found the assay to be more sensitive with higher DNA input, and variant fractions were detected down to 0.003%.
The researchers also assessed how sensitivity and specificity scale with an increasing number of variants – 50, 100, or 200 variants. When tracking 200 variants, the assay was powered to detect lower ctDNA fractions than when tracking 50 variants. On the other hand, specificity was higher with 50 variants (99.8%) than with 200 variants (99.4%).
Next, Dr. Abbosh and colleagues analyzed postoperative cell-free DNA collected at 271 time points from 37 NSCLC patients who did not relapse. This included 11 patients who developed proven second primary malignancies.
Of the 271 time points when MRD negativity was expected, MRD was not detected at 269 time points, which translates to 99.3% specificity for the assay.
Shedding, relapse, and disease-free survival
Dr. Abbosh and colleagues also found that non-adenocarcinoma histology is associated with preoperative ctDNA shedding in NSCLC. The researchers analyzed 88 early-stage preoperative samples from NSCLC patients. ctDNA was detected preoperatively in 49% of lung adenocarcinomas and 100% of lung squamous cell carcinomas.
“This finding is important when it comes to interpreting our non–small cell lung cancer relapse data from 53 TRACERx patients,” Dr. Abbosh said.
Of the 53 patients who relapsed, 42 had ctDNA detected prior to surgery and were thus considered shedders, while 11 were nonshedders. ctDNA was detectable at or before relapse in 91% (38/42) of shedders and 64% (7/11) of nonshedders.
The median time from ctDNA detection to clinical relapse was 164 days in shedders and 22 days in nonshedders. The median disease-free survival was 362 days and 640 days, respectively.
“So what these data suggest is that preoperative ctDNA detection status will be a proxy of the potential utility of ctDNA as an MRD biomarker in a clinical setting,” Dr. Abbosh explained.
Standard-of-care imaging findings in the 53 patients who relapsed further demonstrated the utility of ctDNA in this setting, Dr. Abbosh said.
All scans were divided into three categories: those showing unequivocal relapse, those with a new equivocal change (relapse, inflammation, or a nonspecific finding), and those with no evidence of relapse. Each was further categorized by preimaging MRD status.
Relapse occurred in 9 of 10 patients who were MRD positive but had a scan showing no evidence of relapse. Relapse occurred in 15 of 16 patients who were MRD positive and had scans showing new equivocal changes.
Patients with unequivocal evidence of relapse who were MRD negative at or before the scan were more likely to have a second primary cancer than to have NSCLC relapse (52% vs. 48%), which is a reflection of the specificity of the MRD assay to the primary tumor, Dr. Abbosh said.
Implications of the findings
The researchers’ findings are important because establishing an MRD-driven approach to treating early-stage NSCLC would facilitate escalation of standard-of-care treatment only for those patients at high risk for relapse, thereby overcoming a key challenge in conventional adjuvant drug-trial design, Dr. Abbosh said.
“If we take a patient population with high-risk early-stage disease who have undergone potentially curative resection of their cancer and we offer these patients adjuvant chemotherapy or adjuvant chemoradiation therapy, then we can improve 5-year survival outcomes in this population,” Dr. Abbosh said. “This is striking because, if we give the same treatment in the metastatic setting, we only see a progression-free survival benefit of a short number of months.”
This suggests a potential “vulnerability of low-burden residual cancer to systemic treatment following surgery,” he added. “So if we want to improve outcomes further in non–small cell lung cancer, we really need to focus on innovation in the early-stage space.”
Dr. Abbosh said he and colleagues demonstrated that “personalized cell-free DNA enrichment can detect low-frequency variant DNA in an accurate manner.
“We’ve shown that preoperative ctDNA shedding is associated with utility of ctDNA as an MRD biomarker and that MRD surveillance can lead to detection of relapse in advance of standard-of-care-imaging,” he said. “We feel that the field is now ready for MRD-driven adjuvant trials.”
Questions to be answered
Invited discussant Corey J. Langer, MD, of Penn Medicine in Philadelphia, outlined “fundamental questions” raised by the findings.
“We need more information on the staging and demographics of those who were MRD positive versus MRD negative,” he said.
Dr. Langer also asked about the findings for shedders versus nonshedders.
“Does this mean nonshedders fare better? This needs to addressed formally,” he said.
Another question is whether the assay “simply enables us to detect relapse sooner and increase anxiety,” or if the trajectory and outcomes in those who prove MRD positive ahead of radiographic manifestations can actually be altered.
A study comparing standard observation with early immunotherapy or chemoimmunotherapy in patients with MRD-positive radiographically occult relapse or progression – using progression-free and overall survival, along with time without symptoms of disease or relapse – would be useful, Dr. Langer said.
“A hazard ratio of 0.8 or less would be meaningful,” he added. “In this regard, there are trials looking at enhanced adjuvant treatment both in colorectal and breast cancer, and trials planned in advanced non–small cell [lung cancer].”
Dr. Langer also said it would be interesting to know if the assay can be used as an adjunct to diagnosis in frailer patients with inaccessible tumors or equivocal biopsy results or to avoid invasive procedures in patients who are stereotactic radiation candidates.
“The jury is still out on this,” he said.
TRACERx is funded by University College London in collaboration with Cancer Research UK. Dr. Abbosh disclosed relationships with AstraZeneca, Novartis, Roche Diagnostics, Bristol Myers Squibb, Achilles Therapeutics, and Archer Diagnostics. Dr. Langer reported grant/research support and/or scientific advisory work for multiple companies.
SOURCE: Abbosh C et al. AACR 2020, Abstract CT023.
FROM AACR 2020
Vaccine maintenance improves relapse-free survival in BRCA wild-type ovarian cancer
The autologous tumor cell vaccine gemogenovatucel-T (Vigil Ovarian) is well tolerated as maintenance therapy in stage III-IV ovarian cancer patients and may improve relapse-free survival, particularly in BRCA wild-type disease, according to findings from the ongoing VITAL study.
In patients with and without BRCA1/2 mutations, the median relapse-free survival was longer with gemogenovatucel-T maintenance than with placebo, but the difference did not reach statistical significance (P = .065).
However, among patients with wild-type BRCA, the median relapse-free survival was significantly longer with gemogenovatucel-T (P = .0007).
Rodney P. Rocconi, MD, of the Mitchell Cancer Institute at University of South Alabama, Mobile, reported these results in an abstract that was slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancers. The meeting was canceled because of the COVID-19 pandemic. Some data have been updated from the abstract.
Study rationale
Gemogenovatucel-T (formerly called FANG) is an autologous tumor cell vaccine transfected with a plasmid encoding granulocyte-macrophage colony–stimulating factor and a novel bifunctional short hairpin interfering RNA targeting furin convertase.
“In the era of personalized, targeted medicine, I think this is about as personalized as you can get, this type of vaccine,” Dr. Rocconi said. “Essentially, we harvest patients’ own cancer cells and create a vaccine that is targeted to the antigens on their cells so that it recognizes only that patient’s cancer.”
The vaccine also helps recruit immune cells to the area and has a very limited off-target effect, Dr. Rocconi added.
He noted that gemogenovatucel-T previously demonstrated promising efficacy and limited side effects in a phase 1 study that included patients with advanced ovarian cancer (Mol Ther. 2012 Mar;20[3]:679-86).
“So we thought that, in ovarian cancer, as a maintenance therapy, it made a lot of sense,” Dr. Rocconi said, noting that the overall prognosis for advanced epithelial ovarian cancer remains limited.
Treatment and toxicity
Dr. Rocconi and colleagues reported data on 91 patients in the VITAL study. The patients had achieved a complete response after frontline surgery and chemotherapy, and they were randomized to maintenance with gemogenovatucel-T or placebo.
Patients had a median time from surgery to randomization of 208.5 days in the gemogenovatucel-T group and 200 days in the control group. The patients were treated with 1 x 107 cells/mL of gemogenovatucel-T or placebo intradermally once a month for up to 12 doses.
Gemogenovatucel-T was well tolerated. No added overall toxicity was noted in the gemogenovatucel-T group versus the control group, and no grade 4/5 toxicities were observed, Dr. Rocconi said. Grade 2/3 toxic events were observed in 8% of patients in the gemogenovatucel-T group, compared with 18% in the control group. The most common events were nausea and musculoskeletal pain in the gemogenovatucel-T group, and were bone pain and fatigue in the control group.
Relapse-free and overall survival
In the entire cohort, the median relapse-free survival was longer with gemogenovatucel-T maintenance – 12.6 months versus 8.4 months with placebo (hazard ratio, 0.69) – but the difference did not reach statistical significance (P = .065).
However, in the 67 patients with wild-type BRCA, the median relapse-free survival was 19.4 months with gemogenovatucel-T and 14.8 months with placebo, a statistically significant difference (HR, 0.459; P = .0007).
The median overall survival was not reached in the BRCA wild-type patients treated with gemogenovatucel-T, and it was 41.4 months from the time of randomization in those who received placebo (HR, 0.417; P = .02).
No benefit was seen with gemogenovatucel-T in patients with known BRCA1/2 mutations, Dr. Rocconi said.
‘Encouraging’ results
The overall improvement in the gemogenovatucel-T group was encouraging, particularly in a maintenance-type trial, Dr. Rocconi said. He noted that prior treatments for maintenance have received approval based on shorter survival gains, and the finding of particular benefit in BRCA wild-type disease could have important implications for a population that usually has lesser benefit from treatments, compared with patients who have BRCA mutations.
“So this result is very unique,” Dr. Rocconi said, explaining that about 85% of ovarian cancer patients have BRCA wild-type disease; with this treatment, patients with wild-type BRCA may achieve similar survival rates as those seen in BRCA-mutant disease.
“I think, in general, immunotherapy has been somewhat disappointing in ovarian cancer, so to have a targeted vaccine work in ovarian cancer, just broadly ... is pretty noteworthy,” he said. “We’re really excited, obviously, about the overall success we’ve seen for all patients, but most importantly in those with BRCA wild type. This is a pretty marked significance in recurrence-free intervals and overall survival, and we’re definitely pleased with that.”
Next steps
The findings from this trial have been submitted for publication, and efforts are underway to determine next steps through communication with the Food and Drug Administration, Dr. Rocconi said.
Additionally, other studies are underway to assess gemogenovatucel-T in patients who fall in “the middle ground” – that is, patients who have BRCA wild-type disease but have “some homologous recombination deficiency where the tumor itself might be BRCA deficient or have some other type of deficiency,” Dr. Rocconi explained.
“So we’re trying to tease out specifically what is going on across all the different variations of ovarian cancer patients, and also looking for potential biomarkers for predicting response,” he said. “What we would like to see is a companion test where we’re able to predict which patients can really respond and do best with this technology, and, that way, we know how to stratify patients most appropriately.”
The current trial was sponsored by Gradalis. Dr. Rocconi disclosed relationships with Gradalis, Genentech, Clovis, and Johnson & Johnson.
SOURCE: Rocconi RP et al. SGO 2020, Abstract LBA7.
The autologous tumor cell vaccine gemogenovatucel-T (Vigil Ovarian) is well tolerated as maintenance therapy in stage III-IV ovarian cancer patients and may improve relapse-free survival, particularly in BRCA wild-type disease, according to findings from the ongoing VITAL study.
In patients with and without BRCA1/2 mutations, the median relapse-free survival was longer with gemogenovatucel-T maintenance than with placebo, but the difference did not reach statistical significance (P = .065).
However, among patients with wild-type BRCA, the median relapse-free survival was significantly longer with gemogenovatucel-T (P = .0007).
Rodney P. Rocconi, MD, of the Mitchell Cancer Institute at University of South Alabama, Mobile, reported these results in an abstract that was slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancers. The meeting was canceled because of the COVID-19 pandemic. Some data have been updated from the abstract.
Study rationale
Gemogenovatucel-T (formerly called FANG) is an autologous tumor cell vaccine transfected with a plasmid encoding granulocyte-macrophage colony–stimulating factor and a novel bifunctional short hairpin interfering RNA targeting furin convertase.
“In the era of personalized, targeted medicine, I think this is about as personalized as you can get, this type of vaccine,” Dr. Rocconi said. “Essentially, we harvest patients’ own cancer cells and create a vaccine that is targeted to the antigens on their cells so that it recognizes only that patient’s cancer.”
The vaccine also helps recruit immune cells to the area and has a very limited off-target effect, Dr. Rocconi added.
He noted that gemogenovatucel-T previously demonstrated promising efficacy and limited side effects in a phase 1 study that included patients with advanced ovarian cancer (Mol Ther. 2012 Mar;20[3]:679-86).
“So we thought that, in ovarian cancer, as a maintenance therapy, it made a lot of sense,” Dr. Rocconi said, noting that the overall prognosis for advanced epithelial ovarian cancer remains limited.
Treatment and toxicity
Dr. Rocconi and colleagues reported data on 91 patients in the VITAL study. The patients had achieved a complete response after frontline surgery and chemotherapy, and they were randomized to maintenance with gemogenovatucel-T or placebo.
Patients had a median time from surgery to randomization of 208.5 days in the gemogenovatucel-T group and 200 days in the control group. The patients were treated with 1 x 107 cells/mL of gemogenovatucel-T or placebo intradermally once a month for up to 12 doses.
Gemogenovatucel-T was well tolerated. No added overall toxicity was noted in the gemogenovatucel-T group versus the control group, and no grade 4/5 toxicities were observed, Dr. Rocconi said. Grade 2/3 toxic events were observed in 8% of patients in the gemogenovatucel-T group, compared with 18% in the control group. The most common events were nausea and musculoskeletal pain in the gemogenovatucel-T group, and were bone pain and fatigue in the control group.
Relapse-free and overall survival
In the entire cohort, the median relapse-free survival was longer with gemogenovatucel-T maintenance – 12.6 months versus 8.4 months with placebo (hazard ratio, 0.69) – but the difference did not reach statistical significance (P = .065).
However, in the 67 patients with wild-type BRCA, the median relapse-free survival was 19.4 months with gemogenovatucel-T and 14.8 months with placebo, a statistically significant difference (HR, 0.459; P = .0007).
The median overall survival was not reached in the BRCA wild-type patients treated with gemogenovatucel-T, and it was 41.4 months from the time of randomization in those who received placebo (HR, 0.417; P = .02).
No benefit was seen with gemogenovatucel-T in patients with known BRCA1/2 mutations, Dr. Rocconi said.
‘Encouraging’ results
The overall improvement in the gemogenovatucel-T group was encouraging, particularly in a maintenance-type trial, Dr. Rocconi said. He noted that prior treatments for maintenance have received approval based on shorter survival gains, and the finding of particular benefit in BRCA wild-type disease could have important implications for a population that usually has lesser benefit from treatments, compared with patients who have BRCA mutations.
“So this result is very unique,” Dr. Rocconi said, explaining that about 85% of ovarian cancer patients have BRCA wild-type disease; with this treatment, patients with wild-type BRCA may achieve similar survival rates as those seen in BRCA-mutant disease.
“I think, in general, immunotherapy has been somewhat disappointing in ovarian cancer, so to have a targeted vaccine work in ovarian cancer, just broadly ... is pretty noteworthy,” he said. “We’re really excited, obviously, about the overall success we’ve seen for all patients, but most importantly in those with BRCA wild type. This is a pretty marked significance in recurrence-free intervals and overall survival, and we’re definitely pleased with that.”
Next steps
The findings from this trial have been submitted for publication, and efforts are underway to determine next steps through communication with the Food and Drug Administration, Dr. Rocconi said.
Additionally, other studies are underway to assess gemogenovatucel-T in patients who fall in “the middle ground” – that is, patients who have BRCA wild-type disease but have “some homologous recombination deficiency where the tumor itself might be BRCA deficient or have some other type of deficiency,” Dr. Rocconi explained.
“So we’re trying to tease out specifically what is going on across all the different variations of ovarian cancer patients, and also looking for potential biomarkers for predicting response,” he said. “What we would like to see is a companion test where we’re able to predict which patients can really respond and do best with this technology, and, that way, we know how to stratify patients most appropriately.”
The current trial was sponsored by Gradalis. Dr. Rocconi disclosed relationships with Gradalis, Genentech, Clovis, and Johnson & Johnson.
SOURCE: Rocconi RP et al. SGO 2020, Abstract LBA7.
The autologous tumor cell vaccine gemogenovatucel-T (Vigil Ovarian) is well tolerated as maintenance therapy in stage III-IV ovarian cancer patients and may improve relapse-free survival, particularly in BRCA wild-type disease, according to findings from the ongoing VITAL study.
In patients with and without BRCA1/2 mutations, the median relapse-free survival was longer with gemogenovatucel-T maintenance than with placebo, but the difference did not reach statistical significance (P = .065).
However, among patients with wild-type BRCA, the median relapse-free survival was significantly longer with gemogenovatucel-T (P = .0007).
Rodney P. Rocconi, MD, of the Mitchell Cancer Institute at University of South Alabama, Mobile, reported these results in an abstract that was slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancers. The meeting was canceled because of the COVID-19 pandemic. Some data have been updated from the abstract.
Study rationale
Gemogenovatucel-T (formerly called FANG) is an autologous tumor cell vaccine transfected with a plasmid encoding granulocyte-macrophage colony–stimulating factor and a novel bifunctional short hairpin interfering RNA targeting furin convertase.
“In the era of personalized, targeted medicine, I think this is about as personalized as you can get, this type of vaccine,” Dr. Rocconi said. “Essentially, we harvest patients’ own cancer cells and create a vaccine that is targeted to the antigens on their cells so that it recognizes only that patient’s cancer.”
The vaccine also helps recruit immune cells to the area and has a very limited off-target effect, Dr. Rocconi added.
He noted that gemogenovatucel-T previously demonstrated promising efficacy and limited side effects in a phase 1 study that included patients with advanced ovarian cancer (Mol Ther. 2012 Mar;20[3]:679-86).
“So we thought that, in ovarian cancer, as a maintenance therapy, it made a lot of sense,” Dr. Rocconi said, noting that the overall prognosis for advanced epithelial ovarian cancer remains limited.
Treatment and toxicity
Dr. Rocconi and colleagues reported data on 91 patients in the VITAL study. The patients had achieved a complete response after frontline surgery and chemotherapy, and they were randomized to maintenance with gemogenovatucel-T or placebo.
Patients had a median time from surgery to randomization of 208.5 days in the gemogenovatucel-T group and 200 days in the control group. The patients were treated with 1 x 107 cells/mL of gemogenovatucel-T or placebo intradermally once a month for up to 12 doses.
Gemogenovatucel-T was well tolerated. No added overall toxicity was noted in the gemogenovatucel-T group versus the control group, and no grade 4/5 toxicities were observed, Dr. Rocconi said. Grade 2/3 toxic events were observed in 8% of patients in the gemogenovatucel-T group, compared with 18% in the control group. The most common events were nausea and musculoskeletal pain in the gemogenovatucel-T group, and were bone pain and fatigue in the control group.
Relapse-free and overall survival
In the entire cohort, the median relapse-free survival was longer with gemogenovatucel-T maintenance – 12.6 months versus 8.4 months with placebo (hazard ratio, 0.69) – but the difference did not reach statistical significance (P = .065).
However, in the 67 patients with wild-type BRCA, the median relapse-free survival was 19.4 months with gemogenovatucel-T and 14.8 months with placebo, a statistically significant difference (HR, 0.459; P = .0007).
The median overall survival was not reached in the BRCA wild-type patients treated with gemogenovatucel-T, and it was 41.4 months from the time of randomization in those who received placebo (HR, 0.417; P = .02).
No benefit was seen with gemogenovatucel-T in patients with known BRCA1/2 mutations, Dr. Rocconi said.
‘Encouraging’ results
The overall improvement in the gemogenovatucel-T group was encouraging, particularly in a maintenance-type trial, Dr. Rocconi said. He noted that prior treatments for maintenance have received approval based on shorter survival gains, and the finding of particular benefit in BRCA wild-type disease could have important implications for a population that usually has lesser benefit from treatments, compared with patients who have BRCA mutations.
“So this result is very unique,” Dr. Rocconi said, explaining that about 85% of ovarian cancer patients have BRCA wild-type disease; with this treatment, patients with wild-type BRCA may achieve similar survival rates as those seen in BRCA-mutant disease.
“I think, in general, immunotherapy has been somewhat disappointing in ovarian cancer, so to have a targeted vaccine work in ovarian cancer, just broadly ... is pretty noteworthy,” he said. “We’re really excited, obviously, about the overall success we’ve seen for all patients, but most importantly in those with BRCA wild type. This is a pretty marked significance in recurrence-free intervals and overall survival, and we’re definitely pleased with that.”
Next steps
The findings from this trial have been submitted for publication, and efforts are underway to determine next steps through communication with the Food and Drug Administration, Dr. Rocconi said.
Additionally, other studies are underway to assess gemogenovatucel-T in patients who fall in “the middle ground” – that is, patients who have BRCA wild-type disease but have “some homologous recombination deficiency where the tumor itself might be BRCA deficient or have some other type of deficiency,” Dr. Rocconi explained.
“So we’re trying to tease out specifically what is going on across all the different variations of ovarian cancer patients, and also looking for potential biomarkers for predicting response,” he said. “What we would like to see is a companion test where we’re able to predict which patients can really respond and do best with this technology, and, that way, we know how to stratify patients most appropriately.”
The current trial was sponsored by Gradalis. Dr. Rocconi disclosed relationships with Gradalis, Genentech, Clovis, and Johnson & Johnson.
SOURCE: Rocconi RP et al. SGO 2020, Abstract LBA7.
FROM SGO 2020
The American maternal mortality crisis: The role of racism and bias
April 11-17 marked the third annual national Black Maternal Health Week, an event launched in 2017 by the Atlanta-based Black Mamas Matter Alliance (BMMA), in part to “deepen the national conversation about black maternal health.”
Around the same time, emerging data showing higher mortality rates among black patients versus patients of other races with COVID-19 opened similar dialogue fraught with questions about what might explain the disturbing health disparities.
“It’s kind of surprising to me that people are shocked by these [COVID-19] disparities,” Rebekah Gee, MD, an ob.gyn. who is director of the Louisiana State University Health System in New Orleans and a driving force behind initiatives addressing racial disparities in maternal health, said in an interview. If this is it, great – and certainly every moment is a moment for learning – but these COVID-19 disparities should not be surprising to people who have been looking at data.”
Veronica Gillispie, MD, an ob.gyn. and medical director of the Louisiana Perinatal Quality Collaborative and Pregnancy-Associated Mortality Review, was similarly baffled that the news was treated as a revelation.
That news includes outcomes data from New York showing that in March there were 92.3 and 74.3 deaths per 100,000 black and Hispanic COVID-19 patients, respectively, compared with 45.2 per 100,000 white patients.
“Now there’s a task force and all these initiatives to look at why this is happening, and I think those of us who work in maternal mortality are all saying, ‘We know why it’s happening,’ ” she said. “It’s the same thing we’ve been telling people why it’s been happening in maternal mortality.
“It’s implicit bias and structural racism.”
Facing hard numbers, harder conversations
The U.S. maternal mortality rate in 2018 was 17 per 100,000 live births – the highest of any similarly wealthy industrialized nation, the Centers for Disease Control and Prevention’s National Center for Health Statistics (NCHS) reported in January. That’s a striking statistic in its own right. Perhaps more striking is the breakdown by race.
Hispanic women had the lowest maternal mortality rate at 12 per 100,000 live births, followed by non-Hispanic white women at 15.
The rate for non-Hispanic black women was 37 per 100,000 live births.
Numerous factors contribute to these disparities. Among those listed by the American College of Obstetricians and Gynecologists’ chief executive officer Maureen G. Phipps, MD, in a press statement on the NCHS data, are care access issues, lack of standardization of care, bias, and racism. All of these must be addressed if the disparities in maternal and other areas of care are to be eliminated, according to Dr. Phipps.
“The NCHS data confirmed what we have known from other data sources: The rate of maternal deaths for non-Hispanic black women is substantially higher than the rates for non-Hispanic white women,” she wrote. “Continued efforts to improve the standardization of data and review processes related to U.S. maternal mortality are a necessary step to achieving the goal of eliminating disparities and preventable maternal mortality.”
However, such efforts frequently encounter roadblocks constructed by the reluctance among “many academics, policy makers, scientists, elected officials, journalists, and others responsible for defining and responding to the public discourse” to identify racism as a root cause of health disparities, according to Zinzi D. Bailey, ScD, former director of research and evaluation for the New York City Department of Health and Mental Hygiene, and colleagues.
In the third of a three-part conceptual report in The Lancet, entitled America: Equity and Equality in Health, Dr. Bailey and colleagues argued that advancing health equity requires a focus on structural racism – which they defined as “the totality of ways in which societies foster racial discrimination via mutually reinforcing inequitable systems (e.g., in housing, education, employment, earning, benefits, credit, media, healthcare, and criminal justice, etc.) that in turn reinforce discriminatory beliefs, values, and distribution of resources.”
In their series, the authors peeled back layer upon layer of sociological and political contributors to structural racism throughout history, revealing how each laid a foundation for health inequity over time. They particularly home in on health care quality and access.
“Interpersonal racism, bias, and discrimination in healthcare settings can directly affect health through poor health care,” they wrote, noting that “almost 15 years ago, the Institute of Medicine report entitled Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care, documented systematic and pervasive bias in the treatment of people of color resulting in substandard care.”
That report concluded that “bias, stereotyping, prejudice, and clinical uncertainty on the part of healthcare providers” likely play a role in the continuation of health disparities. More recent data – including the NCHS maternal mortality data – show an ongoing crisis.
A study of 210 experienced primary care providers and 190 community members in the Denver area, for example, found substantial evidence of implicit bias against both Latino and African American patients. The authors defined implicit bias as “unintentional and even unconscious” negative evaluation of one group and its members relative to another that is expressed implicitly, such as through negative nonverbal behavior.
“Activated by situational cues (e.g., a person’s skin color), implicit bias can quickly and unknowingly exert its influence on perception, memory, and behavior,” they wrote.
In their study, Implicit Association Test and self-report measures of bias showed similar rates of implicit bias among the providers and community members, with only a slight weakening of ethnic/racial bias among providers after adjustment for background characteristics, which suggests “a wider societal problem,” they said.
A specific example of how implicit bias can manifest was described in a 2016 report addressing the well-documented under-treatment of pain among black versus white patients. Kelly M. Hoffman, PhD, and colleagues demonstrated that a substantial number of individuals with at least some medical training endorse false beliefs regarding biological differences between black and white patients. For example, 25% of 28 white residents surveyed agreed black individuals have thicker skin, and 4% believed black individuals have faster blood coagulation and less sensitivity in their nerve endings.
Those who more strongly endorsed such erroneous beliefs were more likely to underestimate and undertreat pain among black patients, the authors found.
Another study, which underscored the insidiousness of structural racism, was reported in Science. The authors identified significant racial bias in an algorithm widely used by health systems, insurers, and practitioners to allocate health care resources for patients with complex health needs. The algorithm, which affects millions of patients, uses predictions of future health care costs rather than future illness to determine who should receive extra medical care.
The problem is that unequal care access for black patients skews lower the foundational cost data used for making those predictions. Correcting the algorithm would increase the percentage of black patients receiving additional medical help from 17.7% to 46.5%, the authors concluded.
This evidence of persistent racism and bias in medicine, however, doesn’t mean progress is lacking.
ACOG has partnered with numerous other organizations to promote awareness and change, including through legislation. A recent win was the enactment of the Preventing Maternal Deaths Act of 2018, a bipartisan bill designed to promote and support maternal mortality review committees in every state. A major focus of BMMA’s Black Maternal Health Week was the Black Maternal Health Momnibus Act of 2020, a nine-bill package introduced in March to comprehensively address the crisis.
But efforts like these, whether they aim to elucidate the contributors to health disparities or to directly target structural and overt racism and root out implicit bias in medical care, are nothing new. As Dr. Bailey and colleagues noted, a challenge is getting the message across because efforts to avoid tough conversations around these topics are nothing new, either.
Dr. Gee attested to that during a maternal mortality panel discussion at the 2019 ACOG meeting where she spoke about the resistance she encountered in 2016 when she was appointed secretary of the Louisiana Health Department and worked to make racism and bias a foundational part of the discussion on improving maternal and fetal outcomes.
She established the first Office of Health Equity in the state – and the first in the nation to not only require measurement outcomes by race but also explicitly address racial bias at the outset. The goal wasn’t just to talk about it but to “plan for addressing equity in every single aspect of what we do with ... our case equity action teams.”
“At our first maternal mortality quality meetings we insisted on focusing on equity at the very outset, and we had people that left when we started talking about racism,” she said, noting that others said it was “too political” to discuss during an election year or that equity was something to address later.
“We said no. We insisted on it, and I think that was very important because all ships don’t rise with the tide, not with health disparities,” she said, recounting an earlier experience when she led the Louisiana Birth Outcomes Initiative: “I asked to have a brown-bag focused on racism at the department so we could talk about the impact of implicit bias on decision making, and I was told that I was a Yankee who didn’t understand the South and that racism didn’t really exist here, and what did I know about it – and I couldn’t have the brown-bag.”
That was in 2011.
Fast-forward to April 24, 2020. As Dr. Gee shared her perspective on addressing racism and bias in medicine, she was preparing for a call regarding the racial disparities in COVID-19 outcomes – the first health equity action sanctioned by Louisiana Governor John Bel Edwards (D).
“I think we really set the stage for these discussions,” she said.
Addressing equity to enact change
The efforts in Louisiana also set the stage for better maternal outcomes. At the 2019 ACOG meeting where she spoke as part of the President’s Panel, Dr. Gee said Louisiana had the highest maternal mortality rates in the nation. The NCHC data released in January, however, suggest that may no longer be the case.
Inconsistencies in how the latest and prior data were reported, including in how maternal mortality was defined, make direct comparison impossible. But in the latest report, Louisiana ranked seventh among states with available data.
“Ninety percent of the deliveries in the state happen at hospitals that we worked with,” Dr. Gee said, highlighting the reach of the efforts to improve outcomes there.
She also described a recent case involving an anemic patient whose bleeding risk was identified early thanks to the programs put in place. That enabled early preparation in the event of complications.
The patient experienced a massive hemorrhage, but the preparation, including having units of blood on hand in case of such an emergency, saved her life.
“So we clearly have not just data, but individual stories of people whose lives have been saved by this work,” she said.
More tangible data on maternal morbidity further show that the efforts in the state are making a difference, Dr. Gillispie said, citing preliminary outcomes data from the Pregnancy-Associated Mortality Review launched in 2018.
“We started with an initial goal of reducing severe maternal morbidity related to hypertension and hemorrhage by 20%, as well as reducing the black/white disparity gap by Mother’s Day 2020,” she said.
Final analyses have been delayed because of COVID-19, but early assessments showed a reduction in the disparity gap, she said, again highlighting the importance of focusing on equity.
“Definitely from the standpoint of the Quality Collaborative side ... we’ve been working with our facilities to make them aware of what implicit bias is, helping them to also do the Harvard Implicit Bias Test so they can figure out what their own biases are, start working to acknowledge them and address them, and start working to fight against letting that bias change how they treat individuals,” Dr. Gillispie said.
The work started through these initiatives will continue because there is much left to be done, she said.
Indeed, the surprised reactions in recent weeks to the reports of disparities in COVID-19 outcomes further underscore that reality, and the maternal mortality statistics – with use of the voices of those directly affected by structural and overt racism and bias in maternal care as a megaphone – speak for themselves.
Hearing implicit bias from patients’ perspective
Just ask Timoria McQueen Saba, a black woman who nearly died from a postpartum hemorrhage in 2010. At ACOG 2019, she spoke about how she had to switch ob.gyns. three times during her first pregnancy because she felt she had not received quality care – one doctor neglected to tell her she had placenta previa. She also experienced excessive wait times at prenatal appointments and had been on the receiving end of microaggressions and degrading questions such as “Are you still married?” and “Is your husband your baby’s father?” – and these are all things her white friends who recommended those physicians never experienced, she said.
“The health care system has just sometimes beaten people down so much, just like the world has – people of color, especially – to where you’re dismissed, your concerns are invalidated,” she said. “Some doctors don’t even think black people feel pain [or that] our pain is less.”
Mrs. Saba also spoke about how her health care “improved a billion percent” when her white husband accompanied her to appointments.
Just ask Charles S. Johnson IV, whose wife Kira Dixon Johnson died in 2016 during surgery for postpartum bleeding complications – after he and other family members spent 10 hours pleading for help for her.
Speaking at the ACOG panel discussion with Mrs. Saba, Mr. Johnson described “a clear disconnect” between the medical staff at the hospital and the way they viewed and valued Kira. He shared his frustration in wanting to advocate for his wife, but knowing that, as an African American male, he risked being seen as a threat and removed from the hospital if he didn’t stay calm, if he “tapped into those natural instincts as a man and a husband who wants to just protect his family.”
He fought back emotions, struggling to get the words out, saying that’s what haunts him and keeps him up at night – wondering if he should have “fought harder, grabbed the doctor by the collar, raised his voice, slammed on the counter.
“Maybe they would have done something,” he said.
Such experiences cross all socioeconomic boundaries. Ask U.S. Track and Field Olympic gold medalist Allyson Felix, who testified at a U.S. House Ways and Means Committee hearing on May 16, 2019 after developing severe preeclampsia that threatened her life and that of her baby. Ask tennis champion Serena Williams, who demanded assessment for pulmonary embolism following the birth of her child; she knew the signs, but her health care providers initially dismissed her concerns.
Their experiences aren’t just anecdotal. Data consistently show how racism and bias affect patient treatment and outcomes. Dr. Gee, for example, shared findings from a retrospective assessment of 47 confirmed pregnancy-related deaths in Louisiana between 2011 and 2016 that looked specifically at whether the deaths could potentially have been prevented if blood was given sooner, cardiomyopathy was recognized sooner, hypertension was treated on time, or other changes were made to care.
The answer was “Yes” in 9% of cases involving white patients – and in 59% of cases involving black patients (odds ratio, 14.6).
The study, reported in February in Obstetrics & Gynecology, showed that 27 of the deaths (58%) occurred at level III or IV birth facilities and that those deaths were not less likely than those at level I or II facilities to be categorized as preventable (OR, 2.0).
Findings from the Giving Voice to Mothers study, published in Reproductive Health in 2019, showed how mistreatment during childbirth might contribute to such outcomes.
In an online cross-sectional survey of more than 2,100 U.S. women, one in six reported at least one type of mistreatment, such as loss of autonomy, being yelled at or threatened, being ignored or having requests for help ignored, Saraswathi Vedam, SciD, of the Birth Place Lab at the University of British Columbia, Vancouver, and colleagues reported.
Race was among the factors associated with likelihood of mistreatment, and the rates of mistreatment for women of color were consistently higher – even when looking at interactions between race and other characteristics, such as socioeconomic status (SES). For example, 27.2% of women of color with low SES, compared with 18.7% of white women with low SES, reported mistreatment. Having a partner who was black, regardless of maternal race, was also associated with an increased rate of mistreatment, the authors found.
“I often get the question, ‘Do you think Kira would be alive if she was white,’ ” Mr. Johnson said. “The first way I respond to that question is [by saying that] the simple fact that you have to ask me is a problem.
“When this first happened, I was in so much pain that I couldn’t process the fact that something so egregious and outrageous happened to my wife because of the color of her skin, but as I began to process and really think about it and unpack this scenario, I have to be really frank ... do I think that she would have sat there for 10 hours while we begged and pleaded? Absolutely not.”
He stressed that his words aren’t “an indictment of the profession.”
“This is not an indictment saying that all people are racist or prejudiced,” he said. “But here’s the reality: If you are in this profession, if you are responsible for the well-being of patients and their families, and you are not able to see them in the same way that you see your mother, your wife, your sister, you have two options – you need to find something else to do or you need to take steps to get better.”
Fixing systems, finding solutions
Dr. Gee acknowledged the work that physicians need to do to help improve outcomes.
“The average time we give a patient to talk is 11 seconds before we interrupt them,” she said, as one example. “We have to recognize that.”
But efforts to improve outcomes shouldn’t just focus on changing physician behavior, she said.
“We really need to focus, as has the U.K. – very effectively – on using midwives, doulas, other health care professionals as complements to physicians to make sure that we have women-centered birth experiences.
“So, instead of just blaming the doctors, I think we need to change the system,” Dr. Gee emphasized.
The disruptions in health systems caused by COVID-19 present a unique opportunity to do that, she said. There is now an opportunity to build them back.
“We have a chance to build the systems back, and when we do so, we ought to build them back correcting for implicit bias and some of the systemic issues that lead to poor outcomes for people of color in our country,” she said.
Solutions proposed by Dr. Gee and others include more diversity in the workforce, more inclusion of patient advocates in maternal care, development of culturally appropriate literacy and numeracy communications, measurement by race (and action on the outcomes), standardization of care, and development of new ways to improve care access.
We will focus more specifically on these solutions in Part 2 of this article in our maternal mortality series. Previous articles in the series are available at mdedge.com/obgyn/maternal-mortality.
April 11-17 marked the third annual national Black Maternal Health Week, an event launched in 2017 by the Atlanta-based Black Mamas Matter Alliance (BMMA), in part to “deepen the national conversation about black maternal health.”
Around the same time, emerging data showing higher mortality rates among black patients versus patients of other races with COVID-19 opened similar dialogue fraught with questions about what might explain the disturbing health disparities.
“It’s kind of surprising to me that people are shocked by these [COVID-19] disparities,” Rebekah Gee, MD, an ob.gyn. who is director of the Louisiana State University Health System in New Orleans and a driving force behind initiatives addressing racial disparities in maternal health, said in an interview. If this is it, great – and certainly every moment is a moment for learning – but these COVID-19 disparities should not be surprising to people who have been looking at data.”
Veronica Gillispie, MD, an ob.gyn. and medical director of the Louisiana Perinatal Quality Collaborative and Pregnancy-Associated Mortality Review, was similarly baffled that the news was treated as a revelation.
That news includes outcomes data from New York showing that in March there were 92.3 and 74.3 deaths per 100,000 black and Hispanic COVID-19 patients, respectively, compared with 45.2 per 100,000 white patients.
“Now there’s a task force and all these initiatives to look at why this is happening, and I think those of us who work in maternal mortality are all saying, ‘We know why it’s happening,’ ” she said. “It’s the same thing we’ve been telling people why it’s been happening in maternal mortality.
“It’s implicit bias and structural racism.”
Facing hard numbers, harder conversations
The U.S. maternal mortality rate in 2018 was 17 per 100,000 live births – the highest of any similarly wealthy industrialized nation, the Centers for Disease Control and Prevention’s National Center for Health Statistics (NCHS) reported in January. That’s a striking statistic in its own right. Perhaps more striking is the breakdown by race.
Hispanic women had the lowest maternal mortality rate at 12 per 100,000 live births, followed by non-Hispanic white women at 15.
The rate for non-Hispanic black women was 37 per 100,000 live births.
Numerous factors contribute to these disparities. Among those listed by the American College of Obstetricians and Gynecologists’ chief executive officer Maureen G. Phipps, MD, in a press statement on the NCHS data, are care access issues, lack of standardization of care, bias, and racism. All of these must be addressed if the disparities in maternal and other areas of care are to be eliminated, according to Dr. Phipps.
“The NCHS data confirmed what we have known from other data sources: The rate of maternal deaths for non-Hispanic black women is substantially higher than the rates for non-Hispanic white women,” she wrote. “Continued efforts to improve the standardization of data and review processes related to U.S. maternal mortality are a necessary step to achieving the goal of eliminating disparities and preventable maternal mortality.”
However, such efforts frequently encounter roadblocks constructed by the reluctance among “many academics, policy makers, scientists, elected officials, journalists, and others responsible for defining and responding to the public discourse” to identify racism as a root cause of health disparities, according to Zinzi D. Bailey, ScD, former director of research and evaluation for the New York City Department of Health and Mental Hygiene, and colleagues.
In the third of a three-part conceptual report in The Lancet, entitled America: Equity and Equality in Health, Dr. Bailey and colleagues argued that advancing health equity requires a focus on structural racism – which they defined as “the totality of ways in which societies foster racial discrimination via mutually reinforcing inequitable systems (e.g., in housing, education, employment, earning, benefits, credit, media, healthcare, and criminal justice, etc.) that in turn reinforce discriminatory beliefs, values, and distribution of resources.”
In their series, the authors peeled back layer upon layer of sociological and political contributors to structural racism throughout history, revealing how each laid a foundation for health inequity over time. They particularly home in on health care quality and access.
“Interpersonal racism, bias, and discrimination in healthcare settings can directly affect health through poor health care,” they wrote, noting that “almost 15 years ago, the Institute of Medicine report entitled Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care, documented systematic and pervasive bias in the treatment of people of color resulting in substandard care.”
That report concluded that “bias, stereotyping, prejudice, and clinical uncertainty on the part of healthcare providers” likely play a role in the continuation of health disparities. More recent data – including the NCHS maternal mortality data – show an ongoing crisis.
A study of 210 experienced primary care providers and 190 community members in the Denver area, for example, found substantial evidence of implicit bias against both Latino and African American patients. The authors defined implicit bias as “unintentional and even unconscious” negative evaluation of one group and its members relative to another that is expressed implicitly, such as through negative nonverbal behavior.
“Activated by situational cues (e.g., a person’s skin color), implicit bias can quickly and unknowingly exert its influence on perception, memory, and behavior,” they wrote.
In their study, Implicit Association Test and self-report measures of bias showed similar rates of implicit bias among the providers and community members, with only a slight weakening of ethnic/racial bias among providers after adjustment for background characteristics, which suggests “a wider societal problem,” they said.
A specific example of how implicit bias can manifest was described in a 2016 report addressing the well-documented under-treatment of pain among black versus white patients. Kelly M. Hoffman, PhD, and colleagues demonstrated that a substantial number of individuals with at least some medical training endorse false beliefs regarding biological differences between black and white patients. For example, 25% of 28 white residents surveyed agreed black individuals have thicker skin, and 4% believed black individuals have faster blood coagulation and less sensitivity in their nerve endings.
Those who more strongly endorsed such erroneous beliefs were more likely to underestimate and undertreat pain among black patients, the authors found.
Another study, which underscored the insidiousness of structural racism, was reported in Science. The authors identified significant racial bias in an algorithm widely used by health systems, insurers, and practitioners to allocate health care resources for patients with complex health needs. The algorithm, which affects millions of patients, uses predictions of future health care costs rather than future illness to determine who should receive extra medical care.
The problem is that unequal care access for black patients skews lower the foundational cost data used for making those predictions. Correcting the algorithm would increase the percentage of black patients receiving additional medical help from 17.7% to 46.5%, the authors concluded.
This evidence of persistent racism and bias in medicine, however, doesn’t mean progress is lacking.
ACOG has partnered with numerous other organizations to promote awareness and change, including through legislation. A recent win was the enactment of the Preventing Maternal Deaths Act of 2018, a bipartisan bill designed to promote and support maternal mortality review committees in every state. A major focus of BMMA’s Black Maternal Health Week was the Black Maternal Health Momnibus Act of 2020, a nine-bill package introduced in March to comprehensively address the crisis.
But efforts like these, whether they aim to elucidate the contributors to health disparities or to directly target structural and overt racism and root out implicit bias in medical care, are nothing new. As Dr. Bailey and colleagues noted, a challenge is getting the message across because efforts to avoid tough conversations around these topics are nothing new, either.
Dr. Gee attested to that during a maternal mortality panel discussion at the 2019 ACOG meeting where she spoke about the resistance she encountered in 2016 when she was appointed secretary of the Louisiana Health Department and worked to make racism and bias a foundational part of the discussion on improving maternal and fetal outcomes.
She established the first Office of Health Equity in the state – and the first in the nation to not only require measurement outcomes by race but also explicitly address racial bias at the outset. The goal wasn’t just to talk about it but to “plan for addressing equity in every single aspect of what we do with ... our case equity action teams.”
“At our first maternal mortality quality meetings we insisted on focusing on equity at the very outset, and we had people that left when we started talking about racism,” she said, noting that others said it was “too political” to discuss during an election year or that equity was something to address later.
“We said no. We insisted on it, and I think that was very important because all ships don’t rise with the tide, not with health disparities,” she said, recounting an earlier experience when she led the Louisiana Birth Outcomes Initiative: “I asked to have a brown-bag focused on racism at the department so we could talk about the impact of implicit bias on decision making, and I was told that I was a Yankee who didn’t understand the South and that racism didn’t really exist here, and what did I know about it – and I couldn’t have the brown-bag.”
That was in 2011.
Fast-forward to April 24, 2020. As Dr. Gee shared her perspective on addressing racism and bias in medicine, she was preparing for a call regarding the racial disparities in COVID-19 outcomes – the first health equity action sanctioned by Louisiana Governor John Bel Edwards (D).
“I think we really set the stage for these discussions,” she said.
Addressing equity to enact change
The efforts in Louisiana also set the stage for better maternal outcomes. At the 2019 ACOG meeting where she spoke as part of the President’s Panel, Dr. Gee said Louisiana had the highest maternal mortality rates in the nation. The NCHC data released in January, however, suggest that may no longer be the case.
Inconsistencies in how the latest and prior data were reported, including in how maternal mortality was defined, make direct comparison impossible. But in the latest report, Louisiana ranked seventh among states with available data.
“Ninety percent of the deliveries in the state happen at hospitals that we worked with,” Dr. Gee said, highlighting the reach of the efforts to improve outcomes there.
She also described a recent case involving an anemic patient whose bleeding risk was identified early thanks to the programs put in place. That enabled early preparation in the event of complications.
The patient experienced a massive hemorrhage, but the preparation, including having units of blood on hand in case of such an emergency, saved her life.
“So we clearly have not just data, but individual stories of people whose lives have been saved by this work,” she said.
More tangible data on maternal morbidity further show that the efforts in the state are making a difference, Dr. Gillispie said, citing preliminary outcomes data from the Pregnancy-Associated Mortality Review launched in 2018.
“We started with an initial goal of reducing severe maternal morbidity related to hypertension and hemorrhage by 20%, as well as reducing the black/white disparity gap by Mother’s Day 2020,” she said.
Final analyses have been delayed because of COVID-19, but early assessments showed a reduction in the disparity gap, she said, again highlighting the importance of focusing on equity.
“Definitely from the standpoint of the Quality Collaborative side ... we’ve been working with our facilities to make them aware of what implicit bias is, helping them to also do the Harvard Implicit Bias Test so they can figure out what their own biases are, start working to acknowledge them and address them, and start working to fight against letting that bias change how they treat individuals,” Dr. Gillispie said.
The work started through these initiatives will continue because there is much left to be done, she said.
Indeed, the surprised reactions in recent weeks to the reports of disparities in COVID-19 outcomes further underscore that reality, and the maternal mortality statistics – with use of the voices of those directly affected by structural and overt racism and bias in maternal care as a megaphone – speak for themselves.
Hearing implicit bias from patients’ perspective
Just ask Timoria McQueen Saba, a black woman who nearly died from a postpartum hemorrhage in 2010. At ACOG 2019, she spoke about how she had to switch ob.gyns. three times during her first pregnancy because she felt she had not received quality care – one doctor neglected to tell her she had placenta previa. She also experienced excessive wait times at prenatal appointments and had been on the receiving end of microaggressions and degrading questions such as “Are you still married?” and “Is your husband your baby’s father?” – and these are all things her white friends who recommended those physicians never experienced, she said.
“The health care system has just sometimes beaten people down so much, just like the world has – people of color, especially – to where you’re dismissed, your concerns are invalidated,” she said. “Some doctors don’t even think black people feel pain [or that] our pain is less.”
Mrs. Saba also spoke about how her health care “improved a billion percent” when her white husband accompanied her to appointments.
Just ask Charles S. Johnson IV, whose wife Kira Dixon Johnson died in 2016 during surgery for postpartum bleeding complications – after he and other family members spent 10 hours pleading for help for her.
Speaking at the ACOG panel discussion with Mrs. Saba, Mr. Johnson described “a clear disconnect” between the medical staff at the hospital and the way they viewed and valued Kira. He shared his frustration in wanting to advocate for his wife, but knowing that, as an African American male, he risked being seen as a threat and removed from the hospital if he didn’t stay calm, if he “tapped into those natural instincts as a man and a husband who wants to just protect his family.”
He fought back emotions, struggling to get the words out, saying that’s what haunts him and keeps him up at night – wondering if he should have “fought harder, grabbed the doctor by the collar, raised his voice, slammed on the counter.
“Maybe they would have done something,” he said.
Such experiences cross all socioeconomic boundaries. Ask U.S. Track and Field Olympic gold medalist Allyson Felix, who testified at a U.S. House Ways and Means Committee hearing on May 16, 2019 after developing severe preeclampsia that threatened her life and that of her baby. Ask tennis champion Serena Williams, who demanded assessment for pulmonary embolism following the birth of her child; she knew the signs, but her health care providers initially dismissed her concerns.
Their experiences aren’t just anecdotal. Data consistently show how racism and bias affect patient treatment and outcomes. Dr. Gee, for example, shared findings from a retrospective assessment of 47 confirmed pregnancy-related deaths in Louisiana between 2011 and 2016 that looked specifically at whether the deaths could potentially have been prevented if blood was given sooner, cardiomyopathy was recognized sooner, hypertension was treated on time, or other changes were made to care.
The answer was “Yes” in 9% of cases involving white patients – and in 59% of cases involving black patients (odds ratio, 14.6).
The study, reported in February in Obstetrics & Gynecology, showed that 27 of the deaths (58%) occurred at level III or IV birth facilities and that those deaths were not less likely than those at level I or II facilities to be categorized as preventable (OR, 2.0).
Findings from the Giving Voice to Mothers study, published in Reproductive Health in 2019, showed how mistreatment during childbirth might contribute to such outcomes.
In an online cross-sectional survey of more than 2,100 U.S. women, one in six reported at least one type of mistreatment, such as loss of autonomy, being yelled at or threatened, being ignored or having requests for help ignored, Saraswathi Vedam, SciD, of the Birth Place Lab at the University of British Columbia, Vancouver, and colleagues reported.
Race was among the factors associated with likelihood of mistreatment, and the rates of mistreatment for women of color were consistently higher – even when looking at interactions between race and other characteristics, such as socioeconomic status (SES). For example, 27.2% of women of color with low SES, compared with 18.7% of white women with low SES, reported mistreatment. Having a partner who was black, regardless of maternal race, was also associated with an increased rate of mistreatment, the authors found.
“I often get the question, ‘Do you think Kira would be alive if she was white,’ ” Mr. Johnson said. “The first way I respond to that question is [by saying that] the simple fact that you have to ask me is a problem.
“When this first happened, I was in so much pain that I couldn’t process the fact that something so egregious and outrageous happened to my wife because of the color of her skin, but as I began to process and really think about it and unpack this scenario, I have to be really frank ... do I think that she would have sat there for 10 hours while we begged and pleaded? Absolutely not.”
He stressed that his words aren’t “an indictment of the profession.”
“This is not an indictment saying that all people are racist or prejudiced,” he said. “But here’s the reality: If you are in this profession, if you are responsible for the well-being of patients and their families, and you are not able to see them in the same way that you see your mother, your wife, your sister, you have two options – you need to find something else to do or you need to take steps to get better.”
Fixing systems, finding solutions
Dr. Gee acknowledged the work that physicians need to do to help improve outcomes.
“The average time we give a patient to talk is 11 seconds before we interrupt them,” she said, as one example. “We have to recognize that.”
But efforts to improve outcomes shouldn’t just focus on changing physician behavior, she said.
“We really need to focus, as has the U.K. – very effectively – on using midwives, doulas, other health care professionals as complements to physicians to make sure that we have women-centered birth experiences.
“So, instead of just blaming the doctors, I think we need to change the system,” Dr. Gee emphasized.
The disruptions in health systems caused by COVID-19 present a unique opportunity to do that, she said. There is now an opportunity to build them back.
“We have a chance to build the systems back, and when we do so, we ought to build them back correcting for implicit bias and some of the systemic issues that lead to poor outcomes for people of color in our country,” she said.
Solutions proposed by Dr. Gee and others include more diversity in the workforce, more inclusion of patient advocates in maternal care, development of culturally appropriate literacy and numeracy communications, measurement by race (and action on the outcomes), standardization of care, and development of new ways to improve care access.
We will focus more specifically on these solutions in Part 2 of this article in our maternal mortality series. Previous articles in the series are available at mdedge.com/obgyn/maternal-mortality.
April 11-17 marked the third annual national Black Maternal Health Week, an event launched in 2017 by the Atlanta-based Black Mamas Matter Alliance (BMMA), in part to “deepen the national conversation about black maternal health.”
Around the same time, emerging data showing higher mortality rates among black patients versus patients of other races with COVID-19 opened similar dialogue fraught with questions about what might explain the disturbing health disparities.
“It’s kind of surprising to me that people are shocked by these [COVID-19] disparities,” Rebekah Gee, MD, an ob.gyn. who is director of the Louisiana State University Health System in New Orleans and a driving force behind initiatives addressing racial disparities in maternal health, said in an interview. If this is it, great – and certainly every moment is a moment for learning – but these COVID-19 disparities should not be surprising to people who have been looking at data.”
Veronica Gillispie, MD, an ob.gyn. and medical director of the Louisiana Perinatal Quality Collaborative and Pregnancy-Associated Mortality Review, was similarly baffled that the news was treated as a revelation.
That news includes outcomes data from New York showing that in March there were 92.3 and 74.3 deaths per 100,000 black and Hispanic COVID-19 patients, respectively, compared with 45.2 per 100,000 white patients.
“Now there’s a task force and all these initiatives to look at why this is happening, and I think those of us who work in maternal mortality are all saying, ‘We know why it’s happening,’ ” she said. “It’s the same thing we’ve been telling people why it’s been happening in maternal mortality.
“It’s implicit bias and structural racism.”
Facing hard numbers, harder conversations
The U.S. maternal mortality rate in 2018 was 17 per 100,000 live births – the highest of any similarly wealthy industrialized nation, the Centers for Disease Control and Prevention’s National Center for Health Statistics (NCHS) reported in January. That’s a striking statistic in its own right. Perhaps more striking is the breakdown by race.
Hispanic women had the lowest maternal mortality rate at 12 per 100,000 live births, followed by non-Hispanic white women at 15.
The rate for non-Hispanic black women was 37 per 100,000 live births.
Numerous factors contribute to these disparities. Among those listed by the American College of Obstetricians and Gynecologists’ chief executive officer Maureen G. Phipps, MD, in a press statement on the NCHS data, are care access issues, lack of standardization of care, bias, and racism. All of these must be addressed if the disparities in maternal and other areas of care are to be eliminated, according to Dr. Phipps.
“The NCHS data confirmed what we have known from other data sources: The rate of maternal deaths for non-Hispanic black women is substantially higher than the rates for non-Hispanic white women,” she wrote. “Continued efforts to improve the standardization of data and review processes related to U.S. maternal mortality are a necessary step to achieving the goal of eliminating disparities and preventable maternal mortality.”
However, such efforts frequently encounter roadblocks constructed by the reluctance among “many academics, policy makers, scientists, elected officials, journalists, and others responsible for defining and responding to the public discourse” to identify racism as a root cause of health disparities, according to Zinzi D. Bailey, ScD, former director of research and evaluation for the New York City Department of Health and Mental Hygiene, and colleagues.
In the third of a three-part conceptual report in The Lancet, entitled America: Equity and Equality in Health, Dr. Bailey and colleagues argued that advancing health equity requires a focus on structural racism – which they defined as “the totality of ways in which societies foster racial discrimination via mutually reinforcing inequitable systems (e.g., in housing, education, employment, earning, benefits, credit, media, healthcare, and criminal justice, etc.) that in turn reinforce discriminatory beliefs, values, and distribution of resources.”
In their series, the authors peeled back layer upon layer of sociological and political contributors to structural racism throughout history, revealing how each laid a foundation for health inequity over time. They particularly home in on health care quality and access.
“Interpersonal racism, bias, and discrimination in healthcare settings can directly affect health through poor health care,” they wrote, noting that “almost 15 years ago, the Institute of Medicine report entitled Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care, documented systematic and pervasive bias in the treatment of people of color resulting in substandard care.”
That report concluded that “bias, stereotyping, prejudice, and clinical uncertainty on the part of healthcare providers” likely play a role in the continuation of health disparities. More recent data – including the NCHS maternal mortality data – show an ongoing crisis.
A study of 210 experienced primary care providers and 190 community members in the Denver area, for example, found substantial evidence of implicit bias against both Latino and African American patients. The authors defined implicit bias as “unintentional and even unconscious” negative evaluation of one group and its members relative to another that is expressed implicitly, such as through negative nonverbal behavior.
“Activated by situational cues (e.g., a person’s skin color), implicit bias can quickly and unknowingly exert its influence on perception, memory, and behavior,” they wrote.
In their study, Implicit Association Test and self-report measures of bias showed similar rates of implicit bias among the providers and community members, with only a slight weakening of ethnic/racial bias among providers after adjustment for background characteristics, which suggests “a wider societal problem,” they said.
A specific example of how implicit bias can manifest was described in a 2016 report addressing the well-documented under-treatment of pain among black versus white patients. Kelly M. Hoffman, PhD, and colleagues demonstrated that a substantial number of individuals with at least some medical training endorse false beliefs regarding biological differences between black and white patients. For example, 25% of 28 white residents surveyed agreed black individuals have thicker skin, and 4% believed black individuals have faster blood coagulation and less sensitivity in their nerve endings.
Those who more strongly endorsed such erroneous beliefs were more likely to underestimate and undertreat pain among black patients, the authors found.
Another study, which underscored the insidiousness of structural racism, was reported in Science. The authors identified significant racial bias in an algorithm widely used by health systems, insurers, and practitioners to allocate health care resources for patients with complex health needs. The algorithm, which affects millions of patients, uses predictions of future health care costs rather than future illness to determine who should receive extra medical care.
The problem is that unequal care access for black patients skews lower the foundational cost data used for making those predictions. Correcting the algorithm would increase the percentage of black patients receiving additional medical help from 17.7% to 46.5%, the authors concluded.
This evidence of persistent racism and bias in medicine, however, doesn’t mean progress is lacking.
ACOG has partnered with numerous other organizations to promote awareness and change, including through legislation. A recent win was the enactment of the Preventing Maternal Deaths Act of 2018, a bipartisan bill designed to promote and support maternal mortality review committees in every state. A major focus of BMMA’s Black Maternal Health Week was the Black Maternal Health Momnibus Act of 2020, a nine-bill package introduced in March to comprehensively address the crisis.
But efforts like these, whether they aim to elucidate the contributors to health disparities or to directly target structural and overt racism and root out implicit bias in medical care, are nothing new. As Dr. Bailey and colleagues noted, a challenge is getting the message across because efforts to avoid tough conversations around these topics are nothing new, either.
Dr. Gee attested to that during a maternal mortality panel discussion at the 2019 ACOG meeting where she spoke about the resistance she encountered in 2016 when she was appointed secretary of the Louisiana Health Department and worked to make racism and bias a foundational part of the discussion on improving maternal and fetal outcomes.
She established the first Office of Health Equity in the state – and the first in the nation to not only require measurement outcomes by race but also explicitly address racial bias at the outset. The goal wasn’t just to talk about it but to “plan for addressing equity in every single aspect of what we do with ... our case equity action teams.”
“At our first maternal mortality quality meetings we insisted on focusing on equity at the very outset, and we had people that left when we started talking about racism,” she said, noting that others said it was “too political” to discuss during an election year or that equity was something to address later.
“We said no. We insisted on it, and I think that was very important because all ships don’t rise with the tide, not with health disparities,” she said, recounting an earlier experience when she led the Louisiana Birth Outcomes Initiative: “I asked to have a brown-bag focused on racism at the department so we could talk about the impact of implicit bias on decision making, and I was told that I was a Yankee who didn’t understand the South and that racism didn’t really exist here, and what did I know about it – and I couldn’t have the brown-bag.”
That was in 2011.
Fast-forward to April 24, 2020. As Dr. Gee shared her perspective on addressing racism and bias in medicine, she was preparing for a call regarding the racial disparities in COVID-19 outcomes – the first health equity action sanctioned by Louisiana Governor John Bel Edwards (D).
“I think we really set the stage for these discussions,” she said.
Addressing equity to enact change
The efforts in Louisiana also set the stage for better maternal outcomes. At the 2019 ACOG meeting where she spoke as part of the President’s Panel, Dr. Gee said Louisiana had the highest maternal mortality rates in the nation. The NCHC data released in January, however, suggest that may no longer be the case.
Inconsistencies in how the latest and prior data were reported, including in how maternal mortality was defined, make direct comparison impossible. But in the latest report, Louisiana ranked seventh among states with available data.
“Ninety percent of the deliveries in the state happen at hospitals that we worked with,” Dr. Gee said, highlighting the reach of the efforts to improve outcomes there.
She also described a recent case involving an anemic patient whose bleeding risk was identified early thanks to the programs put in place. That enabled early preparation in the event of complications.
The patient experienced a massive hemorrhage, but the preparation, including having units of blood on hand in case of such an emergency, saved her life.
“So we clearly have not just data, but individual stories of people whose lives have been saved by this work,” she said.
More tangible data on maternal morbidity further show that the efforts in the state are making a difference, Dr. Gillispie said, citing preliminary outcomes data from the Pregnancy-Associated Mortality Review launched in 2018.
“We started with an initial goal of reducing severe maternal morbidity related to hypertension and hemorrhage by 20%, as well as reducing the black/white disparity gap by Mother’s Day 2020,” she said.
Final analyses have been delayed because of COVID-19, but early assessments showed a reduction in the disparity gap, she said, again highlighting the importance of focusing on equity.
“Definitely from the standpoint of the Quality Collaborative side ... we’ve been working with our facilities to make them aware of what implicit bias is, helping them to also do the Harvard Implicit Bias Test so they can figure out what their own biases are, start working to acknowledge them and address them, and start working to fight against letting that bias change how they treat individuals,” Dr. Gillispie said.
The work started through these initiatives will continue because there is much left to be done, she said.
Indeed, the surprised reactions in recent weeks to the reports of disparities in COVID-19 outcomes further underscore that reality, and the maternal mortality statistics – with use of the voices of those directly affected by structural and overt racism and bias in maternal care as a megaphone – speak for themselves.
Hearing implicit bias from patients’ perspective
Just ask Timoria McQueen Saba, a black woman who nearly died from a postpartum hemorrhage in 2010. At ACOG 2019, she spoke about how she had to switch ob.gyns. three times during her first pregnancy because she felt she had not received quality care – one doctor neglected to tell her she had placenta previa. She also experienced excessive wait times at prenatal appointments and had been on the receiving end of microaggressions and degrading questions such as “Are you still married?” and “Is your husband your baby’s father?” – and these are all things her white friends who recommended those physicians never experienced, she said.
“The health care system has just sometimes beaten people down so much, just like the world has – people of color, especially – to where you’re dismissed, your concerns are invalidated,” she said. “Some doctors don’t even think black people feel pain [or that] our pain is less.”
Mrs. Saba also spoke about how her health care “improved a billion percent” when her white husband accompanied her to appointments.
Just ask Charles S. Johnson IV, whose wife Kira Dixon Johnson died in 2016 during surgery for postpartum bleeding complications – after he and other family members spent 10 hours pleading for help for her.
Speaking at the ACOG panel discussion with Mrs. Saba, Mr. Johnson described “a clear disconnect” between the medical staff at the hospital and the way they viewed and valued Kira. He shared his frustration in wanting to advocate for his wife, but knowing that, as an African American male, he risked being seen as a threat and removed from the hospital if he didn’t stay calm, if he “tapped into those natural instincts as a man and a husband who wants to just protect his family.”
He fought back emotions, struggling to get the words out, saying that’s what haunts him and keeps him up at night – wondering if he should have “fought harder, grabbed the doctor by the collar, raised his voice, slammed on the counter.
“Maybe they would have done something,” he said.
Such experiences cross all socioeconomic boundaries. Ask U.S. Track and Field Olympic gold medalist Allyson Felix, who testified at a U.S. House Ways and Means Committee hearing on May 16, 2019 after developing severe preeclampsia that threatened her life and that of her baby. Ask tennis champion Serena Williams, who demanded assessment for pulmonary embolism following the birth of her child; she knew the signs, but her health care providers initially dismissed her concerns.
Their experiences aren’t just anecdotal. Data consistently show how racism and bias affect patient treatment and outcomes. Dr. Gee, for example, shared findings from a retrospective assessment of 47 confirmed pregnancy-related deaths in Louisiana between 2011 and 2016 that looked specifically at whether the deaths could potentially have been prevented if blood was given sooner, cardiomyopathy was recognized sooner, hypertension was treated on time, or other changes were made to care.
The answer was “Yes” in 9% of cases involving white patients – and in 59% of cases involving black patients (odds ratio, 14.6).
The study, reported in February in Obstetrics & Gynecology, showed that 27 of the deaths (58%) occurred at level III or IV birth facilities and that those deaths were not less likely than those at level I or II facilities to be categorized as preventable (OR, 2.0).
Findings from the Giving Voice to Mothers study, published in Reproductive Health in 2019, showed how mistreatment during childbirth might contribute to such outcomes.
In an online cross-sectional survey of more than 2,100 U.S. women, one in six reported at least one type of mistreatment, such as loss of autonomy, being yelled at or threatened, being ignored or having requests for help ignored, Saraswathi Vedam, SciD, of the Birth Place Lab at the University of British Columbia, Vancouver, and colleagues reported.
Race was among the factors associated with likelihood of mistreatment, and the rates of mistreatment for women of color were consistently higher – even when looking at interactions between race and other characteristics, such as socioeconomic status (SES). For example, 27.2% of women of color with low SES, compared with 18.7% of white women with low SES, reported mistreatment. Having a partner who was black, regardless of maternal race, was also associated with an increased rate of mistreatment, the authors found.
“I often get the question, ‘Do you think Kira would be alive if she was white,’ ” Mr. Johnson said. “The first way I respond to that question is [by saying that] the simple fact that you have to ask me is a problem.
“When this first happened, I was in so much pain that I couldn’t process the fact that something so egregious and outrageous happened to my wife because of the color of her skin, but as I began to process and really think about it and unpack this scenario, I have to be really frank ... do I think that she would have sat there for 10 hours while we begged and pleaded? Absolutely not.”
He stressed that his words aren’t “an indictment of the profession.”
“This is not an indictment saying that all people are racist or prejudiced,” he said. “But here’s the reality: If you are in this profession, if you are responsible for the well-being of patients and their families, and you are not able to see them in the same way that you see your mother, your wife, your sister, you have two options – you need to find something else to do or you need to take steps to get better.”
Fixing systems, finding solutions
Dr. Gee acknowledged the work that physicians need to do to help improve outcomes.
“The average time we give a patient to talk is 11 seconds before we interrupt them,” she said, as one example. “We have to recognize that.”
But efforts to improve outcomes shouldn’t just focus on changing physician behavior, she said.
“We really need to focus, as has the U.K. – very effectively – on using midwives, doulas, other health care professionals as complements to physicians to make sure that we have women-centered birth experiences.
“So, instead of just blaming the doctors, I think we need to change the system,” Dr. Gee emphasized.
The disruptions in health systems caused by COVID-19 present a unique opportunity to do that, she said. There is now an opportunity to build them back.
“We have a chance to build the systems back, and when we do so, we ought to build them back correcting for implicit bias and some of the systemic issues that lead to poor outcomes for people of color in our country,” she said.
Solutions proposed by Dr. Gee and others include more diversity in the workforce, more inclusion of patient advocates in maternal care, development of culturally appropriate literacy and numeracy communications, measurement by race (and action on the outcomes), standardization of care, and development of new ways to improve care access.
We will focus more specifically on these solutions in Part 2 of this article in our maternal mortality series. Previous articles in the series are available at mdedge.com/obgyn/maternal-mortality.
Adding a blood test to standard screening may improve early cancer detection
A minimally invasive multicancer blood test used with standard-of-care screening is safe, effective, and feasible for use in routine clinical care, according to interim findings from a large, prospective study.
The DETECT-A blood test, an early version of the CancerSEEK test currently in development, effectively guided patient management in real time, in some cases leading to diagnosis of early cancer and potentially curative surgery in asymptomatic women with no history of cancer.
Nickolas Papadopoulos, PhD, of Johns Hopkins Medicine in Baltimore, reported these findings at the AACR virtual meeting I. The findings were simultaneously published in Science.
The study enrolled 10,006 women, aged 65-75 years, with no prior cancer diagnosis. After exclusion and loss to follow-up, 9,911 women remained.
There were 26 patients who had cancer detected by the DETECT-A blood test, 15 of whom underwent follow-up PET-CT imaging and 9 of whom underwent surgical excision. An additional 24 cancers were detected by standard screening, and 46 were detected by other means.
The positive predictive value of the blood test was 19%. When the blood test was combined with imaging, the positive predictive value was 41%.
Improving upon standard screening
“Standard-of-care screening [was used] for three different organs: breast, lung, and colon. It was more sensitive for breast cancer,” Dr. Papadopoulos noted. “Blood testing, though, identified cancer in 10 different organs.”
In fact, the DETECT-A blood test detected 14 of 45 cancers in 7 organs for which no standard screening test is available.
In addition, 12 cancers in 3 organs (breast, lung, and colon) were first detected by DETECT-A rather than by standard screening. This increased the sensitivity of cancer detection from 47% with standard screening alone to 71% with standard screening plus blood testing.
“More important, 65% [of the cancers detected by blood test] were localized or regional, which have higher chance of successful treatment with intent to cure,” Dr. Papadopoulos said.
DETECT-A covers regions of 16 commonly mutated genes and 9 proteins known to be associated with cancer. In this study, 57% of cancers were detected by mutations.
Safety and additional screening
DETECT-A also proved safe, “without incurring a large number of futile invasive follow-up tests,” Dr. Papadopoulos said.
In fact, only 1% of patients without cancer underwent PET-CT imaging, and only 0.22% underwent a “futile” invasive follow-up procedure.
Three surgeries occurred in patients who were counted as false-positives, but the surgeries were determined to be indicated, Dr. Papadopoulos said. He explained that one was for large colonic polyps with high-grade dysplasia that could not be removed endoscopically, one was for an in situ carcinoma of the appendix, and one was for a 10-cm ovarian lesion that was found to be a mucinous cystadenoma.
The investigators also analyzed whether the availability of a “liquid biopsy” test like DETECT-A would inadvertently reduce patients’ use of standard screening and found that it did not. Mammography screening habits after receiving the baseline DETECT-A blood test did not differ significantly from those prior to study enrollment.
These findings are important because early detection is a key factor in reducing cancer-specific morbidity and mortality, and although minimally invasive screening tests, including liquid biopsies like DETECT-A, hold great promise, prospective clinical studies of these new methods are needed to ensure that the anticipated benefits outweigh the potential risks, Dr. Papadopoulos explained.
“The problem is that most cancers are detected at advanced stages when they are difficult to treat,” he said. “The earlier cancer is detected, the greater the chance of successful treatment.”
Unanswered questions and future studies
This study demonstrates that it is feasible for a minimally invasive blood test to safely detect multiple cancer types in patients without a history of cancer and to enable treatment with curative intent, at least in a subset of individuals, Dr. Papadopoulos said. He added that the findings also inform the design of future randomized trials “to establish clinical utility, cost-effectiveness, and benefit-to-risk ratio of future tests.”
Further studies will also be required to determine the clinical validity and utility of the strategy of using liquid biopsy as a complement to standard-of-care screening, Dr. Papadopoulos said.
Invited discussant David G. Huntsman, MD, of the University of British Columbia in Vancouver, applauded the investigators, saying this study serves to “move the field forward.” However, it still isn’t clear how sensitivity and negative predictive value will be determined and what the optimal testing schedule is.
“This is a prospective study that will provide the data on how this assay will be used [and] whether it should be used going forward,” Dr. Huntsman said, noting that the “much bigger and more important question” is whether it improves survival.
Cost-effectiveness will also be critical, he said.
This research was supported by The Marcus Foundation, Lustgarten Foundation for Pancreatic Cancer Research, The Virginia and D.K. Ludwig Fund for Cancer Research, The Sol Goldman Center for Pancreatic Cancer Research, Susan Wojcicki and Dennis Troper, the Rolfe Foundation, The Conrad R. Hilton Foundation, The John Templeton Foundation, Burroughs Wellcome Career Award For Medical Scientists, and grants/contracts from the National Institutes of Health.
Dr. Papadopoulos disclosed relationships with Thrive Earlier Detection Inc., PGDx Inc., NeoPhore, Cage Pharma, and other companies. Dr. Huntsman is a founder, shareholder, and chief medical officer for Contextual Genomics.
SOURCE: Papadopoulos N et al. AACR 2020, Abstract CT022; Lennon AM et al. Science. 2020 Apr 28. pii: eabb9601. doi: 10.1126/science.abb9601.
A minimally invasive multicancer blood test used with standard-of-care screening is safe, effective, and feasible for use in routine clinical care, according to interim findings from a large, prospective study.
The DETECT-A blood test, an early version of the CancerSEEK test currently in development, effectively guided patient management in real time, in some cases leading to diagnosis of early cancer and potentially curative surgery in asymptomatic women with no history of cancer.
Nickolas Papadopoulos, PhD, of Johns Hopkins Medicine in Baltimore, reported these findings at the AACR virtual meeting I. The findings were simultaneously published in Science.
The study enrolled 10,006 women, aged 65-75 years, with no prior cancer diagnosis. After exclusion and loss to follow-up, 9,911 women remained.
There were 26 patients who had cancer detected by the DETECT-A blood test, 15 of whom underwent follow-up PET-CT imaging and 9 of whom underwent surgical excision. An additional 24 cancers were detected by standard screening, and 46 were detected by other means.
The positive predictive value of the blood test was 19%. When the blood test was combined with imaging, the positive predictive value was 41%.
Improving upon standard screening
“Standard-of-care screening [was used] for three different organs: breast, lung, and colon. It was more sensitive for breast cancer,” Dr. Papadopoulos noted. “Blood testing, though, identified cancer in 10 different organs.”
In fact, the DETECT-A blood test detected 14 of 45 cancers in 7 organs for which no standard screening test is available.
In addition, 12 cancers in 3 organs (breast, lung, and colon) were first detected by DETECT-A rather than by standard screening. This increased the sensitivity of cancer detection from 47% with standard screening alone to 71% with standard screening plus blood testing.
“More important, 65% [of the cancers detected by blood test] were localized or regional, which have higher chance of successful treatment with intent to cure,” Dr. Papadopoulos said.
DETECT-A covers regions of 16 commonly mutated genes and 9 proteins known to be associated with cancer. In this study, 57% of cancers were detected by mutations.
Safety and additional screening
DETECT-A also proved safe, “without incurring a large number of futile invasive follow-up tests,” Dr. Papadopoulos said.
In fact, only 1% of patients without cancer underwent PET-CT imaging, and only 0.22% underwent a “futile” invasive follow-up procedure.
Three surgeries occurred in patients who were counted as false-positives, but the surgeries were determined to be indicated, Dr. Papadopoulos said. He explained that one was for large colonic polyps with high-grade dysplasia that could not be removed endoscopically, one was for an in situ carcinoma of the appendix, and one was for a 10-cm ovarian lesion that was found to be a mucinous cystadenoma.
The investigators also analyzed whether the availability of a “liquid biopsy” test like DETECT-A would inadvertently reduce patients’ use of standard screening and found that it did not. Mammography screening habits after receiving the baseline DETECT-A blood test did not differ significantly from those prior to study enrollment.
These findings are important because early detection is a key factor in reducing cancer-specific morbidity and mortality, and although minimally invasive screening tests, including liquid biopsies like DETECT-A, hold great promise, prospective clinical studies of these new methods are needed to ensure that the anticipated benefits outweigh the potential risks, Dr. Papadopoulos explained.
“The problem is that most cancers are detected at advanced stages when they are difficult to treat,” he said. “The earlier cancer is detected, the greater the chance of successful treatment.”
Unanswered questions and future studies
This study demonstrates that it is feasible for a minimally invasive blood test to safely detect multiple cancer types in patients without a history of cancer and to enable treatment with curative intent, at least in a subset of individuals, Dr. Papadopoulos said. He added that the findings also inform the design of future randomized trials “to establish clinical utility, cost-effectiveness, and benefit-to-risk ratio of future tests.”
Further studies will also be required to determine the clinical validity and utility of the strategy of using liquid biopsy as a complement to standard-of-care screening, Dr. Papadopoulos said.
Invited discussant David G. Huntsman, MD, of the University of British Columbia in Vancouver, applauded the investigators, saying this study serves to “move the field forward.” However, it still isn’t clear how sensitivity and negative predictive value will be determined and what the optimal testing schedule is.
“This is a prospective study that will provide the data on how this assay will be used [and] whether it should be used going forward,” Dr. Huntsman said, noting that the “much bigger and more important question” is whether it improves survival.
Cost-effectiveness will also be critical, he said.
This research was supported by The Marcus Foundation, Lustgarten Foundation for Pancreatic Cancer Research, The Virginia and D.K. Ludwig Fund for Cancer Research, The Sol Goldman Center for Pancreatic Cancer Research, Susan Wojcicki and Dennis Troper, the Rolfe Foundation, The Conrad R. Hilton Foundation, The John Templeton Foundation, Burroughs Wellcome Career Award For Medical Scientists, and grants/contracts from the National Institutes of Health.
Dr. Papadopoulos disclosed relationships with Thrive Earlier Detection Inc., PGDx Inc., NeoPhore, Cage Pharma, and other companies. Dr. Huntsman is a founder, shareholder, and chief medical officer for Contextual Genomics.
SOURCE: Papadopoulos N et al. AACR 2020, Abstract CT022; Lennon AM et al. Science. 2020 Apr 28. pii: eabb9601. doi: 10.1126/science.abb9601.
A minimally invasive multicancer blood test used with standard-of-care screening is safe, effective, and feasible for use in routine clinical care, according to interim findings from a large, prospective study.
The DETECT-A blood test, an early version of the CancerSEEK test currently in development, effectively guided patient management in real time, in some cases leading to diagnosis of early cancer and potentially curative surgery in asymptomatic women with no history of cancer.
Nickolas Papadopoulos, PhD, of Johns Hopkins Medicine in Baltimore, reported these findings at the AACR virtual meeting I. The findings were simultaneously published in Science.
The study enrolled 10,006 women, aged 65-75 years, with no prior cancer diagnosis. After exclusion and loss to follow-up, 9,911 women remained.
There were 26 patients who had cancer detected by the DETECT-A blood test, 15 of whom underwent follow-up PET-CT imaging and 9 of whom underwent surgical excision. An additional 24 cancers were detected by standard screening, and 46 were detected by other means.
The positive predictive value of the blood test was 19%. When the blood test was combined with imaging, the positive predictive value was 41%.
Improving upon standard screening
“Standard-of-care screening [was used] for three different organs: breast, lung, and colon. It was more sensitive for breast cancer,” Dr. Papadopoulos noted. “Blood testing, though, identified cancer in 10 different organs.”
In fact, the DETECT-A blood test detected 14 of 45 cancers in 7 organs for which no standard screening test is available.
In addition, 12 cancers in 3 organs (breast, lung, and colon) were first detected by DETECT-A rather than by standard screening. This increased the sensitivity of cancer detection from 47% with standard screening alone to 71% with standard screening plus blood testing.
“More important, 65% [of the cancers detected by blood test] were localized or regional, which have higher chance of successful treatment with intent to cure,” Dr. Papadopoulos said.
DETECT-A covers regions of 16 commonly mutated genes and 9 proteins known to be associated with cancer. In this study, 57% of cancers were detected by mutations.
Safety and additional screening
DETECT-A also proved safe, “without incurring a large number of futile invasive follow-up tests,” Dr. Papadopoulos said.
In fact, only 1% of patients without cancer underwent PET-CT imaging, and only 0.22% underwent a “futile” invasive follow-up procedure.
Three surgeries occurred in patients who were counted as false-positives, but the surgeries were determined to be indicated, Dr. Papadopoulos said. He explained that one was for large colonic polyps with high-grade dysplasia that could not be removed endoscopically, one was for an in situ carcinoma of the appendix, and one was for a 10-cm ovarian lesion that was found to be a mucinous cystadenoma.
The investigators also analyzed whether the availability of a “liquid biopsy” test like DETECT-A would inadvertently reduce patients’ use of standard screening and found that it did not. Mammography screening habits after receiving the baseline DETECT-A blood test did not differ significantly from those prior to study enrollment.
These findings are important because early detection is a key factor in reducing cancer-specific morbidity and mortality, and although minimally invasive screening tests, including liquid biopsies like DETECT-A, hold great promise, prospective clinical studies of these new methods are needed to ensure that the anticipated benefits outweigh the potential risks, Dr. Papadopoulos explained.
“The problem is that most cancers are detected at advanced stages when they are difficult to treat,” he said. “The earlier cancer is detected, the greater the chance of successful treatment.”
Unanswered questions and future studies
This study demonstrates that it is feasible for a minimally invasive blood test to safely detect multiple cancer types in patients without a history of cancer and to enable treatment with curative intent, at least in a subset of individuals, Dr. Papadopoulos said. He added that the findings also inform the design of future randomized trials “to establish clinical utility, cost-effectiveness, and benefit-to-risk ratio of future tests.”
Further studies will also be required to determine the clinical validity and utility of the strategy of using liquid biopsy as a complement to standard-of-care screening, Dr. Papadopoulos said.
Invited discussant David G. Huntsman, MD, of the University of British Columbia in Vancouver, applauded the investigators, saying this study serves to “move the field forward.” However, it still isn’t clear how sensitivity and negative predictive value will be determined and what the optimal testing schedule is.
“This is a prospective study that will provide the data on how this assay will be used [and] whether it should be used going forward,” Dr. Huntsman said, noting that the “much bigger and more important question” is whether it improves survival.
Cost-effectiveness will also be critical, he said.
This research was supported by The Marcus Foundation, Lustgarten Foundation for Pancreatic Cancer Research, The Virginia and D.K. Ludwig Fund for Cancer Research, The Sol Goldman Center for Pancreatic Cancer Research, Susan Wojcicki and Dennis Troper, the Rolfe Foundation, The Conrad R. Hilton Foundation, The John Templeton Foundation, Burroughs Wellcome Career Award For Medical Scientists, and grants/contracts from the National Institutes of Health.
Dr. Papadopoulos disclosed relationships with Thrive Earlier Detection Inc., PGDx Inc., NeoPhore, Cage Pharma, and other companies. Dr. Huntsman is a founder, shareholder, and chief medical officer for Contextual Genomics.
SOURCE: Papadopoulos N et al. AACR 2020, Abstract CT022; Lennon AM et al. Science. 2020 Apr 28. pii: eabb9601. doi: 10.1126/science.abb9601.
FROM AACR 2020
EMBRACA shows no overall survival benefit with talazoparib
Talazoparib did not confer an overall survival benefit over chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer, according to a final analysis of the phase 3 EMBRACA trial.
The progression-free survival benefit previously seen with talazoparib did not translate to an overall survival benefit. However, patient-reported quality of life continued to favor talazoparib in the final analysis, Jennifer K. Litton, MD, of the University of Texas MD Anderson Cancer Center in Houston, reported at the AACR virtual meeting I.
The EMBRACA trial enrolled adults with HER2-negative locally advanced or metastatic breast cancer and a deleterious or suspected deleterious germline BRCA mutation. They were randomized to talazoparib at 1 mg daily (n = 287) or to physician’s choice of single-agent chemotherapy (n = 144).
In the primary analysis, talazoparib was associated with significantly improved progression-free survival. The median progression-free survival was 8.6 months in the talazoparib arm and 5.6 months in the chemotherapy arm (hazard ratio, 0.54).
“At the time of the primary analysis, the overall survival data were immature, and the hazard ratio for the interim overall survival was 0.761, which was not statistically significant,” Dr. Litton said.
However, patient-reported outcomes favored talazoparib in the primary analysis, with patients in that arm showing “significant overall improvements with a significant delay in time to clinically meaningful deterioration in multiple cancer-related and breast cancer–specific symptoms, functions, quality of life, and global health,” Dr. Litton said.
Final overall survival
At the final analysis, the median follow-up was 44.9 months for the talazoparib arm and 36.8 months for the chemotherapy arm.
The median overall survival was 19.3 months in the talazoparib arm and 19.5 months in the chemotherapy arm (HR, 0.848; P = .17)
The results were “generally consistent” across patient subgroups,” Dr. Litton said, adding that “the effect of treatment with talazoparib was also similar irrespective of BRCA status, as well as triple-negative or hormone-receptor-positive subtypes.”
Of note, most patients received poststudy therapies. These included PARP inhibitors in 4.5% of patients in the talazoparib arm and 32.6% of patients in the chemotherapy arm, and platinum drugs in 46.3% and 41.7%, respectively.
Patients who received chemotherapy on study but did not receive a subsequent PARP inhibitor or platinum therapy had both shorter total treatment duration and shorter overall survival, compared with patients who did receive subsequent treatment.
In the talazoparib arm, outcomes were similar whether or not patients received a subsequent PARP inhibitor or platinum therapy.
“Interpretation of the overall survival results may have been confounded by subsequent treatment, so two sensitivity analyses accounting for subsequent PARP inhibition or platinum therapy were carried out,” Dr. Litton said.
She noted that adjustment for poststudy treatment lowered the hazard ratio, but there was still no significant difference between the talazoparib and chemotherapy arms. These results suggest “the primary overall survival analysis underestimated the treatment benefit of talazoparib,” Dr. Litton said. She also noted that a longer platinum-free interval prior to study entry was generally associated with a longer duration of survival, particularly in the talazoparib arm.
Quality of life and safety
Patient-reported outcomes continued to favor talazoparib with extended follow-up and were consistent with the initial analysis, Dr. Litton noted.
The updated analysis revealed “a significant improvement in estimated overall change from baseline in the global health quality of life scores for those patients receiving talazoparib, while a significant deterioration was observed in patients receiving chemotherapy,” she said.
The estimated overall change in score was a 2.1-point increase in the talazoparib arm and a 5.7-point decrease in the chemotherapy arm (P = .001). The median time to clinically meaningful deterioration in global health quality of life scores was 26.3 months in the talazoparib arm and 6.7 months in the chemotherapy arm (HR, 0.385).
At the final analysis, the overall safety profile was consistent with that reported previously. Talazoparib was generally well tolerated, and no new safety signals were identified.
Grade 3/4 serious adverse events occurred in 28.3% of patients in the talazoparib arm and 27% of those in the chemotherapy arm. Adverse events led to treatment discontinuation in 7.7% and 9.5% of patients, respectively.
Most grade 3/4 adverse events were hematologic, and most were successfully managed by supportive care, including transfusions and dose modifications, Dr. Litton said.
She noted that one patient in the chemotherapy arm assigned to receive capecitabine had been diagnosed with acute myeloid leukemia at the time of the first analysis. “And now we report an additional case of [acute myeloid leukemia] in a patient who was randomized to the talazoparib arm,” Dr. Litton said.
Jury’s still out
Based on existing data, including from EMBRACA, the jury is still out on whether PARP inhibition is associated with an overall survival benefit in this setting, said invited discussant Susan Domcheck, MD, of the University of Pennsylvania in Philadelphia.
She suggested that could change with ongoing efforts to identify biomarkers for treatment response and new approaches to treatment, such as earlier lines of therapy and combinations.
“At this time, germline BRCA 1 and 2 pathogenic variants are the best predictor of PARP inhibitor sensitivity in breast cancer,” Dr. Domcheck said. “Not all the tumors are sensitive, but this is true of [estrogen receptor–positive] breast cancer and hormonal therapy, and HER2-positive breast cancer as well.”
Studies investigating approaches to improve survival are “incredibly important, because the progression-free survival is not as long as we would like it to be and there’s not an overwhelming overall survival benefit, for sure,” she said.
The EMBRACA trial was funded by Medivation (Pfizer). Dr. Litton and colleagues disclosed numerous relationships with pharmaceutical companies and other organizations. Dr. Domcheck disclosed relationships with AstraZeneca, Clovis, and Bristol Myers Squibb.
SOURCE: Litton J et al., AACR 20, Abstract CT071.
Talazoparib did not confer an overall survival benefit over chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer, according to a final analysis of the phase 3 EMBRACA trial.
The progression-free survival benefit previously seen with talazoparib did not translate to an overall survival benefit. However, patient-reported quality of life continued to favor talazoparib in the final analysis, Jennifer K. Litton, MD, of the University of Texas MD Anderson Cancer Center in Houston, reported at the AACR virtual meeting I.
The EMBRACA trial enrolled adults with HER2-negative locally advanced or metastatic breast cancer and a deleterious or suspected deleterious germline BRCA mutation. They were randomized to talazoparib at 1 mg daily (n = 287) or to physician’s choice of single-agent chemotherapy (n = 144).
In the primary analysis, talazoparib was associated with significantly improved progression-free survival. The median progression-free survival was 8.6 months in the talazoparib arm and 5.6 months in the chemotherapy arm (hazard ratio, 0.54).
“At the time of the primary analysis, the overall survival data were immature, and the hazard ratio for the interim overall survival was 0.761, which was not statistically significant,” Dr. Litton said.
However, patient-reported outcomes favored talazoparib in the primary analysis, with patients in that arm showing “significant overall improvements with a significant delay in time to clinically meaningful deterioration in multiple cancer-related and breast cancer–specific symptoms, functions, quality of life, and global health,” Dr. Litton said.
Final overall survival
At the final analysis, the median follow-up was 44.9 months for the talazoparib arm and 36.8 months for the chemotherapy arm.
The median overall survival was 19.3 months in the talazoparib arm and 19.5 months in the chemotherapy arm (HR, 0.848; P = .17)
The results were “generally consistent” across patient subgroups,” Dr. Litton said, adding that “the effect of treatment with talazoparib was also similar irrespective of BRCA status, as well as triple-negative or hormone-receptor-positive subtypes.”
Of note, most patients received poststudy therapies. These included PARP inhibitors in 4.5% of patients in the talazoparib arm and 32.6% of patients in the chemotherapy arm, and platinum drugs in 46.3% and 41.7%, respectively.
Patients who received chemotherapy on study but did not receive a subsequent PARP inhibitor or platinum therapy had both shorter total treatment duration and shorter overall survival, compared with patients who did receive subsequent treatment.
In the talazoparib arm, outcomes were similar whether or not patients received a subsequent PARP inhibitor or platinum therapy.
“Interpretation of the overall survival results may have been confounded by subsequent treatment, so two sensitivity analyses accounting for subsequent PARP inhibition or platinum therapy were carried out,” Dr. Litton said.
She noted that adjustment for poststudy treatment lowered the hazard ratio, but there was still no significant difference between the talazoparib and chemotherapy arms. These results suggest “the primary overall survival analysis underestimated the treatment benefit of talazoparib,” Dr. Litton said. She also noted that a longer platinum-free interval prior to study entry was generally associated with a longer duration of survival, particularly in the talazoparib arm.
Quality of life and safety
Patient-reported outcomes continued to favor talazoparib with extended follow-up and were consistent with the initial analysis, Dr. Litton noted.
The updated analysis revealed “a significant improvement in estimated overall change from baseline in the global health quality of life scores for those patients receiving talazoparib, while a significant deterioration was observed in patients receiving chemotherapy,” she said.
The estimated overall change in score was a 2.1-point increase in the talazoparib arm and a 5.7-point decrease in the chemotherapy arm (P = .001). The median time to clinically meaningful deterioration in global health quality of life scores was 26.3 months in the talazoparib arm and 6.7 months in the chemotherapy arm (HR, 0.385).
At the final analysis, the overall safety profile was consistent with that reported previously. Talazoparib was generally well tolerated, and no new safety signals were identified.
Grade 3/4 serious adverse events occurred in 28.3% of patients in the talazoparib arm and 27% of those in the chemotherapy arm. Adverse events led to treatment discontinuation in 7.7% and 9.5% of patients, respectively.
Most grade 3/4 adverse events were hematologic, and most were successfully managed by supportive care, including transfusions and dose modifications, Dr. Litton said.
She noted that one patient in the chemotherapy arm assigned to receive capecitabine had been diagnosed with acute myeloid leukemia at the time of the first analysis. “And now we report an additional case of [acute myeloid leukemia] in a patient who was randomized to the talazoparib arm,” Dr. Litton said.
Jury’s still out
Based on existing data, including from EMBRACA, the jury is still out on whether PARP inhibition is associated with an overall survival benefit in this setting, said invited discussant Susan Domcheck, MD, of the University of Pennsylvania in Philadelphia.
She suggested that could change with ongoing efforts to identify biomarkers for treatment response and new approaches to treatment, such as earlier lines of therapy and combinations.
“At this time, germline BRCA 1 and 2 pathogenic variants are the best predictor of PARP inhibitor sensitivity in breast cancer,” Dr. Domcheck said. “Not all the tumors are sensitive, but this is true of [estrogen receptor–positive] breast cancer and hormonal therapy, and HER2-positive breast cancer as well.”
Studies investigating approaches to improve survival are “incredibly important, because the progression-free survival is not as long as we would like it to be and there’s not an overwhelming overall survival benefit, for sure,” she said.
The EMBRACA trial was funded by Medivation (Pfizer). Dr. Litton and colleagues disclosed numerous relationships with pharmaceutical companies and other organizations. Dr. Domcheck disclosed relationships with AstraZeneca, Clovis, and Bristol Myers Squibb.
SOURCE: Litton J et al., AACR 20, Abstract CT071.
Talazoparib did not confer an overall survival benefit over chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer, according to a final analysis of the phase 3 EMBRACA trial.
The progression-free survival benefit previously seen with talazoparib did not translate to an overall survival benefit. However, patient-reported quality of life continued to favor talazoparib in the final analysis, Jennifer K. Litton, MD, of the University of Texas MD Anderson Cancer Center in Houston, reported at the AACR virtual meeting I.
The EMBRACA trial enrolled adults with HER2-negative locally advanced or metastatic breast cancer and a deleterious or suspected deleterious germline BRCA mutation. They were randomized to talazoparib at 1 mg daily (n = 287) or to physician’s choice of single-agent chemotherapy (n = 144).
In the primary analysis, talazoparib was associated with significantly improved progression-free survival. The median progression-free survival was 8.6 months in the talazoparib arm and 5.6 months in the chemotherapy arm (hazard ratio, 0.54).
“At the time of the primary analysis, the overall survival data were immature, and the hazard ratio for the interim overall survival was 0.761, which was not statistically significant,” Dr. Litton said.
However, patient-reported outcomes favored talazoparib in the primary analysis, with patients in that arm showing “significant overall improvements with a significant delay in time to clinically meaningful deterioration in multiple cancer-related and breast cancer–specific symptoms, functions, quality of life, and global health,” Dr. Litton said.
Final overall survival
At the final analysis, the median follow-up was 44.9 months for the talazoparib arm and 36.8 months for the chemotherapy arm.
The median overall survival was 19.3 months in the talazoparib arm and 19.5 months in the chemotherapy arm (HR, 0.848; P = .17)
The results were “generally consistent” across patient subgroups,” Dr. Litton said, adding that “the effect of treatment with talazoparib was also similar irrespective of BRCA status, as well as triple-negative or hormone-receptor-positive subtypes.”
Of note, most patients received poststudy therapies. These included PARP inhibitors in 4.5% of patients in the talazoparib arm and 32.6% of patients in the chemotherapy arm, and platinum drugs in 46.3% and 41.7%, respectively.
Patients who received chemotherapy on study but did not receive a subsequent PARP inhibitor or platinum therapy had both shorter total treatment duration and shorter overall survival, compared with patients who did receive subsequent treatment.
In the talazoparib arm, outcomes were similar whether or not patients received a subsequent PARP inhibitor or platinum therapy.
“Interpretation of the overall survival results may have been confounded by subsequent treatment, so two sensitivity analyses accounting for subsequent PARP inhibition or platinum therapy were carried out,” Dr. Litton said.
She noted that adjustment for poststudy treatment lowered the hazard ratio, but there was still no significant difference between the talazoparib and chemotherapy arms. These results suggest “the primary overall survival analysis underestimated the treatment benefit of talazoparib,” Dr. Litton said. She also noted that a longer platinum-free interval prior to study entry was generally associated with a longer duration of survival, particularly in the talazoparib arm.
Quality of life and safety
Patient-reported outcomes continued to favor talazoparib with extended follow-up and were consistent with the initial analysis, Dr. Litton noted.
The updated analysis revealed “a significant improvement in estimated overall change from baseline in the global health quality of life scores for those patients receiving talazoparib, while a significant deterioration was observed in patients receiving chemotherapy,” she said.
The estimated overall change in score was a 2.1-point increase in the talazoparib arm and a 5.7-point decrease in the chemotherapy arm (P = .001). The median time to clinically meaningful deterioration in global health quality of life scores was 26.3 months in the talazoparib arm and 6.7 months in the chemotherapy arm (HR, 0.385).
At the final analysis, the overall safety profile was consistent with that reported previously. Talazoparib was generally well tolerated, and no new safety signals were identified.
Grade 3/4 serious adverse events occurred in 28.3% of patients in the talazoparib arm and 27% of those in the chemotherapy arm. Adverse events led to treatment discontinuation in 7.7% and 9.5% of patients, respectively.
Most grade 3/4 adverse events were hematologic, and most were successfully managed by supportive care, including transfusions and dose modifications, Dr. Litton said.
She noted that one patient in the chemotherapy arm assigned to receive capecitabine had been diagnosed with acute myeloid leukemia at the time of the first analysis. “And now we report an additional case of [acute myeloid leukemia] in a patient who was randomized to the talazoparib arm,” Dr. Litton said.
Jury’s still out
Based on existing data, including from EMBRACA, the jury is still out on whether PARP inhibition is associated with an overall survival benefit in this setting, said invited discussant Susan Domcheck, MD, of the University of Pennsylvania in Philadelphia.
She suggested that could change with ongoing efforts to identify biomarkers for treatment response and new approaches to treatment, such as earlier lines of therapy and combinations.
“At this time, germline BRCA 1 and 2 pathogenic variants are the best predictor of PARP inhibitor sensitivity in breast cancer,” Dr. Domcheck said. “Not all the tumors are sensitive, but this is true of [estrogen receptor–positive] breast cancer and hormonal therapy, and HER2-positive breast cancer as well.”
Studies investigating approaches to improve survival are “incredibly important, because the progression-free survival is not as long as we would like it to be and there’s not an overwhelming overall survival benefit, for sure,” she said.
The EMBRACA trial was funded by Medivation (Pfizer). Dr. Litton and colleagues disclosed numerous relationships with pharmaceutical companies and other organizations. Dr. Domcheck disclosed relationships with AstraZeneca, Clovis, and Bristol Myers Squibb.
SOURCE: Litton J et al., AACR 20, Abstract CT071.
FROM AACR 2020