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MRD-negative status signals better outcomes in CAR T–treated ALL
CHICAGO – Minimal residual disease (MRD)–negative complete remission was strongly associated with improved survival outcomes in patients with B-cell acute lymphocytic leukemia (ALL) who received CD19 chimeric antigen receptor (CAR) T cells, results of a retrospective study showed.
Allogeneic hematopoietic stem cell transplant (HSCT) appeared to improve both disease-free and overall survival in those patients who had achieved MRD-negative complete remission, according to results of the study, which were presented at the annual meeting of the American Society of Clinical Oncology.
“Based upon our interaction testing, the potential benefit [of transplant] appears to exist in both good-risk and bad-risk patients as identified through multivariate modeling,” said study investigator Kevin Anthony Hay, MD, of Fred Hutchinson Cancer Research Center, Seattle.
In a comment on the results, Sarah Cooley, MD, noted that the benefits of allogeneic transplant were apparent regardless of whether the patients met criteria for the good-risk subgroup, which was defined by levels of lactate dehydrogenase (LDH) and platelets along with exposure to fludarabine as part of the conditioning regimen.
“I think this suggests that the goal at this point is to get patients to an MRD-negative state and to potentially curative transplant,” said Dr. Cooley, director of investigator-initiated research at Masonic Medical Center at the University of Minnesota, Minneapolis.
The retrospective analysis by Dr. Hay and his colleagues included 53 adults with relapsed or refractory ALL who had bone marrow or extramedullary disease at baseline and had received CD19 CAR T cells at or under the maximum tolerated dose at least 1 year prior to this analysis. Of that group, 45 (85%) achieved MRD-negative complete remission.
Those patients who did achieve MRD-negative complete remission had an improved median disease-free survival at 7.6 months versus 0.8 months (P less than .0001) and improved overall survival at 20.0 months versus 5.0 months (P = 0.014).
Most of the MRD-negative patients who relapsed did so within the first 6 months, an observation that led investigators to consider whether factors exist that could predict better outcomes.
In a multivariate analysis, they found three variables associated with disease free survival: higher LDH prior to lymphodepletion (hazard ratio, 1.39), along with higher platelet count prior to lymphodepletion and incorporation of fludarabine into the regimen, with hazard ratios of 0.65 and 0.34, respectively.
Using those three characteristics, investigators grouped patients as “good risk” if they had normal LDH, platelet count at or above 100 prior to lymphodepletion that included fludarabine. The 24-month disease-free survival for good-risk patients was 78%, and overall survival was 86%.
The role of allogeneic HSCT after ALL patients achieved MRD-negative complete remission with CAR T-cell therapy was one of the “major questions in the field,” Dr. Hay said.
In this analysis, Dr. Hay and colleagues found that patients who underwent transplant in MRD-negative complete remission had a 24-month disease free survival and overall survival of 61% and 72%, respectively, both of which were significantly higher than in patients with MRD-negative complete remission who had no transplant.
The disease-free survival benefit was not specific to the good-risk group, according to Dr. Hay, who said an interaction test demonstrated no significant interaction between risk group and allogeneic HSCT after CAR T-cell infusion (P = 0.53).
“This is a very important finding that should be further [studied] in an appropriately designed clinical trial,” Dr. Hay said during an oral presentation of the study results.
Dr. Hay and several coauthors reported financial disclosures related to Juno Therapeutics. Other disclosures reported by study coauthors included Cell Medica, Celgene, Eureka Therapeutics, Genentech/Roche, Gilead Sciences, Kite Pharma, Novartis, and others.
SOURCE: Hay KA. ASCO 2018, Abstract 7005.
CHICAGO – Minimal residual disease (MRD)–negative complete remission was strongly associated with improved survival outcomes in patients with B-cell acute lymphocytic leukemia (ALL) who received CD19 chimeric antigen receptor (CAR) T cells, results of a retrospective study showed.
Allogeneic hematopoietic stem cell transplant (HSCT) appeared to improve both disease-free and overall survival in those patients who had achieved MRD-negative complete remission, according to results of the study, which were presented at the annual meeting of the American Society of Clinical Oncology.
“Based upon our interaction testing, the potential benefit [of transplant] appears to exist in both good-risk and bad-risk patients as identified through multivariate modeling,” said study investigator Kevin Anthony Hay, MD, of Fred Hutchinson Cancer Research Center, Seattle.
In a comment on the results, Sarah Cooley, MD, noted that the benefits of allogeneic transplant were apparent regardless of whether the patients met criteria for the good-risk subgroup, which was defined by levels of lactate dehydrogenase (LDH) and platelets along with exposure to fludarabine as part of the conditioning regimen.
“I think this suggests that the goal at this point is to get patients to an MRD-negative state and to potentially curative transplant,” said Dr. Cooley, director of investigator-initiated research at Masonic Medical Center at the University of Minnesota, Minneapolis.
The retrospective analysis by Dr. Hay and his colleagues included 53 adults with relapsed or refractory ALL who had bone marrow or extramedullary disease at baseline and had received CD19 CAR T cells at or under the maximum tolerated dose at least 1 year prior to this analysis. Of that group, 45 (85%) achieved MRD-negative complete remission.
Those patients who did achieve MRD-negative complete remission had an improved median disease-free survival at 7.6 months versus 0.8 months (P less than .0001) and improved overall survival at 20.0 months versus 5.0 months (P = 0.014).
Most of the MRD-negative patients who relapsed did so within the first 6 months, an observation that led investigators to consider whether factors exist that could predict better outcomes.
In a multivariate analysis, they found three variables associated with disease free survival: higher LDH prior to lymphodepletion (hazard ratio, 1.39), along with higher platelet count prior to lymphodepletion and incorporation of fludarabine into the regimen, with hazard ratios of 0.65 and 0.34, respectively.
Using those three characteristics, investigators grouped patients as “good risk” if they had normal LDH, platelet count at or above 100 prior to lymphodepletion that included fludarabine. The 24-month disease-free survival for good-risk patients was 78%, and overall survival was 86%.
The role of allogeneic HSCT after ALL patients achieved MRD-negative complete remission with CAR T-cell therapy was one of the “major questions in the field,” Dr. Hay said.
In this analysis, Dr. Hay and colleagues found that patients who underwent transplant in MRD-negative complete remission had a 24-month disease free survival and overall survival of 61% and 72%, respectively, both of which were significantly higher than in patients with MRD-negative complete remission who had no transplant.
The disease-free survival benefit was not specific to the good-risk group, according to Dr. Hay, who said an interaction test demonstrated no significant interaction between risk group and allogeneic HSCT after CAR T-cell infusion (P = 0.53).
“This is a very important finding that should be further [studied] in an appropriately designed clinical trial,” Dr. Hay said during an oral presentation of the study results.
Dr. Hay and several coauthors reported financial disclosures related to Juno Therapeutics. Other disclosures reported by study coauthors included Cell Medica, Celgene, Eureka Therapeutics, Genentech/Roche, Gilead Sciences, Kite Pharma, Novartis, and others.
SOURCE: Hay KA. ASCO 2018, Abstract 7005.
CHICAGO – Minimal residual disease (MRD)–negative complete remission was strongly associated with improved survival outcomes in patients with B-cell acute lymphocytic leukemia (ALL) who received CD19 chimeric antigen receptor (CAR) T cells, results of a retrospective study showed.
Allogeneic hematopoietic stem cell transplant (HSCT) appeared to improve both disease-free and overall survival in those patients who had achieved MRD-negative complete remission, according to results of the study, which were presented at the annual meeting of the American Society of Clinical Oncology.
“Based upon our interaction testing, the potential benefit [of transplant] appears to exist in both good-risk and bad-risk patients as identified through multivariate modeling,” said study investigator Kevin Anthony Hay, MD, of Fred Hutchinson Cancer Research Center, Seattle.
In a comment on the results, Sarah Cooley, MD, noted that the benefits of allogeneic transplant were apparent regardless of whether the patients met criteria for the good-risk subgroup, which was defined by levels of lactate dehydrogenase (LDH) and platelets along with exposure to fludarabine as part of the conditioning regimen.
“I think this suggests that the goal at this point is to get patients to an MRD-negative state and to potentially curative transplant,” said Dr. Cooley, director of investigator-initiated research at Masonic Medical Center at the University of Minnesota, Minneapolis.
The retrospective analysis by Dr. Hay and his colleagues included 53 adults with relapsed or refractory ALL who had bone marrow or extramedullary disease at baseline and had received CD19 CAR T cells at or under the maximum tolerated dose at least 1 year prior to this analysis. Of that group, 45 (85%) achieved MRD-negative complete remission.
Those patients who did achieve MRD-negative complete remission had an improved median disease-free survival at 7.6 months versus 0.8 months (P less than .0001) and improved overall survival at 20.0 months versus 5.0 months (P = 0.014).
Most of the MRD-negative patients who relapsed did so within the first 6 months, an observation that led investigators to consider whether factors exist that could predict better outcomes.
In a multivariate analysis, they found three variables associated with disease free survival: higher LDH prior to lymphodepletion (hazard ratio, 1.39), along with higher platelet count prior to lymphodepletion and incorporation of fludarabine into the regimen, with hazard ratios of 0.65 and 0.34, respectively.
Using those three characteristics, investigators grouped patients as “good risk” if they had normal LDH, platelet count at or above 100 prior to lymphodepletion that included fludarabine. The 24-month disease-free survival for good-risk patients was 78%, and overall survival was 86%.
The role of allogeneic HSCT after ALL patients achieved MRD-negative complete remission with CAR T-cell therapy was one of the “major questions in the field,” Dr. Hay said.
In this analysis, Dr. Hay and colleagues found that patients who underwent transplant in MRD-negative complete remission had a 24-month disease free survival and overall survival of 61% and 72%, respectively, both of which were significantly higher than in patients with MRD-negative complete remission who had no transplant.
The disease-free survival benefit was not specific to the good-risk group, according to Dr. Hay, who said an interaction test demonstrated no significant interaction between risk group and allogeneic HSCT after CAR T-cell infusion (P = 0.53).
“This is a very important finding that should be further [studied] in an appropriately designed clinical trial,” Dr. Hay said during an oral presentation of the study results.
Dr. Hay and several coauthors reported financial disclosures related to Juno Therapeutics. Other disclosures reported by study coauthors included Cell Medica, Celgene, Eureka Therapeutics, Genentech/Roche, Gilead Sciences, Kite Pharma, Novartis, and others.
SOURCE: Hay KA. ASCO 2018, Abstract 7005.
REPORTING FROM ASCO 2018
Key clinical point:
Major finding: Patients who achieved MRD-negative complete remission had an improved median disease-free survival at 7.6 months versus 0.8 months (P less than .0001)
Study details: A retrospective analysis including 53 patients with ALL who had bone marrow or extramedullary disease at baseline and had received CD19 CAR T cells at or under the maximum tolerated dose at least 1 year prior to this analysis.
Disclosures: Researchers reported financial ties to Juno Therapeutics, Cell Medica, Celgene, Eureka Therapeutics, Genentech/Roche, Gilead Sciences, Kite Pharma, Novartis, and others.
Source: Hay KA. ASCO 2018, Abstract 7005.
Metastatic lung cancer: Pembrolizumab plus chemo prolongs survival
, according to results from the phase 3 KEYNOTE-189 trial.
The researchers found that while patients in all subgroups benefited from the addition of pembrolizumab to chemotherapy, patients with a tumor proportion score of at least 50% benefited the most.
In 2017, accelerated approval was granted for pembrolizumab in combination with carboplatin and pemetrexed as first-line therapy for patients with NSCLC lacking EGFR and ALK mutations. This approval was based on response rates and progression-free survival from the KEYNOTE-024 phase 2 trial.
KEYNOTE-189 solidifies these findings, according to investigators. “Together with the results from KEYNOTE-024, the data from KEYNOTE-189 suggest that introducing immunotherapy as a first-line therapy may have a favorable long-term effect on outcomes,” wrote lead author Leena Gandhi, MD, director of the Perlmutter Cancer Center at New York University, and her colleagues. The report was published in the New England Journal of Medicine.
The double-blind, phase 3 trial assessed 616 treatment-naive patients with metastatic nonsquamous NSCLC without ALK or EGFR mutations. Patients received a platinum-based drug and pemetrexed plus placebo or 200 mg of pembrolizumab every 3 weeks for four cycles. After this, patients received placebo or pembrolizumab with pemetrexed maintenance therapy for up to 35 cycles. Primary endpoints were overall and progression-free survival, determined by a blinded radiologist.
At 12 months, the estimated overall survival was 69.2% for patients treated with pembrolizumab plus chemotherapy, compared with 49.4% for patients treated with chemotherapy alone. For patients treated with the pembrolizumab combination, median progression-free survival was 8.8 months, compared with 4.9 months for those treated with just chemotherapy. Median follow-up time was 10.5 months.
“The survival benefit associated with the pembrolizumab combination was observed in all subgroups of PD-L1 tumor proportion scores,” the authors wrote, “including patients with a score of less than 1%, a population for which single-agent PD-1 and PD-L1 inhibition have a small chance of benefit.” As with previous studies, the subgroup of patients with a tumor proportion score greater than or equal to 50% received the greatest benefit when pembrolizumab was added.
The authors noted that further research is needed to determine whether patients with high PD-L1 expression (TMS ≥ 50%) would benefit more from pembrolizumab combination therapy compared with pembrolizumab monotherapy, which is currently indicated.
SOURCE: Gandhi et al. N Engl J Med. 2018 May 31. doi: 10.1056/NEJMoa1801005.
The recent phase 3 KEYNOTE-189 trial by Gandhi and her colleagues solidifies a shift in first-line standard therapy for some lung cancer patients, according to Joan H. Schiller, MD.
“This trial illustrates that PD-1 pathway inhibitors can be successfully combined with chemotherapy,” Dr. Schiller wrote in an editorial in the New England Journal of Medicine.
In the study, patients treated with carboplatin-pemetrexed-pembrolizumab therapy had longer overall and progression-free survival compared with patients treated with just chemotherapy.
“The magnitude of benefit is impressive,” Dr. Schiller wrote, “with a hazard ratio for death of 0.49 and 12-month overall survival of 69.2% in the pembrolizumab-combination group.”
However, “many unanswered questions remain,” Dr. Schiller said, particularly concerning the utility of the commonly used PD-L1 tumor proportion score, which “appears to be problematic, with some randomized trials showing benefit only with a score of 50% or more and others showing benefit at other cutoff points, including less than 1%.”
In the current study, all subgroups benefited from the addition of pembrolizumab, including patients with a score of less than 1%.
Despite the need for more research, Dr. Schiller said she believes that existing findings have revealed unprecedented benefits. “Is carboplatin-pemetrexed-pembrolizumab now the first-line standard therapy for patients with nonsquamous NSCLC lacking targetable mutations? In my opinion, the answer is yes.”
Dr. Schiller is with the Inova Schar Cancer Institute. These comments are adapted from an editorial (N Eng J Med. 2018 May 31. doi: 10.1056/NEJMe1804364 ). The author reported financial support from Merck, Lily, AstraZeneca, Genentech/Roche, OncoGenex, Halozyme, Synta, Vertex, Bristol-Myers Squibb, Clovis, Xcovery, AbbVie, Astex, Janssen, and Free to Breathe.
The recent phase 3 KEYNOTE-189 trial by Gandhi and her colleagues solidifies a shift in first-line standard therapy for some lung cancer patients, according to Joan H. Schiller, MD.
“This trial illustrates that PD-1 pathway inhibitors can be successfully combined with chemotherapy,” Dr. Schiller wrote in an editorial in the New England Journal of Medicine.
In the study, patients treated with carboplatin-pemetrexed-pembrolizumab therapy had longer overall and progression-free survival compared with patients treated with just chemotherapy.
“The magnitude of benefit is impressive,” Dr. Schiller wrote, “with a hazard ratio for death of 0.49 and 12-month overall survival of 69.2% in the pembrolizumab-combination group.”
However, “many unanswered questions remain,” Dr. Schiller said, particularly concerning the utility of the commonly used PD-L1 tumor proportion score, which “appears to be problematic, with some randomized trials showing benefit only with a score of 50% or more and others showing benefit at other cutoff points, including less than 1%.”
In the current study, all subgroups benefited from the addition of pembrolizumab, including patients with a score of less than 1%.
Despite the need for more research, Dr. Schiller said she believes that existing findings have revealed unprecedented benefits. “Is carboplatin-pemetrexed-pembrolizumab now the first-line standard therapy for patients with nonsquamous NSCLC lacking targetable mutations? In my opinion, the answer is yes.”
Dr. Schiller is with the Inova Schar Cancer Institute. These comments are adapted from an editorial (N Eng J Med. 2018 May 31. doi: 10.1056/NEJMe1804364 ). The author reported financial support from Merck, Lily, AstraZeneca, Genentech/Roche, OncoGenex, Halozyme, Synta, Vertex, Bristol-Myers Squibb, Clovis, Xcovery, AbbVie, Astex, Janssen, and Free to Breathe.
The recent phase 3 KEYNOTE-189 trial by Gandhi and her colleagues solidifies a shift in first-line standard therapy for some lung cancer patients, according to Joan H. Schiller, MD.
“This trial illustrates that PD-1 pathway inhibitors can be successfully combined with chemotherapy,” Dr. Schiller wrote in an editorial in the New England Journal of Medicine.
In the study, patients treated with carboplatin-pemetrexed-pembrolizumab therapy had longer overall and progression-free survival compared with patients treated with just chemotherapy.
“The magnitude of benefit is impressive,” Dr. Schiller wrote, “with a hazard ratio for death of 0.49 and 12-month overall survival of 69.2% in the pembrolizumab-combination group.”
However, “many unanswered questions remain,” Dr. Schiller said, particularly concerning the utility of the commonly used PD-L1 tumor proportion score, which “appears to be problematic, with some randomized trials showing benefit only with a score of 50% or more and others showing benefit at other cutoff points, including less than 1%.”
In the current study, all subgroups benefited from the addition of pembrolizumab, including patients with a score of less than 1%.
Despite the need for more research, Dr. Schiller said she believes that existing findings have revealed unprecedented benefits. “Is carboplatin-pemetrexed-pembrolizumab now the first-line standard therapy for patients with nonsquamous NSCLC lacking targetable mutations? In my opinion, the answer is yes.”
Dr. Schiller is with the Inova Schar Cancer Institute. These comments are adapted from an editorial (N Eng J Med. 2018 May 31. doi: 10.1056/NEJMe1804364 ). The author reported financial support from Merck, Lily, AstraZeneca, Genentech/Roche, OncoGenex, Halozyme, Synta, Vertex, Bristol-Myers Squibb, Clovis, Xcovery, AbbVie, Astex, Janssen, and Free to Breathe.
, according to results from the phase 3 KEYNOTE-189 trial.
The researchers found that while patients in all subgroups benefited from the addition of pembrolizumab to chemotherapy, patients with a tumor proportion score of at least 50% benefited the most.
In 2017, accelerated approval was granted for pembrolizumab in combination with carboplatin and pemetrexed as first-line therapy for patients with NSCLC lacking EGFR and ALK mutations. This approval was based on response rates and progression-free survival from the KEYNOTE-024 phase 2 trial.
KEYNOTE-189 solidifies these findings, according to investigators. “Together with the results from KEYNOTE-024, the data from KEYNOTE-189 suggest that introducing immunotherapy as a first-line therapy may have a favorable long-term effect on outcomes,” wrote lead author Leena Gandhi, MD, director of the Perlmutter Cancer Center at New York University, and her colleagues. The report was published in the New England Journal of Medicine.
The double-blind, phase 3 trial assessed 616 treatment-naive patients with metastatic nonsquamous NSCLC without ALK or EGFR mutations. Patients received a platinum-based drug and pemetrexed plus placebo or 200 mg of pembrolizumab every 3 weeks for four cycles. After this, patients received placebo or pembrolizumab with pemetrexed maintenance therapy for up to 35 cycles. Primary endpoints were overall and progression-free survival, determined by a blinded radiologist.
At 12 months, the estimated overall survival was 69.2% for patients treated with pembrolizumab plus chemotherapy, compared with 49.4% for patients treated with chemotherapy alone. For patients treated with the pembrolizumab combination, median progression-free survival was 8.8 months, compared with 4.9 months for those treated with just chemotherapy. Median follow-up time was 10.5 months.
“The survival benefit associated with the pembrolizumab combination was observed in all subgroups of PD-L1 tumor proportion scores,” the authors wrote, “including patients with a score of less than 1%, a population for which single-agent PD-1 and PD-L1 inhibition have a small chance of benefit.” As with previous studies, the subgroup of patients with a tumor proportion score greater than or equal to 50% received the greatest benefit when pembrolizumab was added.
The authors noted that further research is needed to determine whether patients with high PD-L1 expression (TMS ≥ 50%) would benefit more from pembrolizumab combination therapy compared with pembrolizumab monotherapy, which is currently indicated.
SOURCE: Gandhi et al. N Engl J Med. 2018 May 31. doi: 10.1056/NEJMoa1801005.
, according to results from the phase 3 KEYNOTE-189 trial.
The researchers found that while patients in all subgroups benefited from the addition of pembrolizumab to chemotherapy, patients with a tumor proportion score of at least 50% benefited the most.
In 2017, accelerated approval was granted for pembrolizumab in combination with carboplatin and pemetrexed as first-line therapy for patients with NSCLC lacking EGFR and ALK mutations. This approval was based on response rates and progression-free survival from the KEYNOTE-024 phase 2 trial.
KEYNOTE-189 solidifies these findings, according to investigators. “Together with the results from KEYNOTE-024, the data from KEYNOTE-189 suggest that introducing immunotherapy as a first-line therapy may have a favorable long-term effect on outcomes,” wrote lead author Leena Gandhi, MD, director of the Perlmutter Cancer Center at New York University, and her colleagues. The report was published in the New England Journal of Medicine.
The double-blind, phase 3 trial assessed 616 treatment-naive patients with metastatic nonsquamous NSCLC without ALK or EGFR mutations. Patients received a platinum-based drug and pemetrexed plus placebo or 200 mg of pembrolizumab every 3 weeks for four cycles. After this, patients received placebo or pembrolizumab with pemetrexed maintenance therapy for up to 35 cycles. Primary endpoints were overall and progression-free survival, determined by a blinded radiologist.
At 12 months, the estimated overall survival was 69.2% for patients treated with pembrolizumab plus chemotherapy, compared with 49.4% for patients treated with chemotherapy alone. For patients treated with the pembrolizumab combination, median progression-free survival was 8.8 months, compared with 4.9 months for those treated with just chemotherapy. Median follow-up time was 10.5 months.
“The survival benefit associated with the pembrolizumab combination was observed in all subgroups of PD-L1 tumor proportion scores,” the authors wrote, “including patients with a score of less than 1%, a population for which single-agent PD-1 and PD-L1 inhibition have a small chance of benefit.” As with previous studies, the subgroup of patients with a tumor proportion score greater than or equal to 50% received the greatest benefit when pembrolizumab was added.
The authors noted that further research is needed to determine whether patients with high PD-L1 expression (TMS ≥ 50%) would benefit more from pembrolizumab combination therapy compared with pembrolizumab monotherapy, which is currently indicated.
SOURCE: Gandhi et al. N Engl J Med. 2018 May 31. doi: 10.1056/NEJMoa1801005.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: In patients with advanced NSCLC without targetable mutations, the addition of pembrolizumab to standard combination chemotherapy improves overall survival and progression-free survival.
Major finding: The estimated rate of overall survival at 12 months in patients treated with pembrolizumab-combination therapy was 69.2% (95% CI, 64.1-73.8) compared with 49.4% (95% CI, 42.1-56.2) in patients treated with placebo-combination therapy.
Study details: A double-blind, phase 3 trial of 616 patients with metastatic NSCLC lacking ALK or EGFR mutations (KEYNOTE-189).
Disclosures: Merck sponsored the study. Researchers reported financial support from Genentech/Roche, Pfizer, Ignyta, AbbVie, Eli Lilly, and other companies.
Source: Gandhi et al. N Engl J Med. 2018 May 31. doi: 10.1056/NEJMoa1801005.
Pembrolizumab monotherapy shows activity in advanced recurrent ovarian cancer
CHICAGO – Pembrolizumab monotherapy is associated with antitumor activity in patients with advanced recurrent ovarian cancer, interim results from the phase 2 KEYNOTE-100 study suggest.
Notably, objective response rates among study subjects increased in tandem with increased programmed death-ligand 1 (PD-L1) expression, which helps define the population most likely to benefit from single agent pembrolizumab (Keytruda), Ursula A. Matulonis reported during an oral abstract session at the annual meeting of the American Society of Clinical Oncology.
Further, no new safety signals were identified, said Dr. Matulonis, medical director and program leader of the Medical Gynecologic Oncology Program at of Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston.
All patients received intravenous pembrolizumab at 200 mg every 3 weeks for 2 years or until progression, death, unacceptable toxicity, or consent withdrawal, and tumor imaging was performed every 9 weeks for a year, then every 12 weeks thereafter until progressive disease, death, or study completion.
The overall response rate (ORR) among 285 patients in Cohort A, who had one to three prior chemotherapy lines for recurrent advanced ovarian cancer and a platinum-free or treatment-free interval of 3-12 months, was 7.4%, with mean duration of response of 8.2 months. The ORR among 91 patients in Cohort B, who had four to six prior chemotherapy lines and a platinum-free or treatment-free interval of at least 3 months, was 9.9%; the mean duration of response was not reached in Cohort B.
Among all-comers, the ORR was 8.0%, including 7 complete responses and 23 partial responses. Mean duration of response was 8.2 months, and 65.5% of responses lasted at least 6 months. Further, responses were observed across all subgroups, Dr. Matulonis said, noting that responses were seen regardless of age, prior lines of treatment, progression-free/treatment-free interval duration, platinum sensitivity, and histology.
“The one factor that did predict response was a [combined positive score] of 10 or higher, where there were more responses,” she said.
The ORRs among those with PD-L1 expression as measured using the combined positive score (CPS), which is defined as the number of PD-L1–positive cells out of the total number of tumor cells x 100, was 5.0% in those with CPS less than 1, 10.2% in those with CPS of 1 or greater, and 17.1% in those with CPS of 10 or greater (vs. the 8.0% ORR in the study), she explained, noting that all complete responses occurred in those with CPS of 10 or higher.
Grade 3-4 treatment-related adverse events occurred in 19.7% of patients, and included fatigue in 2.7%, and anemia, colitis, increased amylase, increased blood alkaline phosphatase, ascites, and diarrhea in 0.8-1.3%. One treatment-related death occurred in a patient with Stevens-Johnson syndrome, and another occurred in a patient with hypoaldosteronism. Immune-mediated adverse events and infusion reactions were most commonly hyperthyroidism and hypothyroidism, and most cases were grade 1-2, she said.
KEYNOTE-100 is an ongoing study that followed KEYNOTE-028, which demonstrated the clinical activity of pembrolizumab in patients with advanced ovarian cancer. To date, KEYNOTE-100 has enrolled 376 patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer and confirmed recurrence after frontline platinum-based therapy. All had a tumor sample available for biomarker analysis.
The patients had a mean age of 61 years, 64% and 35% had performance status scores of 0 and 1, respectively, and 75% had high-grade serous disease.
Median follow-up in Cohort A at the time of the current analysis was 16.7 months, and in Cohort B, the median follow-up was 17.3 months. Treatment was ongoing in 15 and 6 patients in the cohorts, respectively. Reasons for discontinuation included radiographic progression (204 and 62 patients), clinical progression (24 and 17 patients), adverse events (22 and 3 patients), and patient withdrawal (9 and 3 patients). Complete responses occurred in 1 and 0 patients in the groups, respectively.
Median progression-free survival in both cohorts was 2.1 months, and overall survival was not reached in Cohort A, while it was 17.6 months in the more heavily pretreated Cohort B.
“Recurrent ovarian cancer is the leading cause of death from gynecologic cancer. The majority of our patients relapse after first-line platinum and taxane-based chemotherapy, and the degree of platinum sensitivity will predict the tumor response rates with platinum, as well as survival time,” she said, noting that subsequent recurrences become increasingly platinum and treatment resistant.
Current treatment options in these patients include chemotherapy with or without bevacizumab; the ORRs with single-agent immune checkpoint blockade are about 10%, but in KEYNOTE-028, patients with PD-L1–positive advanced recurrent ovarian cancer had an ORR of 11.5% with pembrolizumab treatment, she said.
“With 16.9 months median follow-up, the results confirm that pembrolizumab monotherapy in recurrent ovarian cancer elicits modest antitumor efficacy,” Dr. Matulonis concluded, noting that further analysis for biomarkers predictive of pembrolizumab response are ongoing.
Invited discussant Janos Laszlo Tanyi, MD, of the University of Pennsylvania, Philadelphia, said the findings underscore the overall modest ORRs of 5.9%-15% seen with anti-PD-1 or PD-L1 monotherapy in patients with advanced recurrent ovarian cancer, but noted the importance of the finding that the subpopulation of patients with increased PD-L1 expression may experience greater benefit.
Dr. Matulonis reported consulting or advisory roles with 2X Oncology, Clovis Oncology, Fujifilm, Geneos Therapeutics, Lilly, Merck, and Myriad Genetics, and research funding from Merck and Novartis. Dr .Tanyi reported having no disclosures.
SOURCE: Matulonis UA et al. ASCO 2018, Abstract 5511.
CHICAGO – Pembrolizumab monotherapy is associated with antitumor activity in patients with advanced recurrent ovarian cancer, interim results from the phase 2 KEYNOTE-100 study suggest.
Notably, objective response rates among study subjects increased in tandem with increased programmed death-ligand 1 (PD-L1) expression, which helps define the population most likely to benefit from single agent pembrolizumab (Keytruda), Ursula A. Matulonis reported during an oral abstract session at the annual meeting of the American Society of Clinical Oncology.
Further, no new safety signals were identified, said Dr. Matulonis, medical director and program leader of the Medical Gynecologic Oncology Program at of Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston.
All patients received intravenous pembrolizumab at 200 mg every 3 weeks for 2 years or until progression, death, unacceptable toxicity, or consent withdrawal, and tumor imaging was performed every 9 weeks for a year, then every 12 weeks thereafter until progressive disease, death, or study completion.
The overall response rate (ORR) among 285 patients in Cohort A, who had one to three prior chemotherapy lines for recurrent advanced ovarian cancer and a platinum-free or treatment-free interval of 3-12 months, was 7.4%, with mean duration of response of 8.2 months. The ORR among 91 patients in Cohort B, who had four to six prior chemotherapy lines and a platinum-free or treatment-free interval of at least 3 months, was 9.9%; the mean duration of response was not reached in Cohort B.
Among all-comers, the ORR was 8.0%, including 7 complete responses and 23 partial responses. Mean duration of response was 8.2 months, and 65.5% of responses lasted at least 6 months. Further, responses were observed across all subgroups, Dr. Matulonis said, noting that responses were seen regardless of age, prior lines of treatment, progression-free/treatment-free interval duration, platinum sensitivity, and histology.
“The one factor that did predict response was a [combined positive score] of 10 or higher, where there were more responses,” she said.
The ORRs among those with PD-L1 expression as measured using the combined positive score (CPS), which is defined as the number of PD-L1–positive cells out of the total number of tumor cells x 100, was 5.0% in those with CPS less than 1, 10.2% in those with CPS of 1 or greater, and 17.1% in those with CPS of 10 or greater (vs. the 8.0% ORR in the study), she explained, noting that all complete responses occurred in those with CPS of 10 or higher.
Grade 3-4 treatment-related adverse events occurred in 19.7% of patients, and included fatigue in 2.7%, and anemia, colitis, increased amylase, increased blood alkaline phosphatase, ascites, and diarrhea in 0.8-1.3%. One treatment-related death occurred in a patient with Stevens-Johnson syndrome, and another occurred in a patient with hypoaldosteronism. Immune-mediated adverse events and infusion reactions were most commonly hyperthyroidism and hypothyroidism, and most cases were grade 1-2, she said.
KEYNOTE-100 is an ongoing study that followed KEYNOTE-028, which demonstrated the clinical activity of pembrolizumab in patients with advanced ovarian cancer. To date, KEYNOTE-100 has enrolled 376 patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer and confirmed recurrence after frontline platinum-based therapy. All had a tumor sample available for biomarker analysis.
The patients had a mean age of 61 years, 64% and 35% had performance status scores of 0 and 1, respectively, and 75% had high-grade serous disease.
Median follow-up in Cohort A at the time of the current analysis was 16.7 months, and in Cohort B, the median follow-up was 17.3 months. Treatment was ongoing in 15 and 6 patients in the cohorts, respectively. Reasons for discontinuation included radiographic progression (204 and 62 patients), clinical progression (24 and 17 patients), adverse events (22 and 3 patients), and patient withdrawal (9 and 3 patients). Complete responses occurred in 1 and 0 patients in the groups, respectively.
Median progression-free survival in both cohorts was 2.1 months, and overall survival was not reached in Cohort A, while it was 17.6 months in the more heavily pretreated Cohort B.
“Recurrent ovarian cancer is the leading cause of death from gynecologic cancer. The majority of our patients relapse after first-line platinum and taxane-based chemotherapy, and the degree of platinum sensitivity will predict the tumor response rates with platinum, as well as survival time,” she said, noting that subsequent recurrences become increasingly platinum and treatment resistant.
Current treatment options in these patients include chemotherapy with or without bevacizumab; the ORRs with single-agent immune checkpoint blockade are about 10%, but in KEYNOTE-028, patients with PD-L1–positive advanced recurrent ovarian cancer had an ORR of 11.5% with pembrolizumab treatment, she said.
“With 16.9 months median follow-up, the results confirm that pembrolizumab monotherapy in recurrent ovarian cancer elicits modest antitumor efficacy,” Dr. Matulonis concluded, noting that further analysis for biomarkers predictive of pembrolizumab response are ongoing.
Invited discussant Janos Laszlo Tanyi, MD, of the University of Pennsylvania, Philadelphia, said the findings underscore the overall modest ORRs of 5.9%-15% seen with anti-PD-1 or PD-L1 monotherapy in patients with advanced recurrent ovarian cancer, but noted the importance of the finding that the subpopulation of patients with increased PD-L1 expression may experience greater benefit.
Dr. Matulonis reported consulting or advisory roles with 2X Oncology, Clovis Oncology, Fujifilm, Geneos Therapeutics, Lilly, Merck, and Myriad Genetics, and research funding from Merck and Novartis. Dr .Tanyi reported having no disclosures.
SOURCE: Matulonis UA et al. ASCO 2018, Abstract 5511.
CHICAGO – Pembrolizumab monotherapy is associated with antitumor activity in patients with advanced recurrent ovarian cancer, interim results from the phase 2 KEYNOTE-100 study suggest.
Notably, objective response rates among study subjects increased in tandem with increased programmed death-ligand 1 (PD-L1) expression, which helps define the population most likely to benefit from single agent pembrolizumab (Keytruda), Ursula A. Matulonis reported during an oral abstract session at the annual meeting of the American Society of Clinical Oncology.
Further, no new safety signals were identified, said Dr. Matulonis, medical director and program leader of the Medical Gynecologic Oncology Program at of Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston.
All patients received intravenous pembrolizumab at 200 mg every 3 weeks for 2 years or until progression, death, unacceptable toxicity, or consent withdrawal, and tumor imaging was performed every 9 weeks for a year, then every 12 weeks thereafter until progressive disease, death, or study completion.
The overall response rate (ORR) among 285 patients in Cohort A, who had one to three prior chemotherapy lines for recurrent advanced ovarian cancer and a platinum-free or treatment-free interval of 3-12 months, was 7.4%, with mean duration of response of 8.2 months. The ORR among 91 patients in Cohort B, who had four to six prior chemotherapy lines and a platinum-free or treatment-free interval of at least 3 months, was 9.9%; the mean duration of response was not reached in Cohort B.
Among all-comers, the ORR was 8.0%, including 7 complete responses and 23 partial responses. Mean duration of response was 8.2 months, and 65.5% of responses lasted at least 6 months. Further, responses were observed across all subgroups, Dr. Matulonis said, noting that responses were seen regardless of age, prior lines of treatment, progression-free/treatment-free interval duration, platinum sensitivity, and histology.
“The one factor that did predict response was a [combined positive score] of 10 or higher, where there were more responses,” she said.
The ORRs among those with PD-L1 expression as measured using the combined positive score (CPS), which is defined as the number of PD-L1–positive cells out of the total number of tumor cells x 100, was 5.0% in those with CPS less than 1, 10.2% in those with CPS of 1 or greater, and 17.1% in those with CPS of 10 or greater (vs. the 8.0% ORR in the study), she explained, noting that all complete responses occurred in those with CPS of 10 or higher.
Grade 3-4 treatment-related adverse events occurred in 19.7% of patients, and included fatigue in 2.7%, and anemia, colitis, increased amylase, increased blood alkaline phosphatase, ascites, and diarrhea in 0.8-1.3%. One treatment-related death occurred in a patient with Stevens-Johnson syndrome, and another occurred in a patient with hypoaldosteronism. Immune-mediated adverse events and infusion reactions were most commonly hyperthyroidism and hypothyroidism, and most cases were grade 1-2, she said.
KEYNOTE-100 is an ongoing study that followed KEYNOTE-028, which demonstrated the clinical activity of pembrolizumab in patients with advanced ovarian cancer. To date, KEYNOTE-100 has enrolled 376 patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer and confirmed recurrence after frontline platinum-based therapy. All had a tumor sample available for biomarker analysis.
The patients had a mean age of 61 years, 64% and 35% had performance status scores of 0 and 1, respectively, and 75% had high-grade serous disease.
Median follow-up in Cohort A at the time of the current analysis was 16.7 months, and in Cohort B, the median follow-up was 17.3 months. Treatment was ongoing in 15 and 6 patients in the cohorts, respectively. Reasons for discontinuation included radiographic progression (204 and 62 patients), clinical progression (24 and 17 patients), adverse events (22 and 3 patients), and patient withdrawal (9 and 3 patients). Complete responses occurred in 1 and 0 patients in the groups, respectively.
Median progression-free survival in both cohorts was 2.1 months, and overall survival was not reached in Cohort A, while it was 17.6 months in the more heavily pretreated Cohort B.
“Recurrent ovarian cancer is the leading cause of death from gynecologic cancer. The majority of our patients relapse after first-line platinum and taxane-based chemotherapy, and the degree of platinum sensitivity will predict the tumor response rates with platinum, as well as survival time,” she said, noting that subsequent recurrences become increasingly platinum and treatment resistant.
Current treatment options in these patients include chemotherapy with or without bevacizumab; the ORRs with single-agent immune checkpoint blockade are about 10%, but in KEYNOTE-028, patients with PD-L1–positive advanced recurrent ovarian cancer had an ORR of 11.5% with pembrolizumab treatment, she said.
“With 16.9 months median follow-up, the results confirm that pembrolizumab monotherapy in recurrent ovarian cancer elicits modest antitumor efficacy,” Dr. Matulonis concluded, noting that further analysis for biomarkers predictive of pembrolizumab response are ongoing.
Invited discussant Janos Laszlo Tanyi, MD, of the University of Pennsylvania, Philadelphia, said the findings underscore the overall modest ORRs of 5.9%-15% seen with anti-PD-1 or PD-L1 monotherapy in patients with advanced recurrent ovarian cancer, but noted the importance of the finding that the subpopulation of patients with increased PD-L1 expression may experience greater benefit.
Dr. Matulonis reported consulting or advisory roles with 2X Oncology, Clovis Oncology, Fujifilm, Geneos Therapeutics, Lilly, Merck, and Myriad Genetics, and research funding from Merck and Novartis. Dr .Tanyi reported having no disclosures.
SOURCE: Matulonis UA et al. ASCO 2018, Abstract 5511.
REPORTING FROM ASCO 2018
Key clinical point: Pembrolizumab monotherapy shows antitumor activity in advanced recurrent OC, particularly in those with higher PD-L1 expression.
Major finding: Overall response rates: 8.0% overall, 5.0% with CPS up to 1, 10.2% with CPS of 1+, and 17.1% with CPS of 10+.
Study details: Interim findings from the 376-patient phase 2 KEYNOTE-100 study.
Disclosures: Dr. Matulonis reported consulting or advisory roles with 2X Oncology, Clovis Oncology, Fujifilm, Geneos Therapeutics, Lilly, Merck, and Myriad Genetics, and research funding from Merck and Novartis. Dr. Tanyi reported having no disclosures.
Source: Matulonis UA et al. ASCO 2018, Abstract 5511.
Checkpoint inhibitors well tolerated by NSCLC patients with preexisting autoimmune disease
For patients with non–small-cell lung cancer (NSCLC), preexisting autoimmune disease (AID) does not increase the risk of immune-related adverse events (irAEs) with checkpoint inhibitor therapy, according to investigators.
Flares of AID during therapy were generally mild, and toxicity rates were only slightly increased in patients with AID, they wrote in Journal of Clinical Oncology.
Approximately 14%-25% of patients with lung cancer also have AID, but patients with AID are typically excluded from clinical trials. “This presents a tremendous knowledge gap,” wrote lead author Giulia C. Leonardi, MD, of the Dana-Farber Cancer Institute in Boston, and coauthors.
The retrospective study comprised 56 patients with NSCLC and preexisting autoimmune disease from five academic cancer centers. Almost half of the patients had a rheumatologic disorder, 29% had a dermatologic disorder, 16% had an endocrine disorder, 11% had inflammatory bowel disease, 5% had a neurologic condition, 3% had rheumatic fever, and one patient (2%) had autoimmune hemolytic anemia.
Patients received either a programmed death-1 or programmed death-ligand 1 inhibitor as monotherapy. Median treatment time was 3.1 months, and median follow-up time after starting therapy was 17.5 months.
Eleven percent of patients with preexisting AID developed grade 3 or 4 irAEs, which is similar to 7%-15% of patients in clinical trials. Although 23% of patients experienced a flare of their preexisting AID, these flares were generally mild – no patients discontinued immunotherapy because of a flare. In contrast, 14% of patients halted therapy because of toxicity, a marginally higher number than 3%-8% of patients in trials.
Checkpoint inhibitors are now a mainstay treatment for a lung cancer, including three approved drugs: nivolumab, pembrolizumab, and atezolizumab. “Almost every patient with advanced NSCLC will likely receive a [checkpoint] inhibitor at some point over the course of their disease,” the authors noted. As checkpoint inhibitors may lead to fatal irAEs, the possible interplay between these immunotherapies and AID requires investigation.
“Our study adds to the growing body of evidence supporting the use of immunotherapy in patients with cancer with preexisting AID, albeit with close monitoring for adverse events,” the researchers concluded.
SOURCE: Leonardi GC et al. J Clin Oncol. 2018* May 20. doi: 10.1200/JCO.2017.77.0305.
*Correction, 5/22/18: An earlier version of this article misstated the year in this citation.
For patients with non–small-cell lung cancer (NSCLC), preexisting autoimmune disease (AID) does not increase the risk of immune-related adverse events (irAEs) with checkpoint inhibitor therapy, according to investigators.
Flares of AID during therapy were generally mild, and toxicity rates were only slightly increased in patients with AID, they wrote in Journal of Clinical Oncology.
Approximately 14%-25% of patients with lung cancer also have AID, but patients with AID are typically excluded from clinical trials. “This presents a tremendous knowledge gap,” wrote lead author Giulia C. Leonardi, MD, of the Dana-Farber Cancer Institute in Boston, and coauthors.
The retrospective study comprised 56 patients with NSCLC and preexisting autoimmune disease from five academic cancer centers. Almost half of the patients had a rheumatologic disorder, 29% had a dermatologic disorder, 16% had an endocrine disorder, 11% had inflammatory bowel disease, 5% had a neurologic condition, 3% had rheumatic fever, and one patient (2%) had autoimmune hemolytic anemia.
Patients received either a programmed death-1 or programmed death-ligand 1 inhibitor as monotherapy. Median treatment time was 3.1 months, and median follow-up time after starting therapy was 17.5 months.
Eleven percent of patients with preexisting AID developed grade 3 or 4 irAEs, which is similar to 7%-15% of patients in clinical trials. Although 23% of patients experienced a flare of their preexisting AID, these flares were generally mild – no patients discontinued immunotherapy because of a flare. In contrast, 14% of patients halted therapy because of toxicity, a marginally higher number than 3%-8% of patients in trials.
Checkpoint inhibitors are now a mainstay treatment for a lung cancer, including three approved drugs: nivolumab, pembrolizumab, and atezolizumab. “Almost every patient with advanced NSCLC will likely receive a [checkpoint] inhibitor at some point over the course of their disease,” the authors noted. As checkpoint inhibitors may lead to fatal irAEs, the possible interplay between these immunotherapies and AID requires investigation.
“Our study adds to the growing body of evidence supporting the use of immunotherapy in patients with cancer with preexisting AID, albeit with close monitoring for adverse events,” the researchers concluded.
SOURCE: Leonardi GC et al. J Clin Oncol. 2018* May 20. doi: 10.1200/JCO.2017.77.0305.
*Correction, 5/22/18: An earlier version of this article misstated the year in this citation.
For patients with non–small-cell lung cancer (NSCLC), preexisting autoimmune disease (AID) does not increase the risk of immune-related adverse events (irAEs) with checkpoint inhibitor therapy, according to investigators.
Flares of AID during therapy were generally mild, and toxicity rates were only slightly increased in patients with AID, they wrote in Journal of Clinical Oncology.
Approximately 14%-25% of patients with lung cancer also have AID, but patients with AID are typically excluded from clinical trials. “This presents a tremendous knowledge gap,” wrote lead author Giulia C. Leonardi, MD, of the Dana-Farber Cancer Institute in Boston, and coauthors.
The retrospective study comprised 56 patients with NSCLC and preexisting autoimmune disease from five academic cancer centers. Almost half of the patients had a rheumatologic disorder, 29% had a dermatologic disorder, 16% had an endocrine disorder, 11% had inflammatory bowel disease, 5% had a neurologic condition, 3% had rheumatic fever, and one patient (2%) had autoimmune hemolytic anemia.
Patients received either a programmed death-1 or programmed death-ligand 1 inhibitor as monotherapy. Median treatment time was 3.1 months, and median follow-up time after starting therapy was 17.5 months.
Eleven percent of patients with preexisting AID developed grade 3 or 4 irAEs, which is similar to 7%-15% of patients in clinical trials. Although 23% of patients experienced a flare of their preexisting AID, these flares were generally mild – no patients discontinued immunotherapy because of a flare. In contrast, 14% of patients halted therapy because of toxicity, a marginally higher number than 3%-8% of patients in trials.
Checkpoint inhibitors are now a mainstay treatment for a lung cancer, including three approved drugs: nivolumab, pembrolizumab, and atezolizumab. “Almost every patient with advanced NSCLC will likely receive a [checkpoint] inhibitor at some point over the course of their disease,” the authors noted. As checkpoint inhibitors may lead to fatal irAEs, the possible interplay between these immunotherapies and AID requires investigation.
“Our study adds to the growing body of evidence supporting the use of immunotherapy in patients with cancer with preexisting AID, albeit with close monitoring for adverse events,” the researchers concluded.
SOURCE: Leonardi GC et al. J Clin Oncol. 2018* May 20. doi: 10.1200/JCO.2017.77.0305.
*Correction, 5/22/18: An earlier version of this article misstated the year in this citation.
FROM JOURNAL OF CLINICAL ONCOLOGY
Key clinical point:
Major finding: Eleven percent of patients with autoimmune disease experienced grade 3 or 4 immune-related adverse events, compared with 7%-15% of patients without autoimmune disease.
Study details: A retrospective study of 56 patients with NSCLC and preexisting autoimmune disease from five academic cancer centers.
Disclosures: The Kaplan Research Fund and Jeni Fund, Memorial Sloan Kettering Cancer Center, the American Cancer Society, and the University of Texas MD Anderson Cancer Center sponsored the study. The researchers reported receiving financial support from Merck, Novartis, Genentech, and other companies.
Source: Leonardi GC et al. J Clin Oncol. 2018 May 20. doi: 10.1200/JCO.2017.77.0305.
Cemiplimab impresses in advanced CSCC
CHICAGO – The investigational programmed cell death protein 1 checkpoint inhibitor cemiplimab proved highly effective for the treatment of locally advanced or metastatic cutaneous squamous cell carcinoma in a phase 1 clinical trial, Michael R. Migden, MD, reported at the annual meeting of the American College of Mohs Surgery.
And this was no ordinary phase 1 study, he noted. Because there is no Food and Drug Administration–approved treatment for advanced cutaneous squamous cell carcinoma (CSCC), cemiplimab has been granted both Breakthrough Drug and Orphan Drug status by the FDA and the European Medicines Agency.
Given the likelihood that cemiplimab will receive expeditious regulatory approval to address this major unmet need, he offered his colleagues practical tips on its use, including information about the drug’s chief side effects as well as a heads-up regarding the importance of early recognition of the pseudoprogression phenomenon that can occur with the drug.
He predicted this fully human monoclonal antibody directed at programmed cell death protein 1 (PD-1) is going to be an important drug for Mohs surgeons.
“Immunotherapy is becoming increasingly relevant to micrographic surgery and dermatologic oncology practice and fellowship training. Care for larger, advanced CSCC falls within our scope of practice and we should play an essential role, inclusive of multidisciplinary care, in the management and follow-up of these patients,” asserted Dr. Migden, a dermatologic surgeon at the University of Texas MD Anderson Cancer Center, Houston.
The open-label, phase 1 study included seven patients with distant metastatic CSCC and nine with locally and/or regionally advanced disease. They were treated with 3 mg/kg IV cemiplimab every 2 weeks for 48 weeks, with Response Evaluation Criteria In Solid Tumors 1.1 criteria used for assessment of response status every 8 weeks. More than 80% of the tumors were located in the head and neck. The great majority of study participants had previously been treated with radiation therapy and systemic agents, to little effect.
The complete response rate at 48 weeks was 12.5%, with tumor clearance occurring as quickly as 14 weeks. Another 25% of patients had a partial response, for an overall response rate of 37.5%. But that’s not the full success story, as another 31% of patients had stable disease. Thus, 11 of 16 patients, or 69%, experienced disease control.
“A disease-control rate of nearly 70% is really important because these are patients with life-threatening tumors. To be able to hold them steady is a big deal,” Dr. Migden observed.
One-quarter of study participants experienced progressive disease. The remainder weren’t evaluated for various reasons.
The dermatologist pointed out that locally advanced disease was particularly responsive to cemiplimab, with four of nine affected patients experiencing complete or partial response, for an overall response rate of 44%. This is consistent with the preliminary results of the pivotal phase 2 study, in which the overall response rate in the 78 participants with unresectable, locally advanced CSCC was 46%.
The phase 2 trial also includes another 59 patients with metastatic CSCC on 3 mg/kg IV cemiplimab every 14 days, as well as 56 patients with metastatic disease assigned to flat-dose 350-mg IV cemiplimab every 21 days.
Treatment side effects
In the phase 1 study, immunotherapy with cemiplimab was far better tolerated than in traditional cancer chemotherapy. There were two grade 3 cases of elevated liver enzymes and one of arthralgia, but no significant fatigue or nausea and no hypothyroidism. However, judging from the cumulative experience accrued with the five PD-1 checkpoint inhibitors already approved for treatment of other cancers, one must be prepared to encounter hypothyroidism and other endocrinopathies, pneumonitis, hepatitis, and rashes.
“The clinician must have a very high index of suspicion for these immune-related adverse events and a low threshold to consult with colleagues in other specialties – pulmonary, endocrine, and medical oncology – for evaluation and management of these possible side effects. I tell all the patients who are on cemiplimab, ‘Any new anything – a slight cough, mild diarrhea – you’re coming in and you’re getting checked,’ ” according to Dr. Migden.
That being said, the majority of immune-related adverse events because of PD-1 inhibitors are mild to moderate. Of the few that reach grade 3 or above, most can be successfully managed by pausing or discontinuing anti–PD-1 therapy coupled with prompt initiation of immunosuppressive therapy, typically with high-dose steroids, he added.
Look sharp for pseudoprogression
Pseudoprogression is a phenomenon whereby immunotherapy results in inflammatory changes bringing about a temporary increase in tumor size that precedes tumor shrinkage. It’s uncommon, occurring in 3 of 16 patients in the phase 1 study. The mechanism probably involves tumor infiltration by massive numbers of activated T cells. And there is evidence from other PD-1 inhibitor studies in advanced cancers that pseudoprogression may actually be a marker for increased likelihood of survival beyond 1 year.
“Pseudoprogression is important to recognize because the patients you treat with cemiplimab can get worse before they get better,” the dermatologist explained. “So you don’t want to prematurely discontinue treatment because you’re misclassifying it as tumor progression.”
The rationale for anti-PD-1 therapy in CSCC
Tumors that express PD-1 bind to PD–ligand 1 on T cells, switching off T-cell mediated tumor destruction and thereby allowing the malignancy to thrive.
“Simplified, the strategy here is to interfere with the interaction at the T-cell off switch, either with an antibody to PD–ligand 1, such as atezolizumab [Tecentriq], or an antibody to the PD-1 receptor, where cemiplimab works. By turning off the off switch, we get a T cell fully on and attacking the tumor cell,” Dr. Migden said.
“The more the tumor mutation burden, the better immunotherapy works – and CSCC has the highest tumor mutation burden of any tumor type in the Cancer Genome Atlas, several times higher than melanoma. Interestingly, basal cell carcinoma has an even higher tumor mutation burden than CSCC, but it’s not part of the atlas,” he continued.
Although the proportion of CSCCs that are locally advanced hasn’t been well established, it’s clear that CSCC is the deadliest nonmelanoma skin cancer, accounting for 3,900-8,800 deaths annually in the United States.
The cemiplimab phase 1 and 2 clinical trials for CSCC were jointly sponsored by Regeneron and Sanofi. The monoclonal antibody is also being developed for treatment of myeloma and lung cancer. Dr. Migden reported receiving honoraria from Regeneron and Sanofi, as well as from Genentech, Lilly, Novartis, and Sun Pharmaceuticals.
CHICAGO – The investigational programmed cell death protein 1 checkpoint inhibitor cemiplimab proved highly effective for the treatment of locally advanced or metastatic cutaneous squamous cell carcinoma in a phase 1 clinical trial, Michael R. Migden, MD, reported at the annual meeting of the American College of Mohs Surgery.
And this was no ordinary phase 1 study, he noted. Because there is no Food and Drug Administration–approved treatment for advanced cutaneous squamous cell carcinoma (CSCC), cemiplimab has been granted both Breakthrough Drug and Orphan Drug status by the FDA and the European Medicines Agency.
Given the likelihood that cemiplimab will receive expeditious regulatory approval to address this major unmet need, he offered his colleagues practical tips on its use, including information about the drug’s chief side effects as well as a heads-up regarding the importance of early recognition of the pseudoprogression phenomenon that can occur with the drug.
He predicted this fully human monoclonal antibody directed at programmed cell death protein 1 (PD-1) is going to be an important drug for Mohs surgeons.
“Immunotherapy is becoming increasingly relevant to micrographic surgery and dermatologic oncology practice and fellowship training. Care for larger, advanced CSCC falls within our scope of practice and we should play an essential role, inclusive of multidisciplinary care, in the management and follow-up of these patients,” asserted Dr. Migden, a dermatologic surgeon at the University of Texas MD Anderson Cancer Center, Houston.
The open-label, phase 1 study included seven patients with distant metastatic CSCC and nine with locally and/or regionally advanced disease. They were treated with 3 mg/kg IV cemiplimab every 2 weeks for 48 weeks, with Response Evaluation Criteria In Solid Tumors 1.1 criteria used for assessment of response status every 8 weeks. More than 80% of the tumors were located in the head and neck. The great majority of study participants had previously been treated with radiation therapy and systemic agents, to little effect.
The complete response rate at 48 weeks was 12.5%, with tumor clearance occurring as quickly as 14 weeks. Another 25% of patients had a partial response, for an overall response rate of 37.5%. But that’s not the full success story, as another 31% of patients had stable disease. Thus, 11 of 16 patients, or 69%, experienced disease control.
“A disease-control rate of nearly 70% is really important because these are patients with life-threatening tumors. To be able to hold them steady is a big deal,” Dr. Migden observed.
One-quarter of study participants experienced progressive disease. The remainder weren’t evaluated for various reasons.
The dermatologist pointed out that locally advanced disease was particularly responsive to cemiplimab, with four of nine affected patients experiencing complete or partial response, for an overall response rate of 44%. This is consistent with the preliminary results of the pivotal phase 2 study, in which the overall response rate in the 78 participants with unresectable, locally advanced CSCC was 46%.
The phase 2 trial also includes another 59 patients with metastatic CSCC on 3 mg/kg IV cemiplimab every 14 days, as well as 56 patients with metastatic disease assigned to flat-dose 350-mg IV cemiplimab every 21 days.
Treatment side effects
In the phase 1 study, immunotherapy with cemiplimab was far better tolerated than in traditional cancer chemotherapy. There were two grade 3 cases of elevated liver enzymes and one of arthralgia, but no significant fatigue or nausea and no hypothyroidism. However, judging from the cumulative experience accrued with the five PD-1 checkpoint inhibitors already approved for treatment of other cancers, one must be prepared to encounter hypothyroidism and other endocrinopathies, pneumonitis, hepatitis, and rashes.
“The clinician must have a very high index of suspicion for these immune-related adverse events and a low threshold to consult with colleagues in other specialties – pulmonary, endocrine, and medical oncology – for evaluation and management of these possible side effects. I tell all the patients who are on cemiplimab, ‘Any new anything – a slight cough, mild diarrhea – you’re coming in and you’re getting checked,’ ” according to Dr. Migden.
That being said, the majority of immune-related adverse events because of PD-1 inhibitors are mild to moderate. Of the few that reach grade 3 or above, most can be successfully managed by pausing or discontinuing anti–PD-1 therapy coupled with prompt initiation of immunosuppressive therapy, typically with high-dose steroids, he added.
Look sharp for pseudoprogression
Pseudoprogression is a phenomenon whereby immunotherapy results in inflammatory changes bringing about a temporary increase in tumor size that precedes tumor shrinkage. It’s uncommon, occurring in 3 of 16 patients in the phase 1 study. The mechanism probably involves tumor infiltration by massive numbers of activated T cells. And there is evidence from other PD-1 inhibitor studies in advanced cancers that pseudoprogression may actually be a marker for increased likelihood of survival beyond 1 year.
“Pseudoprogression is important to recognize because the patients you treat with cemiplimab can get worse before they get better,” the dermatologist explained. “So you don’t want to prematurely discontinue treatment because you’re misclassifying it as tumor progression.”
The rationale for anti-PD-1 therapy in CSCC
Tumors that express PD-1 bind to PD–ligand 1 on T cells, switching off T-cell mediated tumor destruction and thereby allowing the malignancy to thrive.
“Simplified, the strategy here is to interfere with the interaction at the T-cell off switch, either with an antibody to PD–ligand 1, such as atezolizumab [Tecentriq], or an antibody to the PD-1 receptor, where cemiplimab works. By turning off the off switch, we get a T cell fully on and attacking the tumor cell,” Dr. Migden said.
“The more the tumor mutation burden, the better immunotherapy works – and CSCC has the highest tumor mutation burden of any tumor type in the Cancer Genome Atlas, several times higher than melanoma. Interestingly, basal cell carcinoma has an even higher tumor mutation burden than CSCC, but it’s not part of the atlas,” he continued.
Although the proportion of CSCCs that are locally advanced hasn’t been well established, it’s clear that CSCC is the deadliest nonmelanoma skin cancer, accounting for 3,900-8,800 deaths annually in the United States.
The cemiplimab phase 1 and 2 clinical trials for CSCC were jointly sponsored by Regeneron and Sanofi. The monoclonal antibody is also being developed for treatment of myeloma and lung cancer. Dr. Migden reported receiving honoraria from Regeneron and Sanofi, as well as from Genentech, Lilly, Novartis, and Sun Pharmaceuticals.
CHICAGO – The investigational programmed cell death protein 1 checkpoint inhibitor cemiplimab proved highly effective for the treatment of locally advanced or metastatic cutaneous squamous cell carcinoma in a phase 1 clinical trial, Michael R. Migden, MD, reported at the annual meeting of the American College of Mohs Surgery.
And this was no ordinary phase 1 study, he noted. Because there is no Food and Drug Administration–approved treatment for advanced cutaneous squamous cell carcinoma (CSCC), cemiplimab has been granted both Breakthrough Drug and Orphan Drug status by the FDA and the European Medicines Agency.
Given the likelihood that cemiplimab will receive expeditious regulatory approval to address this major unmet need, he offered his colleagues practical tips on its use, including information about the drug’s chief side effects as well as a heads-up regarding the importance of early recognition of the pseudoprogression phenomenon that can occur with the drug.
He predicted this fully human monoclonal antibody directed at programmed cell death protein 1 (PD-1) is going to be an important drug for Mohs surgeons.
“Immunotherapy is becoming increasingly relevant to micrographic surgery and dermatologic oncology practice and fellowship training. Care for larger, advanced CSCC falls within our scope of practice and we should play an essential role, inclusive of multidisciplinary care, in the management and follow-up of these patients,” asserted Dr. Migden, a dermatologic surgeon at the University of Texas MD Anderson Cancer Center, Houston.
The open-label, phase 1 study included seven patients with distant metastatic CSCC and nine with locally and/or regionally advanced disease. They were treated with 3 mg/kg IV cemiplimab every 2 weeks for 48 weeks, with Response Evaluation Criteria In Solid Tumors 1.1 criteria used for assessment of response status every 8 weeks. More than 80% of the tumors were located in the head and neck. The great majority of study participants had previously been treated with radiation therapy and systemic agents, to little effect.
The complete response rate at 48 weeks was 12.5%, with tumor clearance occurring as quickly as 14 weeks. Another 25% of patients had a partial response, for an overall response rate of 37.5%. But that’s not the full success story, as another 31% of patients had stable disease. Thus, 11 of 16 patients, or 69%, experienced disease control.
“A disease-control rate of nearly 70% is really important because these are patients with life-threatening tumors. To be able to hold them steady is a big deal,” Dr. Migden observed.
One-quarter of study participants experienced progressive disease. The remainder weren’t evaluated for various reasons.
The dermatologist pointed out that locally advanced disease was particularly responsive to cemiplimab, with four of nine affected patients experiencing complete or partial response, for an overall response rate of 44%. This is consistent with the preliminary results of the pivotal phase 2 study, in which the overall response rate in the 78 participants with unresectable, locally advanced CSCC was 46%.
The phase 2 trial also includes another 59 patients with metastatic CSCC on 3 mg/kg IV cemiplimab every 14 days, as well as 56 patients with metastatic disease assigned to flat-dose 350-mg IV cemiplimab every 21 days.
Treatment side effects
In the phase 1 study, immunotherapy with cemiplimab was far better tolerated than in traditional cancer chemotherapy. There were two grade 3 cases of elevated liver enzymes and one of arthralgia, but no significant fatigue or nausea and no hypothyroidism. However, judging from the cumulative experience accrued with the five PD-1 checkpoint inhibitors already approved for treatment of other cancers, one must be prepared to encounter hypothyroidism and other endocrinopathies, pneumonitis, hepatitis, and rashes.
“The clinician must have a very high index of suspicion for these immune-related adverse events and a low threshold to consult with colleagues in other specialties – pulmonary, endocrine, and medical oncology – for evaluation and management of these possible side effects. I tell all the patients who are on cemiplimab, ‘Any new anything – a slight cough, mild diarrhea – you’re coming in and you’re getting checked,’ ” according to Dr. Migden.
That being said, the majority of immune-related adverse events because of PD-1 inhibitors are mild to moderate. Of the few that reach grade 3 or above, most can be successfully managed by pausing or discontinuing anti–PD-1 therapy coupled with prompt initiation of immunosuppressive therapy, typically with high-dose steroids, he added.
Look sharp for pseudoprogression
Pseudoprogression is a phenomenon whereby immunotherapy results in inflammatory changes bringing about a temporary increase in tumor size that precedes tumor shrinkage. It’s uncommon, occurring in 3 of 16 patients in the phase 1 study. The mechanism probably involves tumor infiltration by massive numbers of activated T cells. And there is evidence from other PD-1 inhibitor studies in advanced cancers that pseudoprogression may actually be a marker for increased likelihood of survival beyond 1 year.
“Pseudoprogression is important to recognize because the patients you treat with cemiplimab can get worse before they get better,” the dermatologist explained. “So you don’t want to prematurely discontinue treatment because you’re misclassifying it as tumor progression.”
The rationale for anti-PD-1 therapy in CSCC
Tumors that express PD-1 bind to PD–ligand 1 on T cells, switching off T-cell mediated tumor destruction and thereby allowing the malignancy to thrive.
“Simplified, the strategy here is to interfere with the interaction at the T-cell off switch, either with an antibody to PD–ligand 1, such as atezolizumab [Tecentriq], or an antibody to the PD-1 receptor, where cemiplimab works. By turning off the off switch, we get a T cell fully on and attacking the tumor cell,” Dr. Migden said.
“The more the tumor mutation burden, the better immunotherapy works – and CSCC has the highest tumor mutation burden of any tumor type in the Cancer Genome Atlas, several times higher than melanoma. Interestingly, basal cell carcinoma has an even higher tumor mutation burden than CSCC, but it’s not part of the atlas,” he continued.
Although the proportion of CSCCs that are locally advanced hasn’t been well established, it’s clear that CSCC is the deadliest nonmelanoma skin cancer, accounting for 3,900-8,800 deaths annually in the United States.
The cemiplimab phase 1 and 2 clinical trials for CSCC were jointly sponsored by Regeneron and Sanofi. The monoclonal antibody is also being developed for treatment of myeloma and lung cancer. Dr. Migden reported receiving honoraria from Regeneron and Sanofi, as well as from Genentech, Lilly, Novartis, and Sun Pharmaceuticals.
REPORTING FROM THE ACMS ANNUAL MEETING
Key clinical point:
Major finding: Disease control was achieved in 11 of 16 patients (69%).
Study details: The open-label, phase 1 study included seven patients with distant metastatic cutaneous squamous cell carcinoma and nine with locally and/or regionally advanced disease.
Disclosures: The cemiplimab phase 1 and 2 clinical trials for CSCC were jointly sponsored by Regeneron and Sanofi. Dr. Migden reported receiving honoraria from Regeneron and Sanofi as well as from Genentech, Lilly, Novartis, and Sun Pharmaceuticals.
Multiple solid tumors targeted by concept CAR T
PITTSBURGH – Call it the CAR of the future – an investigational chimeric antigen receptor–T cell construct targeted against an antigen highly expressed on pediatric solid tumors has shown promising efficacy in preclinical studies.
Investigators found that the antigen, labeled B7-H3, was expressed on 84% of microarrays of pediatric solid tumors. More importantly, a single dose of CAR targeted to B7-H3 caused complete regression of osteosarcoma and Ewing sarcoma xenografts and improved survival over an untransduced, CD19-targeted CAR in mice, Robbie Majzner, MD, reported at the annual meeting of the American Society of Pediatric Hematology/Oncology.
Dr. Majzner was the recipient of an ASPHO young investigator award for his team’s research into developing a CAR T that could be as effective against solid tumors as other CAR Ts have been against hematologic malignancies such as acute lymphoblastic leukemia.
Solid tumors are more challenging to target than leukemias or lymphomas because of the small number of antigens expressed on most pediatric tumors, he said.
“Over 95% of tumors have a very low rate of mutations, which means that they have very few neoantigens which the immune system can recognize in order to attack,” he said.
In the Children’s Oncology Group ADVL1412 trial, single-agent immunotherapy with the anti–programmed death protein 1 (PD-1) inhibitor nivolumab (Opdivo) showed no evidence of efficacy against either Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, or measurable neuroblastoma. PD–ligand 1 was found to be expressed in only a few of the 43 tumors studied, suggesting that checkpoint inhibitor therapy is unlikely to work in these solid tumors, he said.
In contrast, B7-H3 is highly expressed on many different pediatric solid tumors, including rhabdomyosarcoma (95% of tumors stained), Ewing sarcoma (89%), Wilms tumor (100%), neuroblastoma (82%), ganglioneuroblastoma and ganglioneuroma (53%), medulloblastoma (96%), glioblastoma multiforme (84%), and diffuse intrinsic pontine glioma (100%).
To see whether CAR T therapy might have better efficacy than checkpoint inhibitors in this population, the investigators created a B7-H3 CAR using the B7-H3 tumor–specific monoclonal antibody MGA271, which has been shown to be safe in both adults and children in early clinical trials.
In human tumor xenograft models of osteosarcoma, all mice who received a single dose of the B7-H3 CAR survived at least 70 days after tumor engraftment, whereas all control mice, who received the CD19 CAR, died by day 60 (P = .0067). Similarly, in a model of Ewing sarcoma, all mice treated with B7-H3 survived at least 100 days, whereas all controls were dead by day 50 (P = .0015).
The B7-H3 construct also showed good activity against a model of medulloblastoma, showing that it was capable of crossing the blood-brain barrier.
Since B7-H3 has been reported to be expressed on both myeloid and lymphoid leukemia cells, the investigators also tested the CAR against a murine model of leukemia generated by injection of K562, a well-characterized line of myeloid leukemia cells.
“While we found some increase in survival in the mice that received the B7-H3 CAR T cells, compared to mice that received untransduced CAR T cells, this clearly is not as effective as in our solid tumor models,” Dr. Majzner said.
Going back to the cell line, they discovered that expression of B7-H3 was considerably lower in the K562 cells than in either the osteosarcoma or medulloblastoma cell lines used in their other models.
They found that both in vitro and in vivo, high levels of B7-H3 expression were necessary to provoke the immune system into releasing cytokines necessary for an adequate antitumor response.
The investigators are currently planning clinical trials using the B7-H3 CAR T-cell construct in patients with solid tumors.
The work is supported by the Sarcoma Alliance for Research through Collaboration, the St. Baldrick’s Foundation, and Stand Up to Cancer. Dr. Majzner reported having no financial disclosures.
SOURCE: Majzner RG et al. ASPHO 2018, Abstract #PS2003.
PITTSBURGH – Call it the CAR of the future – an investigational chimeric antigen receptor–T cell construct targeted against an antigen highly expressed on pediatric solid tumors has shown promising efficacy in preclinical studies.
Investigators found that the antigen, labeled B7-H3, was expressed on 84% of microarrays of pediatric solid tumors. More importantly, a single dose of CAR targeted to B7-H3 caused complete regression of osteosarcoma and Ewing sarcoma xenografts and improved survival over an untransduced, CD19-targeted CAR in mice, Robbie Majzner, MD, reported at the annual meeting of the American Society of Pediatric Hematology/Oncology.
Dr. Majzner was the recipient of an ASPHO young investigator award for his team’s research into developing a CAR T that could be as effective against solid tumors as other CAR Ts have been against hematologic malignancies such as acute lymphoblastic leukemia.
Solid tumors are more challenging to target than leukemias or lymphomas because of the small number of antigens expressed on most pediatric tumors, he said.
“Over 95% of tumors have a very low rate of mutations, which means that they have very few neoantigens which the immune system can recognize in order to attack,” he said.
In the Children’s Oncology Group ADVL1412 trial, single-agent immunotherapy with the anti–programmed death protein 1 (PD-1) inhibitor nivolumab (Opdivo) showed no evidence of efficacy against either Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, or measurable neuroblastoma. PD–ligand 1 was found to be expressed in only a few of the 43 tumors studied, suggesting that checkpoint inhibitor therapy is unlikely to work in these solid tumors, he said.
In contrast, B7-H3 is highly expressed on many different pediatric solid tumors, including rhabdomyosarcoma (95% of tumors stained), Ewing sarcoma (89%), Wilms tumor (100%), neuroblastoma (82%), ganglioneuroblastoma and ganglioneuroma (53%), medulloblastoma (96%), glioblastoma multiforme (84%), and diffuse intrinsic pontine glioma (100%).
To see whether CAR T therapy might have better efficacy than checkpoint inhibitors in this population, the investigators created a B7-H3 CAR using the B7-H3 tumor–specific monoclonal antibody MGA271, which has been shown to be safe in both adults and children in early clinical trials.
In human tumor xenograft models of osteosarcoma, all mice who received a single dose of the B7-H3 CAR survived at least 70 days after tumor engraftment, whereas all control mice, who received the CD19 CAR, died by day 60 (P = .0067). Similarly, in a model of Ewing sarcoma, all mice treated with B7-H3 survived at least 100 days, whereas all controls were dead by day 50 (P = .0015).
The B7-H3 construct also showed good activity against a model of medulloblastoma, showing that it was capable of crossing the blood-brain barrier.
Since B7-H3 has been reported to be expressed on both myeloid and lymphoid leukemia cells, the investigators also tested the CAR against a murine model of leukemia generated by injection of K562, a well-characterized line of myeloid leukemia cells.
“While we found some increase in survival in the mice that received the B7-H3 CAR T cells, compared to mice that received untransduced CAR T cells, this clearly is not as effective as in our solid tumor models,” Dr. Majzner said.
Going back to the cell line, they discovered that expression of B7-H3 was considerably lower in the K562 cells than in either the osteosarcoma or medulloblastoma cell lines used in their other models.
They found that both in vitro and in vivo, high levels of B7-H3 expression were necessary to provoke the immune system into releasing cytokines necessary for an adequate antitumor response.
The investigators are currently planning clinical trials using the B7-H3 CAR T-cell construct in patients with solid tumors.
The work is supported by the Sarcoma Alliance for Research through Collaboration, the St. Baldrick’s Foundation, and Stand Up to Cancer. Dr. Majzner reported having no financial disclosures.
SOURCE: Majzner RG et al. ASPHO 2018, Abstract #PS2003.
PITTSBURGH – Call it the CAR of the future – an investigational chimeric antigen receptor–T cell construct targeted against an antigen highly expressed on pediatric solid tumors has shown promising efficacy in preclinical studies.
Investigators found that the antigen, labeled B7-H3, was expressed on 84% of microarrays of pediatric solid tumors. More importantly, a single dose of CAR targeted to B7-H3 caused complete regression of osteosarcoma and Ewing sarcoma xenografts and improved survival over an untransduced, CD19-targeted CAR in mice, Robbie Majzner, MD, reported at the annual meeting of the American Society of Pediatric Hematology/Oncology.
Dr. Majzner was the recipient of an ASPHO young investigator award for his team’s research into developing a CAR T that could be as effective against solid tumors as other CAR Ts have been against hematologic malignancies such as acute lymphoblastic leukemia.
Solid tumors are more challenging to target than leukemias or lymphomas because of the small number of antigens expressed on most pediatric tumors, he said.
“Over 95% of tumors have a very low rate of mutations, which means that they have very few neoantigens which the immune system can recognize in order to attack,” he said.
In the Children’s Oncology Group ADVL1412 trial, single-agent immunotherapy with the anti–programmed death protein 1 (PD-1) inhibitor nivolumab (Opdivo) showed no evidence of efficacy against either Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, or measurable neuroblastoma. PD–ligand 1 was found to be expressed in only a few of the 43 tumors studied, suggesting that checkpoint inhibitor therapy is unlikely to work in these solid tumors, he said.
In contrast, B7-H3 is highly expressed on many different pediatric solid tumors, including rhabdomyosarcoma (95% of tumors stained), Ewing sarcoma (89%), Wilms tumor (100%), neuroblastoma (82%), ganglioneuroblastoma and ganglioneuroma (53%), medulloblastoma (96%), glioblastoma multiforme (84%), and diffuse intrinsic pontine glioma (100%).
To see whether CAR T therapy might have better efficacy than checkpoint inhibitors in this population, the investigators created a B7-H3 CAR using the B7-H3 tumor–specific monoclonal antibody MGA271, which has been shown to be safe in both adults and children in early clinical trials.
In human tumor xenograft models of osteosarcoma, all mice who received a single dose of the B7-H3 CAR survived at least 70 days after tumor engraftment, whereas all control mice, who received the CD19 CAR, died by day 60 (P = .0067). Similarly, in a model of Ewing sarcoma, all mice treated with B7-H3 survived at least 100 days, whereas all controls were dead by day 50 (P = .0015).
The B7-H3 construct also showed good activity against a model of medulloblastoma, showing that it was capable of crossing the blood-brain barrier.
Since B7-H3 has been reported to be expressed on both myeloid and lymphoid leukemia cells, the investigators also tested the CAR against a murine model of leukemia generated by injection of K562, a well-characterized line of myeloid leukemia cells.
“While we found some increase in survival in the mice that received the B7-H3 CAR T cells, compared to mice that received untransduced CAR T cells, this clearly is not as effective as in our solid tumor models,” Dr. Majzner said.
Going back to the cell line, they discovered that expression of B7-H3 was considerably lower in the K562 cells than in either the osteosarcoma or medulloblastoma cell lines used in their other models.
They found that both in vitro and in vivo, high levels of B7-H3 expression were necessary to provoke the immune system into releasing cytokines necessary for an adequate antitumor response.
The investigators are currently planning clinical trials using the B7-H3 CAR T-cell construct in patients with solid tumors.
The work is supported by the Sarcoma Alliance for Research through Collaboration, the St. Baldrick’s Foundation, and Stand Up to Cancer. Dr. Majzner reported having no financial disclosures.
SOURCE: Majzner RG et al. ASPHO 2018, Abstract #PS2003.
REPORTING FROM ASPHO 2018
Key clinical point:
Major finding: A single dose of the B7-H3 CAR caused complete regression of osteosarcoma and Ewing sarcoma xenografts and extended survival in mice.
Study details: Preclinical research.
Disclosures: The work is supported by the Sarcoma Alliance for Research through Collaboration, St. Baldrick’s Foundation, and Stand Up to Cancer. Dr. Majzner reported having no financial disclosures.
Source: Majzner RG et al. ASPHO 2018, Abstract #PS2003.
Is cancer immunotherapy more effective in men than women?
Cancer immunotherapy using checkpoint inhibitors may achieve greater mortality reductions in men than they do in women, new research has suggested.
In a meta-analysis and systematic review published in Lancet Oncology, researchers analyzed 20 randomized, controlled trials of immune checkpoint inhibitors that included detail on overall survival and patients’ sex; altogether, these studies involved 11,351 patients with advanced or metastatic cancers.
They found that while men treated with checkpoint inhibitors had a significant 28% reduced risk of death, compared with male controls, the survival benefit in women was smaller (14% reduced risk of death, compared with female controls).
Fabio Conforti, MD, from the European Institute of Oncology, Milan, and coauthors commented that the magnitude of the difference between the effect seen men and that in women was clinically significant.
“The pooled reduction of risk of death was double the size for male patients than for female patients – a difference that is similar to the size of the difference in survival benefit observed between patients with non–small cell lung cancer with PD-L1 positive (greater than 1%) tumors versus negative tumors, who were treated with anti-PD-1,” they wrote.
This difference between the benefit seen men and that in women was evident across all the subgroups in the study, which included subgroups based on cancer histotype, line of treatment, drugs used, and type of control.
However there was greater heterogeneity in the magnitude of the effect of checkpoint inhibitors on mortality in men than there was in women. The authors suggested this could be explained by the fact that the drugs have lower efficacy in women and this may therefore reduce the variability of results when compared with those in men.
The authors also looked at whether the studies that compared immunotherapies with nonimmunological therapies might show a different effect, but they still found a significantly higher benefit in men, compared with women.
The overall study population was two-thirds male and one-third female. The checkpoint inhibitors used were ipilimumab, tremelimumab, nivolumab, and pembrolizumab, and the trials were conducted in patients with melanoma, non–small cell lung cancer, head and neck cancer, renal cell carcinoma, urothelial tumors, gastric tumors, and mesothelioma.
Men have almost double the risk of mortality from cancer than do women, the authors said, with the greatest differences seen in melanoma, lung cancer, larynx cancer, esophagus cancer, and bladder cancer.
“This male-biased mortality is hypothesized to reflect differences not only in behavioral and biological factors, including causes of cancer and hormonal regulation, but also in the immune system.”
Despite this, sex is rarely taken into account when new therapeutic approaches are tested, the authors said.
They also commented on the fact that there was a relatively low number of women included in each trial, an issue that was recognized as far back as the 1990s as a major problem in medical trials.
“Our results further highlight this problem, showing clinically relevant differences in the efficacy of two important classes of immunological drugs, namely anti–CTLA-4 and anti–PD-1 antibodies, when compared with controls in male and female patients with advanced solid tumors,” they wrote.
They noted that they couldn’t exclude the possibility that the effect may be the result of other variables that were distributed differently between the sexes. However, they also qualified this by saying that variables known to affect the efficacy of immune checkpoint inhibitors, such as PD-L1 expression and mutation status, were not likely to explain the results.
Given their findings, the authors said a patient’s sex should be taken into account when weighing the risks and benefits of checkpoint inhibitors given the magnitude of benefit was sex-dependent. They also called for future immunotherapy studies to include more women.
No funding or conflicts of interest were declared.
SOURCE: Conforti F et al. Lancet Oncol. 2018 May 16. doi: 10.1016/S1470-2045(18)30261-4.
While cancer immunotherapy represents one of the most significant clinical advances in cancer treatment in the past decade, the basic but important clinical question about different effects between men and woman has not been addressed until now. The authors of this study are to be congratulated on such a comprehensive and well-conducted analysis, but the data does not completely support their final conclusion that checkpoint inhibitors benefit men more than women.
There are a large number of baseline characteristics of solid tumors that might differ between men and women and that have also been reported to impact the outcomes of patients treated with checkpoint inhibitors. Some of these may be lifestyle or behavioral characteristics – such as different smoking habits between men and women with non–small cell lung cancer – or differences in the distribution of oncogenic driver mutations between men and women.
We should therefore be cautious in jumping to conclusions and changing the current standard of care with respect to checkpoint inhibitors. In particular, we should not be denying treatment to women who are otherwise indicated for checkpoint inhibitors, based on these findings.
Omar Abdel-Rahman, MD, is from the clinical oncology department of the faculty of medicine at Ain Shams University in Cairo and from the Tom Baker Cancer Centre in Calgary. These comments are taken from an accompanying editorial (Lancet Oncol. 2018 May 16. doi: 10.1016/S1470-2045[18]30270-5.) No conflicts of interest were declared.
While cancer immunotherapy represents one of the most significant clinical advances in cancer treatment in the past decade, the basic but important clinical question about different effects between men and woman has not been addressed until now. The authors of this study are to be congratulated on such a comprehensive and well-conducted analysis, but the data does not completely support their final conclusion that checkpoint inhibitors benefit men more than women.
There are a large number of baseline characteristics of solid tumors that might differ between men and women and that have also been reported to impact the outcomes of patients treated with checkpoint inhibitors. Some of these may be lifestyle or behavioral characteristics – such as different smoking habits between men and women with non–small cell lung cancer – or differences in the distribution of oncogenic driver mutations between men and women.
We should therefore be cautious in jumping to conclusions and changing the current standard of care with respect to checkpoint inhibitors. In particular, we should not be denying treatment to women who are otherwise indicated for checkpoint inhibitors, based on these findings.
Omar Abdel-Rahman, MD, is from the clinical oncology department of the faculty of medicine at Ain Shams University in Cairo and from the Tom Baker Cancer Centre in Calgary. These comments are taken from an accompanying editorial (Lancet Oncol. 2018 May 16. doi: 10.1016/S1470-2045[18]30270-5.) No conflicts of interest were declared.
While cancer immunotherapy represents one of the most significant clinical advances in cancer treatment in the past decade, the basic but important clinical question about different effects between men and woman has not been addressed until now. The authors of this study are to be congratulated on such a comprehensive and well-conducted analysis, but the data does not completely support their final conclusion that checkpoint inhibitors benefit men more than women.
There are a large number of baseline characteristics of solid tumors that might differ between men and women and that have also been reported to impact the outcomes of patients treated with checkpoint inhibitors. Some of these may be lifestyle or behavioral characteristics – such as different smoking habits between men and women with non–small cell lung cancer – or differences in the distribution of oncogenic driver mutations between men and women.
We should therefore be cautious in jumping to conclusions and changing the current standard of care with respect to checkpoint inhibitors. In particular, we should not be denying treatment to women who are otherwise indicated for checkpoint inhibitors, based on these findings.
Omar Abdel-Rahman, MD, is from the clinical oncology department of the faculty of medicine at Ain Shams University in Cairo and from the Tom Baker Cancer Centre in Calgary. These comments are taken from an accompanying editorial (Lancet Oncol. 2018 May 16. doi: 10.1016/S1470-2045[18]30270-5.) No conflicts of interest were declared.
Cancer immunotherapy using checkpoint inhibitors may achieve greater mortality reductions in men than they do in women, new research has suggested.
In a meta-analysis and systematic review published in Lancet Oncology, researchers analyzed 20 randomized, controlled trials of immune checkpoint inhibitors that included detail on overall survival and patients’ sex; altogether, these studies involved 11,351 patients with advanced or metastatic cancers.
They found that while men treated with checkpoint inhibitors had a significant 28% reduced risk of death, compared with male controls, the survival benefit in women was smaller (14% reduced risk of death, compared with female controls).
Fabio Conforti, MD, from the European Institute of Oncology, Milan, and coauthors commented that the magnitude of the difference between the effect seen men and that in women was clinically significant.
“The pooled reduction of risk of death was double the size for male patients than for female patients – a difference that is similar to the size of the difference in survival benefit observed between patients with non–small cell lung cancer with PD-L1 positive (greater than 1%) tumors versus negative tumors, who were treated with anti-PD-1,” they wrote.
This difference between the benefit seen men and that in women was evident across all the subgroups in the study, which included subgroups based on cancer histotype, line of treatment, drugs used, and type of control.
However there was greater heterogeneity in the magnitude of the effect of checkpoint inhibitors on mortality in men than there was in women. The authors suggested this could be explained by the fact that the drugs have lower efficacy in women and this may therefore reduce the variability of results when compared with those in men.
The authors also looked at whether the studies that compared immunotherapies with nonimmunological therapies might show a different effect, but they still found a significantly higher benefit in men, compared with women.
The overall study population was two-thirds male and one-third female. The checkpoint inhibitors used were ipilimumab, tremelimumab, nivolumab, and pembrolizumab, and the trials were conducted in patients with melanoma, non–small cell lung cancer, head and neck cancer, renal cell carcinoma, urothelial tumors, gastric tumors, and mesothelioma.
Men have almost double the risk of mortality from cancer than do women, the authors said, with the greatest differences seen in melanoma, lung cancer, larynx cancer, esophagus cancer, and bladder cancer.
“This male-biased mortality is hypothesized to reflect differences not only in behavioral and biological factors, including causes of cancer and hormonal regulation, but also in the immune system.”
Despite this, sex is rarely taken into account when new therapeutic approaches are tested, the authors said.
They also commented on the fact that there was a relatively low number of women included in each trial, an issue that was recognized as far back as the 1990s as a major problem in medical trials.
“Our results further highlight this problem, showing clinically relevant differences in the efficacy of two important classes of immunological drugs, namely anti–CTLA-4 and anti–PD-1 antibodies, when compared with controls in male and female patients with advanced solid tumors,” they wrote.
They noted that they couldn’t exclude the possibility that the effect may be the result of other variables that were distributed differently between the sexes. However, they also qualified this by saying that variables known to affect the efficacy of immune checkpoint inhibitors, such as PD-L1 expression and mutation status, were not likely to explain the results.
Given their findings, the authors said a patient’s sex should be taken into account when weighing the risks and benefits of checkpoint inhibitors given the magnitude of benefit was sex-dependent. They also called for future immunotherapy studies to include more women.
No funding or conflicts of interest were declared.
SOURCE: Conforti F et al. Lancet Oncol. 2018 May 16. doi: 10.1016/S1470-2045(18)30261-4.
Cancer immunotherapy using checkpoint inhibitors may achieve greater mortality reductions in men than they do in women, new research has suggested.
In a meta-analysis and systematic review published in Lancet Oncology, researchers analyzed 20 randomized, controlled trials of immune checkpoint inhibitors that included detail on overall survival and patients’ sex; altogether, these studies involved 11,351 patients with advanced or metastatic cancers.
They found that while men treated with checkpoint inhibitors had a significant 28% reduced risk of death, compared with male controls, the survival benefit in women was smaller (14% reduced risk of death, compared with female controls).
Fabio Conforti, MD, from the European Institute of Oncology, Milan, and coauthors commented that the magnitude of the difference between the effect seen men and that in women was clinically significant.
“The pooled reduction of risk of death was double the size for male patients than for female patients – a difference that is similar to the size of the difference in survival benefit observed between patients with non–small cell lung cancer with PD-L1 positive (greater than 1%) tumors versus negative tumors, who were treated with anti-PD-1,” they wrote.
This difference between the benefit seen men and that in women was evident across all the subgroups in the study, which included subgroups based on cancer histotype, line of treatment, drugs used, and type of control.
However there was greater heterogeneity in the magnitude of the effect of checkpoint inhibitors on mortality in men than there was in women. The authors suggested this could be explained by the fact that the drugs have lower efficacy in women and this may therefore reduce the variability of results when compared with those in men.
The authors also looked at whether the studies that compared immunotherapies with nonimmunological therapies might show a different effect, but they still found a significantly higher benefit in men, compared with women.
The overall study population was two-thirds male and one-third female. The checkpoint inhibitors used were ipilimumab, tremelimumab, nivolumab, and pembrolizumab, and the trials were conducted in patients with melanoma, non–small cell lung cancer, head and neck cancer, renal cell carcinoma, urothelial tumors, gastric tumors, and mesothelioma.
Men have almost double the risk of mortality from cancer than do women, the authors said, with the greatest differences seen in melanoma, lung cancer, larynx cancer, esophagus cancer, and bladder cancer.
“This male-biased mortality is hypothesized to reflect differences not only in behavioral and biological factors, including causes of cancer and hormonal regulation, but also in the immune system.”
Despite this, sex is rarely taken into account when new therapeutic approaches are tested, the authors said.
They also commented on the fact that there was a relatively low number of women included in each trial, an issue that was recognized as far back as the 1990s as a major problem in medical trials.
“Our results further highlight this problem, showing clinically relevant differences in the efficacy of two important classes of immunological drugs, namely anti–CTLA-4 and anti–PD-1 antibodies, when compared with controls in male and female patients with advanced solid tumors,” they wrote.
They noted that they couldn’t exclude the possibility that the effect may be the result of other variables that were distributed differently between the sexes. However, they also qualified this by saying that variables known to affect the efficacy of immune checkpoint inhibitors, such as PD-L1 expression and mutation status, were not likely to explain the results.
Given their findings, the authors said a patient’s sex should be taken into account when weighing the risks and benefits of checkpoint inhibitors given the magnitude of benefit was sex-dependent. They also called for future immunotherapy studies to include more women.
No funding or conflicts of interest were declared.
SOURCE: Conforti F et al. Lancet Oncol. 2018 May 16. doi: 10.1016/S1470-2045(18)30261-4.
FROM LANCET ONCOLOGY
Key clinical point: Checkpoint inhibitors are linked with greater mortality reductions in men than in women.
Major finding: Checkpoint inhibitors are associated with a 28% reduction in cancer mortality in men and 14% in women.
Study details: Systematic review and meta-analysis of 20 randomized, controlled trials involving 11,351 patients.
Disclosures: No funding or conflicts of interest were declared.
Source: Conforti F et al. Lancet Oncol. 2018 May 16. doi: 10.1016/S1470-2045(18)30261-4.
Checkpoint inhibitors get to patients quickly
Checkpoint inhibitors got to melanoma, non–small cell lung cancer, and renal cell carcinoma patients quickly in clinical practice after Food and Drug Administration approval – usually within 4 months – but the patients treated in clinical settings tended to be older than those treated in trials, which has caused concern about whether real-world efficacy will prove to be the same, according to a study in JAMA Oncology.
“Such rapid adoption stands in contrast to older estimates that suggest it takes years or even decades for new treatments to be adopted,” wrote lead author Cary Gross, MD, professor of medicine at Yale University, New Haven, and his coauthors. “We found significant differences in age between patients treated in practice and those treated in trials, which highlights the need to clarify the risks and benefits of checkpoint inhibitors in general populations of patients.”
Researchers drew data on nivolumab and pembrolizumab use from the Flatiron Health longitudinal EHR database, which included 233 academic and community oncology practices. In each of the three disease cohorts, adoption was seen within 4 months for at least 60% of patients. Uptake was quickest for the melanoma patients, 76% of whom received a checkpoint inhibitor within 4 months, investigators wrote. Factors for the fast adoption could include high disease severity, a preference for novelty, perceived gains over existing treatments, and promotional activities, such as media reports and advertising directly to consumers, they wrote.
More patients in real-world practice were aged 65 years or older, ranging from as little as 61% at the lowest end of the range at one center to as much as 64% at the highest end at another. In the clinical trials, the percentage of patients aged 65 years or older ranged from 32% in one trial to 41% in another. Researchers wrote that these higher real-world rates are concerning because there are still questions regarding whether differences in immune responses will cause differences in efficacy between older and younger patients, as well as safety considerations among different age groups.
“Although data suggest that outcomes are similar between older and younger patients receiving anti–PD-1 agents for melanoma, there is little evidence to guide anti–PD-1 treatment of older patients with NSCLC [non–small cell lung cancer],” Dr. Gross and his coinvestigators wrote.
Investigators wrote that the findings are cause for caution.
“As FDA officials develop more flexible standards for approval, which the 21st Century Cures Act requires them to do, it is possible that many patients will receive drugs before much is known about clinical outcomes,” Dr. Gross said. “Further integrations of real-world evidence might allow the FDA to better assess the drugs that they approve on the basis of nonrepresentative trial participants.”
SOURCE: Gross C et al. JAMA Oncol. 2018 May 10. doi: 10.1001/jamaoncol.2018.0798.
Checkpoint inhibitors got to melanoma, non–small cell lung cancer, and renal cell carcinoma patients quickly in clinical practice after Food and Drug Administration approval – usually within 4 months – but the patients treated in clinical settings tended to be older than those treated in trials, which has caused concern about whether real-world efficacy will prove to be the same, according to a study in JAMA Oncology.
“Such rapid adoption stands in contrast to older estimates that suggest it takes years or even decades for new treatments to be adopted,” wrote lead author Cary Gross, MD, professor of medicine at Yale University, New Haven, and his coauthors. “We found significant differences in age between patients treated in practice and those treated in trials, which highlights the need to clarify the risks and benefits of checkpoint inhibitors in general populations of patients.”
Researchers drew data on nivolumab and pembrolizumab use from the Flatiron Health longitudinal EHR database, which included 233 academic and community oncology practices. In each of the three disease cohorts, adoption was seen within 4 months for at least 60% of patients. Uptake was quickest for the melanoma patients, 76% of whom received a checkpoint inhibitor within 4 months, investigators wrote. Factors for the fast adoption could include high disease severity, a preference for novelty, perceived gains over existing treatments, and promotional activities, such as media reports and advertising directly to consumers, they wrote.
More patients in real-world practice were aged 65 years or older, ranging from as little as 61% at the lowest end of the range at one center to as much as 64% at the highest end at another. In the clinical trials, the percentage of patients aged 65 years or older ranged from 32% in one trial to 41% in another. Researchers wrote that these higher real-world rates are concerning because there are still questions regarding whether differences in immune responses will cause differences in efficacy between older and younger patients, as well as safety considerations among different age groups.
“Although data suggest that outcomes are similar between older and younger patients receiving anti–PD-1 agents for melanoma, there is little evidence to guide anti–PD-1 treatment of older patients with NSCLC [non–small cell lung cancer],” Dr. Gross and his coinvestigators wrote.
Investigators wrote that the findings are cause for caution.
“As FDA officials develop more flexible standards for approval, which the 21st Century Cures Act requires them to do, it is possible that many patients will receive drugs before much is known about clinical outcomes,” Dr. Gross said. “Further integrations of real-world evidence might allow the FDA to better assess the drugs that they approve on the basis of nonrepresentative trial participants.”
SOURCE: Gross C et al. JAMA Oncol. 2018 May 10. doi: 10.1001/jamaoncol.2018.0798.
Checkpoint inhibitors got to melanoma, non–small cell lung cancer, and renal cell carcinoma patients quickly in clinical practice after Food and Drug Administration approval – usually within 4 months – but the patients treated in clinical settings tended to be older than those treated in trials, which has caused concern about whether real-world efficacy will prove to be the same, according to a study in JAMA Oncology.
“Such rapid adoption stands in contrast to older estimates that suggest it takes years or even decades for new treatments to be adopted,” wrote lead author Cary Gross, MD, professor of medicine at Yale University, New Haven, and his coauthors. “We found significant differences in age between patients treated in practice and those treated in trials, which highlights the need to clarify the risks and benefits of checkpoint inhibitors in general populations of patients.”
Researchers drew data on nivolumab and pembrolizumab use from the Flatiron Health longitudinal EHR database, which included 233 academic and community oncology practices. In each of the three disease cohorts, adoption was seen within 4 months for at least 60% of patients. Uptake was quickest for the melanoma patients, 76% of whom received a checkpoint inhibitor within 4 months, investigators wrote. Factors for the fast adoption could include high disease severity, a preference for novelty, perceived gains over existing treatments, and promotional activities, such as media reports and advertising directly to consumers, they wrote.
More patients in real-world practice were aged 65 years or older, ranging from as little as 61% at the lowest end of the range at one center to as much as 64% at the highest end at another. In the clinical trials, the percentage of patients aged 65 years or older ranged from 32% in one trial to 41% in another. Researchers wrote that these higher real-world rates are concerning because there are still questions regarding whether differences in immune responses will cause differences in efficacy between older and younger patients, as well as safety considerations among different age groups.
“Although data suggest that outcomes are similar between older and younger patients receiving anti–PD-1 agents for melanoma, there is little evidence to guide anti–PD-1 treatment of older patients with NSCLC [non–small cell lung cancer],” Dr. Gross and his coinvestigators wrote.
Investigators wrote that the findings are cause for caution.
“As FDA officials develop more flexible standards for approval, which the 21st Century Cures Act requires them to do, it is possible that many patients will receive drugs before much is known about clinical outcomes,” Dr. Gross said. “Further integrations of real-world evidence might allow the FDA to better assess the drugs that they approve on the basis of nonrepresentative trial participants.”
SOURCE: Gross C et al. JAMA Oncol. 2018 May 10. doi: 10.1001/jamaoncol.2018.0798.
FROM JAMA ONCOLOGY
Key clinical point: Fast adoption but older patient age is seen in clinical use of checkpoint inhibitors.
Major finding: About 60% of patients were aged 65 years and older in clinical settings, compared with about 30%-40% in trials.
Study details: A retrospective study of data from the Flatiron Health longitudinal EHR database, which includes 233 academic and community practices.
Disclosures: The study was sponsored by the National Institutes of Health. Investigators reported receiving financial support from Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, and other companies.
Source: Gross C et al. JAMA Oncology. 2018 May 10. doi: 10.1001/jamaoncol.2018.0798.
New drugs provide new options in HCC
PHILADELPHIA – Recent approvals and investigations of targeted and immune treatments for advanced hepatocellular carcinoma (HCC) are encouraging, Nikolaos Pyrsopoulos, MD, MBA, said at Digestive Diseases: New Advances, jointly provided by Rutgers and Global Academy for Medical Education.
“I am excited, because a few years ago, there was only one [Food and Drug Administration] approved medication,” Dr. Pyrsopoulos, division director for gastroenterology and hepatology at Rutgers New Jersey Medical School, Newark, said in an interview. “We are on the cusp where new compounds not only are being tested, but they are being approved.”
Median overall survival in CELESTIAL was 10.2 months for cabozantinib versus 8.0 for placebo (P = .0049), according to the published report, and investigators also reported significant improvements in progression-free survival and response versus placebo.
“It is very encouraging,” Dr. Pyrsopoulos said of the cabozantinib results in a presentation on advances in HCC that he gave at the conference.
For years, the only FDA-approved treatment for advanced HCC was sorafenib. In the randomized phase 3 SHARP trial, published in the New England Journal of Medicine in 2008, patients receiving the multikinase inhibitor had a median survival of 10.7 months, versus 7.9 months for placebo (P less than .001).
In April 2017, the FDA approved regorafenib for patients with HCC previously treated with sorafenib. In the randomized phase 3 RESORCE trial, published in The Lancet in 2017, median overall survival was 10.6 months for regorafenib-treated patients versus 7.8 months in the placebo group. Investigators reported that regorafenib improved overall survival with a hazard ratio of 0.63 (P less than .0001).
Dr. Pyrsopoulos noted that a strategy of sorafenib followed by regorafenib would combine two treatments, each of which in clinical trials had a median overall survival approaching 11 months.
“In essence, you have an approximate 2-year survival,” he said.
More agents are under investigation, including lenvatinib, another multikinase inhibitor. In results of a phase 3 randomized trial presented at the 2017 meeting of the American Society of Clinical Oncology, lenvatinib was noninferior to sorafenib in overall survival, with treatment-related adverse effects such as hypertension and diarrhea that were expected based on previous experience with the drug, investigators said.
Cancer immunotherapy is making inroads into HCC. Just a few months after approving regorafenib, the FDA granted approval to nivolumab, a PD-1 inhibitor, for patients with HCC previously treated with sorafenib. The September 2017 approval of this checkpoint inhibitor was based in part on data from the CheckMate-040 trial that included a 14.3% response rate in the 154-patient subgroup of patients who had progressive disease on sorafenib or were intolerant of the treatment.
Dr. Pyrsopoulos highlighted another checkpoint inhibitor, known as BGB-A317, or tislelizumab. In January, BeiGene announced the initiation of a global phase 3 trial of this anti-PD-1 antibody versus sorafenib as first-line treatment of patients with unresectable HCC.
Although cancer immunotherapy holds great promise for HCC and other cancers, the treatments are associated with unique immune-related adverse events (irAEs) including immune-related hepatitis that may require corticosteroid treatment, according to Dr. Pyrsopoulos.
Dr. Pyrsopoulos reported disclosures related to AbbVie, Bayer, Genfit, Gilead Sciences, Hologic, Merck, Prometheus, Shire, and Vital Therapies.
Global Academy for Medical Education and this news organization are owned by the same company.
PHILADELPHIA – Recent approvals and investigations of targeted and immune treatments for advanced hepatocellular carcinoma (HCC) are encouraging, Nikolaos Pyrsopoulos, MD, MBA, said at Digestive Diseases: New Advances, jointly provided by Rutgers and Global Academy for Medical Education.
“I am excited, because a few years ago, there was only one [Food and Drug Administration] approved medication,” Dr. Pyrsopoulos, division director for gastroenterology and hepatology at Rutgers New Jersey Medical School, Newark, said in an interview. “We are on the cusp where new compounds not only are being tested, but they are being approved.”
Median overall survival in CELESTIAL was 10.2 months for cabozantinib versus 8.0 for placebo (P = .0049), according to the published report, and investigators also reported significant improvements in progression-free survival and response versus placebo.
“It is very encouraging,” Dr. Pyrsopoulos said of the cabozantinib results in a presentation on advances in HCC that he gave at the conference.
For years, the only FDA-approved treatment for advanced HCC was sorafenib. In the randomized phase 3 SHARP trial, published in the New England Journal of Medicine in 2008, patients receiving the multikinase inhibitor had a median survival of 10.7 months, versus 7.9 months for placebo (P less than .001).
In April 2017, the FDA approved regorafenib for patients with HCC previously treated with sorafenib. In the randomized phase 3 RESORCE trial, published in The Lancet in 2017, median overall survival was 10.6 months for regorafenib-treated patients versus 7.8 months in the placebo group. Investigators reported that regorafenib improved overall survival with a hazard ratio of 0.63 (P less than .0001).
Dr. Pyrsopoulos noted that a strategy of sorafenib followed by regorafenib would combine two treatments, each of which in clinical trials had a median overall survival approaching 11 months.
“In essence, you have an approximate 2-year survival,” he said.
More agents are under investigation, including lenvatinib, another multikinase inhibitor. In results of a phase 3 randomized trial presented at the 2017 meeting of the American Society of Clinical Oncology, lenvatinib was noninferior to sorafenib in overall survival, with treatment-related adverse effects such as hypertension and diarrhea that were expected based on previous experience with the drug, investigators said.
Cancer immunotherapy is making inroads into HCC. Just a few months after approving regorafenib, the FDA granted approval to nivolumab, a PD-1 inhibitor, for patients with HCC previously treated with sorafenib. The September 2017 approval of this checkpoint inhibitor was based in part on data from the CheckMate-040 trial that included a 14.3% response rate in the 154-patient subgroup of patients who had progressive disease on sorafenib or were intolerant of the treatment.
Dr. Pyrsopoulos highlighted another checkpoint inhibitor, known as BGB-A317, or tislelizumab. In January, BeiGene announced the initiation of a global phase 3 trial of this anti-PD-1 antibody versus sorafenib as first-line treatment of patients with unresectable HCC.
Although cancer immunotherapy holds great promise for HCC and other cancers, the treatments are associated with unique immune-related adverse events (irAEs) including immune-related hepatitis that may require corticosteroid treatment, according to Dr. Pyrsopoulos.
Dr. Pyrsopoulos reported disclosures related to AbbVie, Bayer, Genfit, Gilead Sciences, Hologic, Merck, Prometheus, Shire, and Vital Therapies.
Global Academy for Medical Education and this news organization are owned by the same company.
PHILADELPHIA – Recent approvals and investigations of targeted and immune treatments for advanced hepatocellular carcinoma (HCC) are encouraging, Nikolaos Pyrsopoulos, MD, MBA, said at Digestive Diseases: New Advances, jointly provided by Rutgers and Global Academy for Medical Education.
“I am excited, because a few years ago, there was only one [Food and Drug Administration] approved medication,” Dr. Pyrsopoulos, division director for gastroenterology and hepatology at Rutgers New Jersey Medical School, Newark, said in an interview. “We are on the cusp where new compounds not only are being tested, but they are being approved.”
Median overall survival in CELESTIAL was 10.2 months for cabozantinib versus 8.0 for placebo (P = .0049), according to the published report, and investigators also reported significant improvements in progression-free survival and response versus placebo.
“It is very encouraging,” Dr. Pyrsopoulos said of the cabozantinib results in a presentation on advances in HCC that he gave at the conference.
For years, the only FDA-approved treatment for advanced HCC was sorafenib. In the randomized phase 3 SHARP trial, published in the New England Journal of Medicine in 2008, patients receiving the multikinase inhibitor had a median survival of 10.7 months, versus 7.9 months for placebo (P less than .001).
In April 2017, the FDA approved regorafenib for patients with HCC previously treated with sorafenib. In the randomized phase 3 RESORCE trial, published in The Lancet in 2017, median overall survival was 10.6 months for regorafenib-treated patients versus 7.8 months in the placebo group. Investigators reported that regorafenib improved overall survival with a hazard ratio of 0.63 (P less than .0001).
Dr. Pyrsopoulos noted that a strategy of sorafenib followed by regorafenib would combine two treatments, each of which in clinical trials had a median overall survival approaching 11 months.
“In essence, you have an approximate 2-year survival,” he said.
More agents are under investigation, including lenvatinib, another multikinase inhibitor. In results of a phase 3 randomized trial presented at the 2017 meeting of the American Society of Clinical Oncology, lenvatinib was noninferior to sorafenib in overall survival, with treatment-related adverse effects such as hypertension and diarrhea that were expected based on previous experience with the drug, investigators said.
Cancer immunotherapy is making inroads into HCC. Just a few months after approving regorafenib, the FDA granted approval to nivolumab, a PD-1 inhibitor, for patients with HCC previously treated with sorafenib. The September 2017 approval of this checkpoint inhibitor was based in part on data from the CheckMate-040 trial that included a 14.3% response rate in the 154-patient subgroup of patients who had progressive disease on sorafenib or were intolerant of the treatment.
Dr. Pyrsopoulos highlighted another checkpoint inhibitor, known as BGB-A317, or tislelizumab. In January, BeiGene announced the initiation of a global phase 3 trial of this anti-PD-1 antibody versus sorafenib as first-line treatment of patients with unresectable HCC.
Although cancer immunotherapy holds great promise for HCC and other cancers, the treatments are associated with unique immune-related adverse events (irAEs) including immune-related hepatitis that may require corticosteroid treatment, according to Dr. Pyrsopoulos.
Dr. Pyrsopoulos reported disclosures related to AbbVie, Bayer, Genfit, Gilead Sciences, Hologic, Merck, Prometheus, Shire, and Vital Therapies.
Global Academy for Medical Education and this news organization are owned by the same company.
REPORTING FROM DIGESTIVE DISEASES: NEW ADVANCES
Early results favorable for combo TLR9 agonist + pembro in advanced melanoma
CHICAGO – The intratumoral Toll-Like Receptor 9 (TLR-9) agonist, CMP-001, in combination with pembrolizumab in advanced melanoma patients, was well tolerated with a durable systemic clinical response, according to early results from an ongoing phase 1 trial.
Objective response rates on weekly (n = 56) and every 3 weeks schedules (n = 13) were 23% (13%-36%) and 15% (2%-45%) respectively, reported Mohammed M. Milhem, MBBS, of the University of Iowa, Iowa City.
For those dosed weekly at low dose (less than 5 mL) and high dose (5 mL or more), the ORR was 19% (n = 43, 95% confidence interval, 8%-33%) and 27% (n = 26, 95% CI, 12%-48%), respectively. Activity was demonstrated in subjects regardless of tumor burden, Dr. Milhem said at the annual meeting of the American Association for Cancer Research.
In this phase 1b study with a 3+3 design of dose escalation and expansion, the researchers enrolled patients with advanced melanoma who did not respond or had progressed resistant on prior anti-PD-1 monotherapy or in combination. CMP-001 was injected intratumorally in combination with pembrolizumab as per label intravenously.
The study drug CMP-001 has two components, a 30-mer CpG-A DNA oligonucleotide and a nonvirulent virus-like particle (VLP). The CpG-A DNA is packaged within the VLP that protects it from degradation and also allows TLR9 receptor uptake. CpG-A DNA acts as a TLR9 agonist by binding to it, thereby activating plasmacytoid dendritic cells (pDCs) within the tumor microenvironment. The activation results in secretion of large amounts of type 1 interferon and Th1 chemokines, changing the microenvironment from a “cold/desert-like” immune suppressed state to a “hot” antitumor inflamed state, Dr. Milhem said.
“The T cells thus generated can mediate tumor rejection both in the injected and noninjected tumor,” he said. Two CMP-001 schedules were evaluated, weekly for 7 weeks or weekly for 2 weeks, followed thereafter by every 3 weeks until discontinuation (due to progression, toxicity, investigator decision, or withdrawal of consent). Scans were done every 12 weeks and tumor response was assessed by RECIST v1.1.
The CMP-001 dose escalation scheme ranged from 1 mg to 10 mg. The maximum tolerated dose was not reached and the dose of 5 mg/weekly plus pembrolizumab was used for the dose expansion phase. It was up to the investigator to increase the dose to 10 mg since maximum tolerated dose was not reached. The key inclusion criteria were metastatic or unresectable melanoma; in the dose escalation phase prior best response to anti-PD1-based therapy was disease progression or stable disease. In the dose expansion phase, patients who had progressed on anti-PD1 based therapy were allowed regardless of best response. There was no restriction on the number of prior lines of therapy.
A total of 69 subjects were treated, 44 subjects from dose escalation and 25 in the expansion phase (ongoing). Two subjects discontinued because of treatment-related adverse events. The rest of the patients had a manageable toxicity profile consisting predominantly of fever, nausea/vomiting, hypotension and rigors. Severe grade 3/4 treatment-related adverse events were reported in more than 1 subject, with hypotension (n = 9, 13%) being the most prominent AE, followed by anemia (n = 2, 3%), chills (n = 2, 3%), and hypertension (n = 2, 3%). Hypotension was manageable by responsive fluid resuscitation and in some patients required stress dose steroids. Most of these side effects occurred 1-4 hours after the CMP-001 injection.
Of the 18 responders, 1 progressed, 2 withdrew consent, and 13 remain on study with 2 subjects maintaining their response though week 72. The median duration of response was not reached. Regression of noninjected tumors occurred in cutaneous, nodal, hepatic, and splenic metastases.
“CMP-001 plus pembrolizumab induced systemic antitumor activity, and not just local efficacy since both injected and noninjected target lesions changed from baseline per RECIST,” Dr. Milhem said. Not only did the responders show a rapid reduction in target lesions from baseline, but also a durable tumor regression as usually seen with other immunotherapeutics.
Immunohistochemical analysis of tumor biopsies demonstrated increase in CD8 (greater than fivefold) and PD-L1 expression, 5 weeks after therapy in a subset of patients with pre- and posttreatment biopsies. Transcriptional analysis by RNA-seq revealed induction of T cell inflamed gene signature, notably significant upregulation of TLR, and IFN-responsive genes.
It would be interesting to further investigate how this combination therapy compares with other strategies in a similar clinical scenario, such as oncolytic virus, other TLR ligands or means of APC activation, discussant Jedd Wolchok, MD, PhD, pointed out. Understanding resistance mechanisms at an individual patient level and optimal patient selection for this combination therapy remains a challenge, he said.
Dr. Milhem had no financial relationships to disclose.
SOURCE: Milhem MD et al. AACR Annual Meeting Abstract CT144.
CHICAGO – The intratumoral Toll-Like Receptor 9 (TLR-9) agonist, CMP-001, in combination with pembrolizumab in advanced melanoma patients, was well tolerated with a durable systemic clinical response, according to early results from an ongoing phase 1 trial.
Objective response rates on weekly (n = 56) and every 3 weeks schedules (n = 13) were 23% (13%-36%) and 15% (2%-45%) respectively, reported Mohammed M. Milhem, MBBS, of the University of Iowa, Iowa City.
For those dosed weekly at low dose (less than 5 mL) and high dose (5 mL or more), the ORR was 19% (n = 43, 95% confidence interval, 8%-33%) and 27% (n = 26, 95% CI, 12%-48%), respectively. Activity was demonstrated in subjects regardless of tumor burden, Dr. Milhem said at the annual meeting of the American Association for Cancer Research.
In this phase 1b study with a 3+3 design of dose escalation and expansion, the researchers enrolled patients with advanced melanoma who did not respond or had progressed resistant on prior anti-PD-1 monotherapy or in combination. CMP-001 was injected intratumorally in combination with pembrolizumab as per label intravenously.
The study drug CMP-001 has two components, a 30-mer CpG-A DNA oligonucleotide and a nonvirulent virus-like particle (VLP). The CpG-A DNA is packaged within the VLP that protects it from degradation and also allows TLR9 receptor uptake. CpG-A DNA acts as a TLR9 agonist by binding to it, thereby activating plasmacytoid dendritic cells (pDCs) within the tumor microenvironment. The activation results in secretion of large amounts of type 1 interferon and Th1 chemokines, changing the microenvironment from a “cold/desert-like” immune suppressed state to a “hot” antitumor inflamed state, Dr. Milhem said.
“The T cells thus generated can mediate tumor rejection both in the injected and noninjected tumor,” he said. Two CMP-001 schedules were evaluated, weekly for 7 weeks or weekly for 2 weeks, followed thereafter by every 3 weeks until discontinuation (due to progression, toxicity, investigator decision, or withdrawal of consent). Scans were done every 12 weeks and tumor response was assessed by RECIST v1.1.
The CMP-001 dose escalation scheme ranged from 1 mg to 10 mg. The maximum tolerated dose was not reached and the dose of 5 mg/weekly plus pembrolizumab was used for the dose expansion phase. It was up to the investigator to increase the dose to 10 mg since maximum tolerated dose was not reached. The key inclusion criteria were metastatic or unresectable melanoma; in the dose escalation phase prior best response to anti-PD1-based therapy was disease progression or stable disease. In the dose expansion phase, patients who had progressed on anti-PD1 based therapy were allowed regardless of best response. There was no restriction on the number of prior lines of therapy.
A total of 69 subjects were treated, 44 subjects from dose escalation and 25 in the expansion phase (ongoing). Two subjects discontinued because of treatment-related adverse events. The rest of the patients had a manageable toxicity profile consisting predominantly of fever, nausea/vomiting, hypotension and rigors. Severe grade 3/4 treatment-related adverse events were reported in more than 1 subject, with hypotension (n = 9, 13%) being the most prominent AE, followed by anemia (n = 2, 3%), chills (n = 2, 3%), and hypertension (n = 2, 3%). Hypotension was manageable by responsive fluid resuscitation and in some patients required stress dose steroids. Most of these side effects occurred 1-4 hours after the CMP-001 injection.
Of the 18 responders, 1 progressed, 2 withdrew consent, and 13 remain on study with 2 subjects maintaining their response though week 72. The median duration of response was not reached. Regression of noninjected tumors occurred in cutaneous, nodal, hepatic, and splenic metastases.
“CMP-001 plus pembrolizumab induced systemic antitumor activity, and not just local efficacy since both injected and noninjected target lesions changed from baseline per RECIST,” Dr. Milhem said. Not only did the responders show a rapid reduction in target lesions from baseline, but also a durable tumor regression as usually seen with other immunotherapeutics.
Immunohistochemical analysis of tumor biopsies demonstrated increase in CD8 (greater than fivefold) and PD-L1 expression, 5 weeks after therapy in a subset of patients with pre- and posttreatment biopsies. Transcriptional analysis by RNA-seq revealed induction of T cell inflamed gene signature, notably significant upregulation of TLR, and IFN-responsive genes.
It would be interesting to further investigate how this combination therapy compares with other strategies in a similar clinical scenario, such as oncolytic virus, other TLR ligands or means of APC activation, discussant Jedd Wolchok, MD, PhD, pointed out. Understanding resistance mechanisms at an individual patient level and optimal patient selection for this combination therapy remains a challenge, he said.
Dr. Milhem had no financial relationships to disclose.
SOURCE: Milhem MD et al. AACR Annual Meeting Abstract CT144.
CHICAGO – The intratumoral Toll-Like Receptor 9 (TLR-9) agonist, CMP-001, in combination with pembrolizumab in advanced melanoma patients, was well tolerated with a durable systemic clinical response, according to early results from an ongoing phase 1 trial.
Objective response rates on weekly (n = 56) and every 3 weeks schedules (n = 13) were 23% (13%-36%) and 15% (2%-45%) respectively, reported Mohammed M. Milhem, MBBS, of the University of Iowa, Iowa City.
For those dosed weekly at low dose (less than 5 mL) and high dose (5 mL or more), the ORR was 19% (n = 43, 95% confidence interval, 8%-33%) and 27% (n = 26, 95% CI, 12%-48%), respectively. Activity was demonstrated in subjects regardless of tumor burden, Dr. Milhem said at the annual meeting of the American Association for Cancer Research.
In this phase 1b study with a 3+3 design of dose escalation and expansion, the researchers enrolled patients with advanced melanoma who did not respond or had progressed resistant on prior anti-PD-1 monotherapy or in combination. CMP-001 was injected intratumorally in combination with pembrolizumab as per label intravenously.
The study drug CMP-001 has two components, a 30-mer CpG-A DNA oligonucleotide and a nonvirulent virus-like particle (VLP). The CpG-A DNA is packaged within the VLP that protects it from degradation and also allows TLR9 receptor uptake. CpG-A DNA acts as a TLR9 agonist by binding to it, thereby activating plasmacytoid dendritic cells (pDCs) within the tumor microenvironment. The activation results in secretion of large amounts of type 1 interferon and Th1 chemokines, changing the microenvironment from a “cold/desert-like” immune suppressed state to a “hot” antitumor inflamed state, Dr. Milhem said.
“The T cells thus generated can mediate tumor rejection both in the injected and noninjected tumor,” he said. Two CMP-001 schedules were evaluated, weekly for 7 weeks or weekly for 2 weeks, followed thereafter by every 3 weeks until discontinuation (due to progression, toxicity, investigator decision, or withdrawal of consent). Scans were done every 12 weeks and tumor response was assessed by RECIST v1.1.
The CMP-001 dose escalation scheme ranged from 1 mg to 10 mg. The maximum tolerated dose was not reached and the dose of 5 mg/weekly plus pembrolizumab was used for the dose expansion phase. It was up to the investigator to increase the dose to 10 mg since maximum tolerated dose was not reached. The key inclusion criteria were metastatic or unresectable melanoma; in the dose escalation phase prior best response to anti-PD1-based therapy was disease progression or stable disease. In the dose expansion phase, patients who had progressed on anti-PD1 based therapy were allowed regardless of best response. There was no restriction on the number of prior lines of therapy.
A total of 69 subjects were treated, 44 subjects from dose escalation and 25 in the expansion phase (ongoing). Two subjects discontinued because of treatment-related adverse events. The rest of the patients had a manageable toxicity profile consisting predominantly of fever, nausea/vomiting, hypotension and rigors. Severe grade 3/4 treatment-related adverse events were reported in more than 1 subject, with hypotension (n = 9, 13%) being the most prominent AE, followed by anemia (n = 2, 3%), chills (n = 2, 3%), and hypertension (n = 2, 3%). Hypotension was manageable by responsive fluid resuscitation and in some patients required stress dose steroids. Most of these side effects occurred 1-4 hours after the CMP-001 injection.
Of the 18 responders, 1 progressed, 2 withdrew consent, and 13 remain on study with 2 subjects maintaining their response though week 72. The median duration of response was not reached. Regression of noninjected tumors occurred in cutaneous, nodal, hepatic, and splenic metastases.
“CMP-001 plus pembrolizumab induced systemic antitumor activity, and not just local efficacy since both injected and noninjected target lesions changed from baseline per RECIST,” Dr. Milhem said. Not only did the responders show a rapid reduction in target lesions from baseline, but also a durable tumor regression as usually seen with other immunotherapeutics.
Immunohistochemical analysis of tumor biopsies demonstrated increase in CD8 (greater than fivefold) and PD-L1 expression, 5 weeks after therapy in a subset of patients with pre- and posttreatment biopsies. Transcriptional analysis by RNA-seq revealed induction of T cell inflamed gene signature, notably significant upregulation of TLR, and IFN-responsive genes.
It would be interesting to further investigate how this combination therapy compares with other strategies in a similar clinical scenario, such as oncolytic virus, other TLR ligands or means of APC activation, discussant Jedd Wolchok, MD, PhD, pointed out. Understanding resistance mechanisms at an individual patient level and optimal patient selection for this combination therapy remains a challenge, he said.
Dr. Milhem had no financial relationships to disclose.
SOURCE: Milhem MD et al. AACR Annual Meeting Abstract CT144.
REPORTING FROM THE AACR ANNUAL MEETING
Key clinical point: The combination demonstrated a manageable toxicity profile with ORR of 22%.
Major finding: Objective response rates on weekly (n = 56) and every 3 weeks schedules (n = 13) were 23% (13%-36%) and 15% (2%-45%) respectively.
Study details: This phase 1b study comprised 69 patients (44 in escalation and 25 in expansion).
Disclosures: Dr. Milhem had no financial relationships to disclose.
Source: Milhem MD et al. AACR Annual Meeting. Abstract CT144.