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Sharon Worcester is an award-winning medical journalist for MDedge News. She has been with the company since 1996, first as the Southeast Bureau Chief (1996-2009) when the company was known as International Medical News Group, then as a freelance writer (2010-2015) before returning as a reporter in 2015. She previously worked as a daily newspaper reporter covering health and local government. Sharon currently reports primarily on oncology and hematology. She has a BA from Eckerd College and an MA in Mass Communication/Print Journalism from the University of Florida. Connect with her via LinkedIn and follow her on twitter @SW_MedReporter.
GALACTIC CLL trial: Obinutuzumab consolidation helps eradicate MRD
EDINBURGH – Consolidation therapy with obinutuzumab after chemoimmunotherapy for B-cell chronic lymphocytic leukemia (B-CLL) was highly effective for eradicating minimal residual disease (MRD) within 6 months following randomization in the seamless phase 2/3 GALACTIC trial.
Of 14 patients who were MRD positive after chemoimmunotherapy and randomized to consolidation with the type II monoclonal antibody targeting the CD20 antigen, 10 achieved MRD negativity in the bone marrow by 6 months, and 13 achieved MRD negativity in the peripheral blood by 6 months, Talha Munir, MD, reported at the International Workshop on Chronic Lymphocytic Leukemia.
“And that translated into [progression-free survival] improvement in the consolidation arm,” said Dr. Munir of St. James’s University, Leeds, England.
The median progression-free survival in that arm was not reached, whereas progression-free survival in 15 MRD-positive patients randomized to the nonconsolidation arm was 16.6 months, he said.
Further, no difference was seen in median progression-free survival, overall survival, or MRD duration between the consolidation arm and 19 patients who were not randomized because of MRD negativity after chemoimmunotherapy, he noted.
Achieving MRD negativity in CLL confers a survival advantage, and obinutuzumab has shown greater efficacy with respect to MRD in CLL when compared with previous anti-CD20 antibodies, and it is less immune suppressive than the anti-CD52 antibody alemtuzumab, he explained.
The GALACTIC trial was designed to assess the safety and efficacy of obinutuzumab consolidation for eradicating MRD and whether its effects would prolong progression-free survival in patients with B-CLL who recently responded to chemoimmunotherapy. Those achieving complete response or partial response at 3-24 months after chemoimmunotherapy, and who remained MRD-positive, were eligible for randomization.
The planned sample size was 188 patients, but the trial was closed early in February 2017 because of poor recruitment; a total of 48 patients were enrolled, including the 19 nonrandomized, MRD-negative patients.
Patients randomized to consolidation received 1,000 mg of obinutuzumab weekly for the first four doses, and then every other week for four additional doses.
Obinutuzumab was well tolerated with minimal infusion-related reactions and toxicity, Dr. Munir said.
Despite the low recruitment, both the phase 2 and 3 endpoints were assessed as positive, because the consolidation strategy was so efficacious, Dr. Munir noted, concluding that the findings provide further evidence of the value of MRD negativity for improving outcomes in CLL.
The GALACTIC trial was developed by the GALACTIC Trial Management Group with the support of the UKCLL/NCRI CLL Clinical Trials Subgroup. The trial is funded by Cancer Research UK and Roche and sponsored by the University of Leeds. Dr. Munir reported having no disclosures.
[email protected]
EDINBURGH – Consolidation therapy with obinutuzumab after chemoimmunotherapy for B-cell chronic lymphocytic leukemia (B-CLL) was highly effective for eradicating minimal residual disease (MRD) within 6 months following randomization in the seamless phase 2/3 GALACTIC trial.
Of 14 patients who were MRD positive after chemoimmunotherapy and randomized to consolidation with the type II monoclonal antibody targeting the CD20 antigen, 10 achieved MRD negativity in the bone marrow by 6 months, and 13 achieved MRD negativity in the peripheral blood by 6 months, Talha Munir, MD, reported at the International Workshop on Chronic Lymphocytic Leukemia.
“And that translated into [progression-free survival] improvement in the consolidation arm,” said Dr. Munir of St. James’s University, Leeds, England.
The median progression-free survival in that arm was not reached, whereas progression-free survival in 15 MRD-positive patients randomized to the nonconsolidation arm was 16.6 months, he said.
Further, no difference was seen in median progression-free survival, overall survival, or MRD duration between the consolidation arm and 19 patients who were not randomized because of MRD negativity after chemoimmunotherapy, he noted.
Achieving MRD negativity in CLL confers a survival advantage, and obinutuzumab has shown greater efficacy with respect to MRD in CLL when compared with previous anti-CD20 antibodies, and it is less immune suppressive than the anti-CD52 antibody alemtuzumab, he explained.
The GALACTIC trial was designed to assess the safety and efficacy of obinutuzumab consolidation for eradicating MRD and whether its effects would prolong progression-free survival in patients with B-CLL who recently responded to chemoimmunotherapy. Those achieving complete response or partial response at 3-24 months after chemoimmunotherapy, and who remained MRD-positive, were eligible for randomization.
The planned sample size was 188 patients, but the trial was closed early in February 2017 because of poor recruitment; a total of 48 patients were enrolled, including the 19 nonrandomized, MRD-negative patients.
Patients randomized to consolidation received 1,000 mg of obinutuzumab weekly for the first four doses, and then every other week for four additional doses.
Obinutuzumab was well tolerated with minimal infusion-related reactions and toxicity, Dr. Munir said.
Despite the low recruitment, both the phase 2 and 3 endpoints were assessed as positive, because the consolidation strategy was so efficacious, Dr. Munir noted, concluding that the findings provide further evidence of the value of MRD negativity for improving outcomes in CLL.
The GALACTIC trial was developed by the GALACTIC Trial Management Group with the support of the UKCLL/NCRI CLL Clinical Trials Subgroup. The trial is funded by Cancer Research UK and Roche and sponsored by the University of Leeds. Dr. Munir reported having no disclosures.
[email protected]
EDINBURGH – Consolidation therapy with obinutuzumab after chemoimmunotherapy for B-cell chronic lymphocytic leukemia (B-CLL) was highly effective for eradicating minimal residual disease (MRD) within 6 months following randomization in the seamless phase 2/3 GALACTIC trial.
Of 14 patients who were MRD positive after chemoimmunotherapy and randomized to consolidation with the type II monoclonal antibody targeting the CD20 antigen, 10 achieved MRD negativity in the bone marrow by 6 months, and 13 achieved MRD negativity in the peripheral blood by 6 months, Talha Munir, MD, reported at the International Workshop on Chronic Lymphocytic Leukemia.
“And that translated into [progression-free survival] improvement in the consolidation arm,” said Dr. Munir of St. James’s University, Leeds, England.
The median progression-free survival in that arm was not reached, whereas progression-free survival in 15 MRD-positive patients randomized to the nonconsolidation arm was 16.6 months, he said.
Further, no difference was seen in median progression-free survival, overall survival, or MRD duration between the consolidation arm and 19 patients who were not randomized because of MRD negativity after chemoimmunotherapy, he noted.
Achieving MRD negativity in CLL confers a survival advantage, and obinutuzumab has shown greater efficacy with respect to MRD in CLL when compared with previous anti-CD20 antibodies, and it is less immune suppressive than the anti-CD52 antibody alemtuzumab, he explained.
The GALACTIC trial was designed to assess the safety and efficacy of obinutuzumab consolidation for eradicating MRD and whether its effects would prolong progression-free survival in patients with B-CLL who recently responded to chemoimmunotherapy. Those achieving complete response or partial response at 3-24 months after chemoimmunotherapy, and who remained MRD-positive, were eligible for randomization.
The planned sample size was 188 patients, but the trial was closed early in February 2017 because of poor recruitment; a total of 48 patients were enrolled, including the 19 nonrandomized, MRD-negative patients.
Patients randomized to consolidation received 1,000 mg of obinutuzumab weekly for the first four doses, and then every other week for four additional doses.
Obinutuzumab was well tolerated with minimal infusion-related reactions and toxicity, Dr. Munir said.
Despite the low recruitment, both the phase 2 and 3 endpoints were assessed as positive, because the consolidation strategy was so efficacious, Dr. Munir noted, concluding that the findings provide further evidence of the value of MRD negativity for improving outcomes in CLL.
The GALACTIC trial was developed by the GALACTIC Trial Management Group with the support of the UKCLL/NCRI CLL Clinical Trials Subgroup. The trial is funded by Cancer Research UK and Roche and sponsored by the University of Leeds. Dr. Munir reported having no disclosures.
[email protected]
REPORTING FROM iwCLL 2019
OS benefit with pembrolizumab endures long-term in advanced NSCLC
BARCELONA – First-line pembrolizumab provides a durable long-term overall survival (OS) benefit, compared with that of chemotherapy, in patients with advanced nonsquamous non–small cell lung cancer (NSCLC), according to 3-year data from the phase 3 Keynote-024 trial.
As previously reported, first-line treatment with the programmed death-1 (PD-1) inhibitor significantly improved progression-free survival (PFS) and OS, compared with those of platinum-based chemotherapy, and had fewer adverse events after a median of 11.2 months of follow-up in the open-label trial. In 305 patients with advanced NSCLC, high PD-L1 expression, and an absence of targetable epidermal growth factor or anaplastic lymphoma kinase gene alterations, median PFS was 10.3 months vs. 6.0 months, and estimated OS was 80.2% vs. 72.4% in the groups, respectively (hazard ratios, 0.50 and 0.60, respectively).
At 3 years after treatment initiation, median OS was 26.3 months vs. 14.2 months in patients treated with pembrolizumab or chemotherapy (HR, 0.65), respectively, and the OS rates were 43.7% and 24.9%, Martin Reck, MD, reported at the World Conference on Lung Cancer.
This was despite 98 of 151 patients assigned to chemotherapy crossing over to pembrolizumab, Dr. Reck, head of the department of thoracic oncology and the clinical trial department in the department of thoracic oncology at the Lung Clinic Grosshansdorf (Germany), noted at the conference, which was sponsored by the International Association for the Study of Lung Cancer.
Additionally, despite longer mean treatment duration in the pembrolizumab arm than in the chemotherapy arm (11.1 vs. 4.4 months), grade 3-5 treatment-related adverse events were less frequent with pembrolizumab than with chemotherapy (31.2% vs. 53.3%), he said.
Of 38 patients in the pembrolizumab arm who completed 2 years of therapy, 34 were alive at 3 years, and 31 (81.6%) had an objective response, including 2 who had a complete response. Median duration of response was not reached, and OS was 97.4%.
Grade 3-5 adverse events occurred in 5 (13.2%) of those patients; no fatal treatment-related adverse events occurred.
Of note, 7 of 10 patients who completed 2 years of treatment, but who subsequently progressed, experienced an objective response with a second course of pembrolizumab, and 8 remain alive, he said.
Patients in KEYNOTE-024 were randomized to receive 200 mg of pembrolizumab every 3 weeks for 2 years or investigator’s choice of platinum doublet for 4-6 cycles plus optional maintenance, with stratification by performance status, tumor histology, and region.
The findings confirm the long-term efficacy of pembrolizumab, compared with platinum-based chemotherapy, demonstrate “consistent benefit in overall survival ... despite a crossover of 65%,” and show the first signs of efficacy with reexposure to pembrolizumab at the time of progression.
“This is work in progress; currently we have data from 10 [reexposed] patients, but what we do see is clinical activity even after [reexposure] to pembrolizumab, so we do see a stabilization of response to the disease in 70% of the patients, and 50% are ongoing.”
The findings highlight a new reality: “There are really some patients who have this disease as a chronic disease induced by immunotherapy.” Dr. Reck said.
KEYNOTE-024 was funded by Merck Sharp & Dohme. Dr. Reck reported receiving personal fees/honoraria for consultancy and lectures from Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Merck Sharp & Dohme, MSD, Eli Lilly, Pfizer, AbbVie, Roche, and Novartis.
SOURCE: Reck M et al. WCLC 2019, Abstract OA14.01.
BARCELONA – First-line pembrolizumab provides a durable long-term overall survival (OS) benefit, compared with that of chemotherapy, in patients with advanced nonsquamous non–small cell lung cancer (NSCLC), according to 3-year data from the phase 3 Keynote-024 trial.
As previously reported, first-line treatment with the programmed death-1 (PD-1) inhibitor significantly improved progression-free survival (PFS) and OS, compared with those of platinum-based chemotherapy, and had fewer adverse events after a median of 11.2 months of follow-up in the open-label trial. In 305 patients with advanced NSCLC, high PD-L1 expression, and an absence of targetable epidermal growth factor or anaplastic lymphoma kinase gene alterations, median PFS was 10.3 months vs. 6.0 months, and estimated OS was 80.2% vs. 72.4% in the groups, respectively (hazard ratios, 0.50 and 0.60, respectively).
At 3 years after treatment initiation, median OS was 26.3 months vs. 14.2 months in patients treated with pembrolizumab or chemotherapy (HR, 0.65), respectively, and the OS rates were 43.7% and 24.9%, Martin Reck, MD, reported at the World Conference on Lung Cancer.
This was despite 98 of 151 patients assigned to chemotherapy crossing over to pembrolizumab, Dr. Reck, head of the department of thoracic oncology and the clinical trial department in the department of thoracic oncology at the Lung Clinic Grosshansdorf (Germany), noted at the conference, which was sponsored by the International Association for the Study of Lung Cancer.
Additionally, despite longer mean treatment duration in the pembrolizumab arm than in the chemotherapy arm (11.1 vs. 4.4 months), grade 3-5 treatment-related adverse events were less frequent with pembrolizumab than with chemotherapy (31.2% vs. 53.3%), he said.
Of 38 patients in the pembrolizumab arm who completed 2 years of therapy, 34 were alive at 3 years, and 31 (81.6%) had an objective response, including 2 who had a complete response. Median duration of response was not reached, and OS was 97.4%.
Grade 3-5 adverse events occurred in 5 (13.2%) of those patients; no fatal treatment-related adverse events occurred.
Of note, 7 of 10 patients who completed 2 years of treatment, but who subsequently progressed, experienced an objective response with a second course of pembrolizumab, and 8 remain alive, he said.
Patients in KEYNOTE-024 were randomized to receive 200 mg of pembrolizumab every 3 weeks for 2 years or investigator’s choice of platinum doublet for 4-6 cycles plus optional maintenance, with stratification by performance status, tumor histology, and region.
The findings confirm the long-term efficacy of pembrolizumab, compared with platinum-based chemotherapy, demonstrate “consistent benefit in overall survival ... despite a crossover of 65%,” and show the first signs of efficacy with reexposure to pembrolizumab at the time of progression.
“This is work in progress; currently we have data from 10 [reexposed] patients, but what we do see is clinical activity even after [reexposure] to pembrolizumab, so we do see a stabilization of response to the disease in 70% of the patients, and 50% are ongoing.”
The findings highlight a new reality: “There are really some patients who have this disease as a chronic disease induced by immunotherapy.” Dr. Reck said.
KEYNOTE-024 was funded by Merck Sharp & Dohme. Dr. Reck reported receiving personal fees/honoraria for consultancy and lectures from Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Merck Sharp & Dohme, MSD, Eli Lilly, Pfizer, AbbVie, Roche, and Novartis.
SOURCE: Reck M et al. WCLC 2019, Abstract OA14.01.
BARCELONA – First-line pembrolizumab provides a durable long-term overall survival (OS) benefit, compared with that of chemotherapy, in patients with advanced nonsquamous non–small cell lung cancer (NSCLC), according to 3-year data from the phase 3 Keynote-024 trial.
As previously reported, first-line treatment with the programmed death-1 (PD-1) inhibitor significantly improved progression-free survival (PFS) and OS, compared with those of platinum-based chemotherapy, and had fewer adverse events after a median of 11.2 months of follow-up in the open-label trial. In 305 patients with advanced NSCLC, high PD-L1 expression, and an absence of targetable epidermal growth factor or anaplastic lymphoma kinase gene alterations, median PFS was 10.3 months vs. 6.0 months, and estimated OS was 80.2% vs. 72.4% in the groups, respectively (hazard ratios, 0.50 and 0.60, respectively).
At 3 years after treatment initiation, median OS was 26.3 months vs. 14.2 months in patients treated with pembrolizumab or chemotherapy (HR, 0.65), respectively, and the OS rates were 43.7% and 24.9%, Martin Reck, MD, reported at the World Conference on Lung Cancer.
This was despite 98 of 151 patients assigned to chemotherapy crossing over to pembrolizumab, Dr. Reck, head of the department of thoracic oncology and the clinical trial department in the department of thoracic oncology at the Lung Clinic Grosshansdorf (Germany), noted at the conference, which was sponsored by the International Association for the Study of Lung Cancer.
Additionally, despite longer mean treatment duration in the pembrolizumab arm than in the chemotherapy arm (11.1 vs. 4.4 months), grade 3-5 treatment-related adverse events were less frequent with pembrolizumab than with chemotherapy (31.2% vs. 53.3%), he said.
Of 38 patients in the pembrolizumab arm who completed 2 years of therapy, 34 were alive at 3 years, and 31 (81.6%) had an objective response, including 2 who had a complete response. Median duration of response was not reached, and OS was 97.4%.
Grade 3-5 adverse events occurred in 5 (13.2%) of those patients; no fatal treatment-related adverse events occurred.
Of note, 7 of 10 patients who completed 2 years of treatment, but who subsequently progressed, experienced an objective response with a second course of pembrolizumab, and 8 remain alive, he said.
Patients in KEYNOTE-024 were randomized to receive 200 mg of pembrolizumab every 3 weeks for 2 years or investigator’s choice of platinum doublet for 4-6 cycles plus optional maintenance, with stratification by performance status, tumor histology, and region.
The findings confirm the long-term efficacy of pembrolizumab, compared with platinum-based chemotherapy, demonstrate “consistent benefit in overall survival ... despite a crossover of 65%,” and show the first signs of efficacy with reexposure to pembrolizumab at the time of progression.
“This is work in progress; currently we have data from 10 [reexposed] patients, but what we do see is clinical activity even after [reexposure] to pembrolizumab, so we do see a stabilization of response to the disease in 70% of the patients, and 50% are ongoing.”
The findings highlight a new reality: “There are really some patients who have this disease as a chronic disease induced by immunotherapy.” Dr. Reck said.
KEYNOTE-024 was funded by Merck Sharp & Dohme. Dr. Reck reported receiving personal fees/honoraria for consultancy and lectures from Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Merck Sharp & Dohme, MSD, Eli Lilly, Pfizer, AbbVie, Roche, and Novartis.
SOURCE: Reck M et al. WCLC 2019, Abstract OA14.01.
REPORTING FROM WCLC 2019
IMpower131: Improvement in OS for stage IV NSCLC+high-PD-L1 expression
BARCELONA – Final overall survival (OS) did not differ significantly among patients with stage IV squamous non–small cell lung carcinoma who were treated with either first-line atezolizumab + chemotherapy or chemotherapy alone in the phase 3 IMpower131 trial.
Median OS in the intent-to-treat population was 14.2 months vs. 13.5 months with vs. without the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab, respectively (hazard ratio, 0.88), Federico Cappuzzo, MD, director of medical oncology at Azienda Unità Sanitaria Locale della Romagna-Ravenna, Italy, reported at the World Conference on Lung Cancer.
However, patients with high PD-L1 expression (14% and 13% of patients in the groups, respectively), experienced a clinically meaningful improvement in OS with atezolizumab + chemotherapy vs. chemotherapy alone (median of 23.4 vs. 10.2 months; HR, 0.48), Dr. Cappuzzo said at the conference, which was sponsored by the International Association for the Study of Lung Cancer.
“This means we had a reduction in the risk of death that was more than 50%,” he said, adding that no new or unexpected safety signals were reported.
IMpower131 randomized 1,021 patients with a median age of 65 years 1:1:1 to receive either atezolizumab (1,200 mg) + carboplatin (area under the curve 6) + paclitaxel (200 mg/m2) every 3 weeks, or atezolizumab + carboplatin + nab-paclitaxel (100 mg/m2 every week), or carboplatin + nab-paclitaxel for four or six cycles. Patients in the first two arms (A and B) received atezolizumab maintenance therapy until loss of clinical benefit or progressive disease occurred, and those in latter arm (C) received best supportive care after completing the treatment cycles.
The current analysis compared only the OS outcomes for arms B and C. Results of the primary analysis of investigator-assessed progression-free survival (PFS) – a coprimary endpoint of the trial – were reported in 2018 at the annual meeting of the American Society of Clinical Oncology and showed a statistically significant improvement in median PFS in arm B vs. arm C (6.3 vs. 5.6 months; HR, 0.715). The PFS benefit was seen in all PD-L1-positive subgroups.
“This was a very incredible trial, because it was conducted in a group of patients in which we need additional therapies – patients with squamous histology,” Dr. Cappuzzo said during a press briefing at the conference. “IMpower131 is certainly a positive study; we had PFS, as an independent coprimary endpoint, improve significantly, with a meaningful survival difference in the group of patients with strongly positive PD-L1 tumors.
“So these data clearly suggest that [patients with high PD-L1 expression), specifically, may benefit from the combination of chemotherapy and atezolizumab.”
He further noted in a press statement that “the findings provide additional evidence of the efficacy of immunotherapy in patients with lung cancer, and highlight the relevance of biomarkers for patient selection.”
Dr. Cappuzzo reported having no disclosures.
SOURCE: Cappuzzo F et al. WCLC 2019, Abstract OS14.02 .
BARCELONA – Final overall survival (OS) did not differ significantly among patients with stage IV squamous non–small cell lung carcinoma who were treated with either first-line atezolizumab + chemotherapy or chemotherapy alone in the phase 3 IMpower131 trial.
Median OS in the intent-to-treat population was 14.2 months vs. 13.5 months with vs. without the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab, respectively (hazard ratio, 0.88), Federico Cappuzzo, MD, director of medical oncology at Azienda Unità Sanitaria Locale della Romagna-Ravenna, Italy, reported at the World Conference on Lung Cancer.
However, patients with high PD-L1 expression (14% and 13% of patients in the groups, respectively), experienced a clinically meaningful improvement in OS with atezolizumab + chemotherapy vs. chemotherapy alone (median of 23.4 vs. 10.2 months; HR, 0.48), Dr. Cappuzzo said at the conference, which was sponsored by the International Association for the Study of Lung Cancer.
“This means we had a reduction in the risk of death that was more than 50%,” he said, adding that no new or unexpected safety signals were reported.
IMpower131 randomized 1,021 patients with a median age of 65 years 1:1:1 to receive either atezolizumab (1,200 mg) + carboplatin (area under the curve 6) + paclitaxel (200 mg/m2) every 3 weeks, or atezolizumab + carboplatin + nab-paclitaxel (100 mg/m2 every week), or carboplatin + nab-paclitaxel for four or six cycles. Patients in the first two arms (A and B) received atezolizumab maintenance therapy until loss of clinical benefit or progressive disease occurred, and those in latter arm (C) received best supportive care after completing the treatment cycles.
The current analysis compared only the OS outcomes for arms B and C. Results of the primary analysis of investigator-assessed progression-free survival (PFS) – a coprimary endpoint of the trial – were reported in 2018 at the annual meeting of the American Society of Clinical Oncology and showed a statistically significant improvement in median PFS in arm B vs. arm C (6.3 vs. 5.6 months; HR, 0.715). The PFS benefit was seen in all PD-L1-positive subgroups.
“This was a very incredible trial, because it was conducted in a group of patients in which we need additional therapies – patients with squamous histology,” Dr. Cappuzzo said during a press briefing at the conference. “IMpower131 is certainly a positive study; we had PFS, as an independent coprimary endpoint, improve significantly, with a meaningful survival difference in the group of patients with strongly positive PD-L1 tumors.
“So these data clearly suggest that [patients with high PD-L1 expression), specifically, may benefit from the combination of chemotherapy and atezolizumab.”
He further noted in a press statement that “the findings provide additional evidence of the efficacy of immunotherapy in patients with lung cancer, and highlight the relevance of biomarkers for patient selection.”
Dr. Cappuzzo reported having no disclosures.
SOURCE: Cappuzzo F et al. WCLC 2019, Abstract OS14.02 .
BARCELONA – Final overall survival (OS) did not differ significantly among patients with stage IV squamous non–small cell lung carcinoma who were treated with either first-line atezolizumab + chemotherapy or chemotherapy alone in the phase 3 IMpower131 trial.
Median OS in the intent-to-treat population was 14.2 months vs. 13.5 months with vs. without the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab, respectively (hazard ratio, 0.88), Federico Cappuzzo, MD, director of medical oncology at Azienda Unità Sanitaria Locale della Romagna-Ravenna, Italy, reported at the World Conference on Lung Cancer.
However, patients with high PD-L1 expression (14% and 13% of patients in the groups, respectively), experienced a clinically meaningful improvement in OS with atezolizumab + chemotherapy vs. chemotherapy alone (median of 23.4 vs. 10.2 months; HR, 0.48), Dr. Cappuzzo said at the conference, which was sponsored by the International Association for the Study of Lung Cancer.
“This means we had a reduction in the risk of death that was more than 50%,” he said, adding that no new or unexpected safety signals were reported.
IMpower131 randomized 1,021 patients with a median age of 65 years 1:1:1 to receive either atezolizumab (1,200 mg) + carboplatin (area under the curve 6) + paclitaxel (200 mg/m2) every 3 weeks, or atezolizumab + carboplatin + nab-paclitaxel (100 mg/m2 every week), or carboplatin + nab-paclitaxel for four or six cycles. Patients in the first two arms (A and B) received atezolizumab maintenance therapy until loss of clinical benefit or progressive disease occurred, and those in latter arm (C) received best supportive care after completing the treatment cycles.
The current analysis compared only the OS outcomes for arms B and C. Results of the primary analysis of investigator-assessed progression-free survival (PFS) – a coprimary endpoint of the trial – were reported in 2018 at the annual meeting of the American Society of Clinical Oncology and showed a statistically significant improvement in median PFS in arm B vs. arm C (6.3 vs. 5.6 months; HR, 0.715). The PFS benefit was seen in all PD-L1-positive subgroups.
“This was a very incredible trial, because it was conducted in a group of patients in which we need additional therapies – patients with squamous histology,” Dr. Cappuzzo said during a press briefing at the conference. “IMpower131 is certainly a positive study; we had PFS, as an independent coprimary endpoint, improve significantly, with a meaningful survival difference in the group of patients with strongly positive PD-L1 tumors.
“So these data clearly suggest that [patients with high PD-L1 expression), specifically, may benefit from the combination of chemotherapy and atezolizumab.”
He further noted in a press statement that “the findings provide additional evidence of the efficacy of immunotherapy in patients with lung cancer, and highlight the relevance of biomarkers for patient selection.”
Dr. Cappuzzo reported having no disclosures.
SOURCE: Cappuzzo F et al. WCLC 2019, Abstract OS14.02 .
REPORTING FROM WCLC 2019
Tissue TMB disappoints as treatment response biomarker in NSCLC
BARCELONA – Tissue tumor mutational burden (TMB) was not significantly associated with treatment efficacy in patients with metastatic nonsquamous non–small cell lung cancer (NSCLC) in the phase 3 KEYNOTE-189 study and the phase 2 KEYNOTE-021 study.
In 293 patients with evaluable TMB data in KEYNOTE-189, including 207 who were treated with pembrolizumab plus chemotherapy and 86 who received placebo plus chemotherapy, TMB as a continuous variable showed no significant association with either overall survival (OS), progression-free survival (PFS), or objective response rate (ORR), Marina C. Garassino, MD, of Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, reported at the World Conference on Lung Cancer.
Pembrolizumab plus chemotherapy improved OS both in patients with TMB of 175 mutations/exome and greater and in those with TMB of fewer than 175 mutations/exome (hazard ratio for OS, 0.64 for both), and similar results were seen for PFS and ORR, Dr. Garassino said at the conference, which is sponsored by the International Association for the Study of Lung Cancer. Similar results were also seen for those with tissue TMB of 150 mutations/exome or greater and those with fewer than 150 mutations/exome, she noted.
The double-blind KEYNOTE-189 study compared first-line pembrolizumab plus chemotherapy with placebo plus chemotherapy in 616 patients who were randomized 2:1 to the treatment arms, respectively, and showed that adding pembrolizumab to pemetrexed and platinum significantly improved OS (HR, 0.49), PFS (HR, 0.52), and ORR (47.6% vs. 18.9%). Benefit was observed in all analyzed subgroups, including patients with programmed death-ligand 1 (PD-L1) Tissue Polypeptide-specific (TPS) antigen of less than 1%, 1-49%, and 50% or greater, she noted.
In the current analysis, performed to assess the effect of tissue TMB on response rates, a similar benefit was seen in both TMB-high and -low subgroups.
“Our data suggest that tissue TMB may not help select patients who would have better outcomes with pembrolizumab plus pemetrexed and a platinum given as first-line therapy for metastatic nonsquamous NSCLC,” she concluded.
Similarly, an exploratory analysis of data from the open-label, phase 2 KEYNOTE-021 trial – the first trial to show the efficacy and safety of the anti–PD-1 immune checkpoint inhibitor pembrolizumab given with chemotherapy – showed no association between tissue TMB and OS, PFS, or ORR in 70 patients with metastatic nonsquamous NSCLC who were treated with either pembrolizumab plus carboplatin and pemetrexed or with carboplatin and pemetrexed alone, Corey Langer, MD, reported at the conference.
“As you’re well aware,TMB has been widely evaluated as a biomarker for immunotherapy in advanced [NSCLC] and may identify patients who are more likely to respond to immune checkpoint inhibitors,” said Dr. Langer, professor of medicine and director of thoracic surgery at the Hospital of the University of Pennsylvania, Philadelphia. “But we have very limited data on whether TMB is of any value as a biomarker for chemo, either alone or given with an immune checkpoint inhibitor.”
In this analysis, pembrolizumab plus chemotherapy was associated with a high response rate, regardless of tissue TMB status; in those with tissue TMB of 175 mutations/exome or greater and fewer than 175 mutations/exome, the response rates were 71% and 61%, respectively.
“So, tissue TMB assessed by whole-exome sequencing was not significantly associated with efficacy for pembro and combination pem-carbo, or for chemotherapy alone, for first-line treatment of patients with metastatic nonsquamous [NSCLC], nor was there any significant association with PD-L1 expression,” he said. “Obviously an analysis of much larger datasets is needed to assess whether the benefit of pembro plus chemo relative to chemo alone differs in patients with TMB-high or TMB-low tumors,” he said.
For now, tissue TMB should not be used – “at least not yet” – in therapeutic decision making, he said, adding that it is important to distinguish between blood TMB and tissue TMB because the latter “may be more reflective of the entire tumor.”
Dr. Langer noted that he still thinks TMB has a potential role.
“We just haven’t figured it out yet,” he said.
Both KEYNOTE-189 and KEYNOTE-021 were supported by Merck. Dr. Garassino and Dr. Langer reported relationships with several pharmaceutical companies.
SOURCES: Garassino MC et al. WCLC 2019, Abstract OA04.06; Langer C et al. WCLC 2019, Abstract OA04.05.
.
BARCELONA – Tissue tumor mutational burden (TMB) was not significantly associated with treatment efficacy in patients with metastatic nonsquamous non–small cell lung cancer (NSCLC) in the phase 3 KEYNOTE-189 study and the phase 2 KEYNOTE-021 study.
In 293 patients with evaluable TMB data in KEYNOTE-189, including 207 who were treated with pembrolizumab plus chemotherapy and 86 who received placebo plus chemotherapy, TMB as a continuous variable showed no significant association with either overall survival (OS), progression-free survival (PFS), or objective response rate (ORR), Marina C. Garassino, MD, of Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, reported at the World Conference on Lung Cancer.
Pembrolizumab plus chemotherapy improved OS both in patients with TMB of 175 mutations/exome and greater and in those with TMB of fewer than 175 mutations/exome (hazard ratio for OS, 0.64 for both), and similar results were seen for PFS and ORR, Dr. Garassino said at the conference, which is sponsored by the International Association for the Study of Lung Cancer. Similar results were also seen for those with tissue TMB of 150 mutations/exome or greater and those with fewer than 150 mutations/exome, she noted.
The double-blind KEYNOTE-189 study compared first-line pembrolizumab plus chemotherapy with placebo plus chemotherapy in 616 patients who were randomized 2:1 to the treatment arms, respectively, and showed that adding pembrolizumab to pemetrexed and platinum significantly improved OS (HR, 0.49), PFS (HR, 0.52), and ORR (47.6% vs. 18.9%). Benefit was observed in all analyzed subgroups, including patients with programmed death-ligand 1 (PD-L1) Tissue Polypeptide-specific (TPS) antigen of less than 1%, 1-49%, and 50% or greater, she noted.
In the current analysis, performed to assess the effect of tissue TMB on response rates, a similar benefit was seen in both TMB-high and -low subgroups.
“Our data suggest that tissue TMB may not help select patients who would have better outcomes with pembrolizumab plus pemetrexed and a platinum given as first-line therapy for metastatic nonsquamous NSCLC,” she concluded.
Similarly, an exploratory analysis of data from the open-label, phase 2 KEYNOTE-021 trial – the first trial to show the efficacy and safety of the anti–PD-1 immune checkpoint inhibitor pembrolizumab given with chemotherapy – showed no association between tissue TMB and OS, PFS, or ORR in 70 patients with metastatic nonsquamous NSCLC who were treated with either pembrolizumab plus carboplatin and pemetrexed or with carboplatin and pemetrexed alone, Corey Langer, MD, reported at the conference.
“As you’re well aware,TMB has been widely evaluated as a biomarker for immunotherapy in advanced [NSCLC] and may identify patients who are more likely to respond to immune checkpoint inhibitors,” said Dr. Langer, professor of medicine and director of thoracic surgery at the Hospital of the University of Pennsylvania, Philadelphia. “But we have very limited data on whether TMB is of any value as a biomarker for chemo, either alone or given with an immune checkpoint inhibitor.”
In this analysis, pembrolizumab plus chemotherapy was associated with a high response rate, regardless of tissue TMB status; in those with tissue TMB of 175 mutations/exome or greater and fewer than 175 mutations/exome, the response rates were 71% and 61%, respectively.
“So, tissue TMB assessed by whole-exome sequencing was not significantly associated with efficacy for pembro and combination pem-carbo, or for chemotherapy alone, for first-line treatment of patients with metastatic nonsquamous [NSCLC], nor was there any significant association with PD-L1 expression,” he said. “Obviously an analysis of much larger datasets is needed to assess whether the benefit of pembro plus chemo relative to chemo alone differs in patients with TMB-high or TMB-low tumors,” he said.
For now, tissue TMB should not be used – “at least not yet” – in therapeutic decision making, he said, adding that it is important to distinguish between blood TMB and tissue TMB because the latter “may be more reflective of the entire tumor.”
Dr. Langer noted that he still thinks TMB has a potential role.
“We just haven’t figured it out yet,” he said.
Both KEYNOTE-189 and KEYNOTE-021 were supported by Merck. Dr. Garassino and Dr. Langer reported relationships with several pharmaceutical companies.
SOURCES: Garassino MC et al. WCLC 2019, Abstract OA04.06; Langer C et al. WCLC 2019, Abstract OA04.05.
.
BARCELONA – Tissue tumor mutational burden (TMB) was not significantly associated with treatment efficacy in patients with metastatic nonsquamous non–small cell lung cancer (NSCLC) in the phase 3 KEYNOTE-189 study and the phase 2 KEYNOTE-021 study.
In 293 patients with evaluable TMB data in KEYNOTE-189, including 207 who were treated with pembrolizumab plus chemotherapy and 86 who received placebo plus chemotherapy, TMB as a continuous variable showed no significant association with either overall survival (OS), progression-free survival (PFS), or objective response rate (ORR), Marina C. Garassino, MD, of Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, reported at the World Conference on Lung Cancer.
Pembrolizumab plus chemotherapy improved OS both in patients with TMB of 175 mutations/exome and greater and in those with TMB of fewer than 175 mutations/exome (hazard ratio for OS, 0.64 for both), and similar results were seen for PFS and ORR, Dr. Garassino said at the conference, which is sponsored by the International Association for the Study of Lung Cancer. Similar results were also seen for those with tissue TMB of 150 mutations/exome or greater and those with fewer than 150 mutations/exome, she noted.
The double-blind KEYNOTE-189 study compared first-line pembrolizumab plus chemotherapy with placebo plus chemotherapy in 616 patients who were randomized 2:1 to the treatment arms, respectively, and showed that adding pembrolizumab to pemetrexed and platinum significantly improved OS (HR, 0.49), PFS (HR, 0.52), and ORR (47.6% vs. 18.9%). Benefit was observed in all analyzed subgroups, including patients with programmed death-ligand 1 (PD-L1) Tissue Polypeptide-specific (TPS) antigen of less than 1%, 1-49%, and 50% or greater, she noted.
In the current analysis, performed to assess the effect of tissue TMB on response rates, a similar benefit was seen in both TMB-high and -low subgroups.
“Our data suggest that tissue TMB may not help select patients who would have better outcomes with pembrolizumab plus pemetrexed and a platinum given as first-line therapy for metastatic nonsquamous NSCLC,” she concluded.
Similarly, an exploratory analysis of data from the open-label, phase 2 KEYNOTE-021 trial – the first trial to show the efficacy and safety of the anti–PD-1 immune checkpoint inhibitor pembrolizumab given with chemotherapy – showed no association between tissue TMB and OS, PFS, or ORR in 70 patients with metastatic nonsquamous NSCLC who were treated with either pembrolizumab plus carboplatin and pemetrexed or with carboplatin and pemetrexed alone, Corey Langer, MD, reported at the conference.
“As you’re well aware,TMB has been widely evaluated as a biomarker for immunotherapy in advanced [NSCLC] and may identify patients who are more likely to respond to immune checkpoint inhibitors,” said Dr. Langer, professor of medicine and director of thoracic surgery at the Hospital of the University of Pennsylvania, Philadelphia. “But we have very limited data on whether TMB is of any value as a biomarker for chemo, either alone or given with an immune checkpoint inhibitor.”
In this analysis, pembrolizumab plus chemotherapy was associated with a high response rate, regardless of tissue TMB status; in those with tissue TMB of 175 mutations/exome or greater and fewer than 175 mutations/exome, the response rates were 71% and 61%, respectively.
“So, tissue TMB assessed by whole-exome sequencing was not significantly associated with efficacy for pembro and combination pem-carbo, or for chemotherapy alone, for first-line treatment of patients with metastatic nonsquamous [NSCLC], nor was there any significant association with PD-L1 expression,” he said. “Obviously an analysis of much larger datasets is needed to assess whether the benefit of pembro plus chemo relative to chemo alone differs in patients with TMB-high or TMB-low tumors,” he said.
For now, tissue TMB should not be used – “at least not yet” – in therapeutic decision making, he said, adding that it is important to distinguish between blood TMB and tissue TMB because the latter “may be more reflective of the entire tumor.”
Dr. Langer noted that he still thinks TMB has a potential role.
“We just haven’t figured it out yet,” he said.
Both KEYNOTE-189 and KEYNOTE-021 were supported by Merck. Dr. Garassino and Dr. Langer reported relationships with several pharmaceutical companies.
SOURCES: Garassino MC et al. WCLC 2019, Abstract OA04.06; Langer C et al. WCLC 2019, Abstract OA04.05.
.
REPORTING FROM WCLC 2019
LDCT plus miRNA bolsters prevention efforts
BARCELONA – Adding a blood microRNA (miRNA) assay to low-dose computed tomography (LDCT)–based lung cancer screening in heavy smokers bolsters lung cancer prevention efforts, according to findings from the prospective bioMILD trial.
Specifically, the addition of the miRNA assay appears to reduce unnecessary repeat LDCT scans based on individual risk profiles without adversely affecting lung cancer detection or mortality, Ugo Pastorino, MD, director of thoracic surgery at the Istituto Nazionale dei Tumori Foundation, Milan, reported at the World Conference on Lung Cancer.
Of 4,119 volunteers with a median age of 60 years and a median of 42 pack-years who were enrolled between January 2013 and March 2016, 2,384 (58%) were assigned a 3-year LDCT repeat according to their double-negative baseline LDCT and miRNA profile, whereas 1,526 (37%) with a single-positive screen (either a positive miRNA or indeterminate/positive LDCT) and 209 (5%) with double positive (both a positive miRNA and indeterminate/positive LDCT) were assigned to annual or shorter LDCT repeat.
After four screening runs, a total of 115 lung cancers were diagnosed. The cumulative lung cancer rates “were enormously different” in the 3 groups, despite similar group composition with respect to age, gender, and tobacco consumption (0.6% for double-negative screening, 3.8% for single-positive screening, and 20.1% for double-positive screening), and lung cancer mortality was 0.1%, 0.6%, and 3.8% in the groups, respectively, Dr. Pastorino said at the conference, which is sponsored by the International Association for the Study of Lung Cancer.
However, no significant differences were seen in the proportion of stage I lung cancers, resection rates, or interval cancer incidence in subjects sent to 3-year LDCT repeat, he noted.
The bioMILD trial was designed in the wake of the National Lung Screening Trial (NLST), which showed that three annual LDCT rounds for lung cancer screening reduced lung cancer mortality, and the Multicentric Italian Lung Detection (MILD) trial, which provided additional evidence that intervention beyond 5 years with annual or biennial rounds enhanced the benefit of screening.
Dr. Pastorino, the lead author on the MILD trial, previously reported that miRNA expression profiles in tumors and in normal lung tissue indicate aggressive lung cancer development and that specific miRNA signatures can be identified in plasma samples up to 2 years before spiral-CT detection of the disease.
The bioMILD trial tested the additional value of an miRNA assay at the time of LDCT.
Subjects were current (79%) or former heavy smokers, and 39% were women.
The findings suggest that adding the miRNA assay to LDCT for lung cancer screening is a “valuable and safe tool to assess individual risk profile and reduce unnecessary LDCT repeats in lung cancer screening,” Dr. Pastorino said.
“But what is more important for us [is that] the knowledge of individual biologic risk can improve the efficacy of screening, but can [also] guide prevention strategies because the problem in a heavy smoker is not to just detect lung cancer, it’s to reduce mortality,” he said at a press conference highlighting the findings. “And so, personalized prevention is a real option now, and that means diagnosis, but also preventive measures [such as] smoking cessation and chemoprevention.”
Invited discussant Harry J. de Koning, MD, PhD, professor of public health and screening evaluation at Erasmus Medical Center, Rotterdam, the Netherlands, noted that no other studies have evaluated screening intervals longer than 2 years, but he agreed that “reducing regular follow-up scans based on additional risk information is a way forward.”
However, the approach would increase costs, he said, adding that large, prospective, randomized, controlled trials are needed to confirm the safety of such approaches in nationwide programs.
Dr. Pastorino and Dr. de Koning each reported having no disclosures.
SOURCE: Pastorino U et al. WCLC 2019, Abstract PL02.04
BARCELONA – Adding a blood microRNA (miRNA) assay to low-dose computed tomography (LDCT)–based lung cancer screening in heavy smokers bolsters lung cancer prevention efforts, according to findings from the prospective bioMILD trial.
Specifically, the addition of the miRNA assay appears to reduce unnecessary repeat LDCT scans based on individual risk profiles without adversely affecting lung cancer detection or mortality, Ugo Pastorino, MD, director of thoracic surgery at the Istituto Nazionale dei Tumori Foundation, Milan, reported at the World Conference on Lung Cancer.
Of 4,119 volunteers with a median age of 60 years and a median of 42 pack-years who were enrolled between January 2013 and March 2016, 2,384 (58%) were assigned a 3-year LDCT repeat according to their double-negative baseline LDCT and miRNA profile, whereas 1,526 (37%) with a single-positive screen (either a positive miRNA or indeterminate/positive LDCT) and 209 (5%) with double positive (both a positive miRNA and indeterminate/positive LDCT) were assigned to annual or shorter LDCT repeat.
After four screening runs, a total of 115 lung cancers were diagnosed. The cumulative lung cancer rates “were enormously different” in the 3 groups, despite similar group composition with respect to age, gender, and tobacco consumption (0.6% for double-negative screening, 3.8% for single-positive screening, and 20.1% for double-positive screening), and lung cancer mortality was 0.1%, 0.6%, and 3.8% in the groups, respectively, Dr. Pastorino said at the conference, which is sponsored by the International Association for the Study of Lung Cancer.
However, no significant differences were seen in the proportion of stage I lung cancers, resection rates, or interval cancer incidence in subjects sent to 3-year LDCT repeat, he noted.
The bioMILD trial was designed in the wake of the National Lung Screening Trial (NLST), which showed that three annual LDCT rounds for lung cancer screening reduced lung cancer mortality, and the Multicentric Italian Lung Detection (MILD) trial, which provided additional evidence that intervention beyond 5 years with annual or biennial rounds enhanced the benefit of screening.
Dr. Pastorino, the lead author on the MILD trial, previously reported that miRNA expression profiles in tumors and in normal lung tissue indicate aggressive lung cancer development and that specific miRNA signatures can be identified in plasma samples up to 2 years before spiral-CT detection of the disease.
The bioMILD trial tested the additional value of an miRNA assay at the time of LDCT.
Subjects were current (79%) or former heavy smokers, and 39% were women.
The findings suggest that adding the miRNA assay to LDCT for lung cancer screening is a “valuable and safe tool to assess individual risk profile and reduce unnecessary LDCT repeats in lung cancer screening,” Dr. Pastorino said.
“But what is more important for us [is that] the knowledge of individual biologic risk can improve the efficacy of screening, but can [also] guide prevention strategies because the problem in a heavy smoker is not to just detect lung cancer, it’s to reduce mortality,” he said at a press conference highlighting the findings. “And so, personalized prevention is a real option now, and that means diagnosis, but also preventive measures [such as] smoking cessation and chemoprevention.”
Invited discussant Harry J. de Koning, MD, PhD, professor of public health and screening evaluation at Erasmus Medical Center, Rotterdam, the Netherlands, noted that no other studies have evaluated screening intervals longer than 2 years, but he agreed that “reducing regular follow-up scans based on additional risk information is a way forward.”
However, the approach would increase costs, he said, adding that large, prospective, randomized, controlled trials are needed to confirm the safety of such approaches in nationwide programs.
Dr. Pastorino and Dr. de Koning each reported having no disclosures.
SOURCE: Pastorino U et al. WCLC 2019, Abstract PL02.04
BARCELONA – Adding a blood microRNA (miRNA) assay to low-dose computed tomography (LDCT)–based lung cancer screening in heavy smokers bolsters lung cancer prevention efforts, according to findings from the prospective bioMILD trial.
Specifically, the addition of the miRNA assay appears to reduce unnecessary repeat LDCT scans based on individual risk profiles without adversely affecting lung cancer detection or mortality, Ugo Pastorino, MD, director of thoracic surgery at the Istituto Nazionale dei Tumori Foundation, Milan, reported at the World Conference on Lung Cancer.
Of 4,119 volunteers with a median age of 60 years and a median of 42 pack-years who were enrolled between January 2013 and March 2016, 2,384 (58%) were assigned a 3-year LDCT repeat according to their double-negative baseline LDCT and miRNA profile, whereas 1,526 (37%) with a single-positive screen (either a positive miRNA or indeterminate/positive LDCT) and 209 (5%) with double positive (both a positive miRNA and indeterminate/positive LDCT) were assigned to annual or shorter LDCT repeat.
After four screening runs, a total of 115 lung cancers were diagnosed. The cumulative lung cancer rates “were enormously different” in the 3 groups, despite similar group composition with respect to age, gender, and tobacco consumption (0.6% for double-negative screening, 3.8% for single-positive screening, and 20.1% for double-positive screening), and lung cancer mortality was 0.1%, 0.6%, and 3.8% in the groups, respectively, Dr. Pastorino said at the conference, which is sponsored by the International Association for the Study of Lung Cancer.
However, no significant differences were seen in the proportion of stage I lung cancers, resection rates, or interval cancer incidence in subjects sent to 3-year LDCT repeat, he noted.
The bioMILD trial was designed in the wake of the National Lung Screening Trial (NLST), which showed that three annual LDCT rounds for lung cancer screening reduced lung cancer mortality, and the Multicentric Italian Lung Detection (MILD) trial, which provided additional evidence that intervention beyond 5 years with annual or biennial rounds enhanced the benefit of screening.
Dr. Pastorino, the lead author on the MILD trial, previously reported that miRNA expression profiles in tumors and in normal lung tissue indicate aggressive lung cancer development and that specific miRNA signatures can be identified in plasma samples up to 2 years before spiral-CT detection of the disease.
The bioMILD trial tested the additional value of an miRNA assay at the time of LDCT.
Subjects were current (79%) or former heavy smokers, and 39% were women.
The findings suggest that adding the miRNA assay to LDCT for lung cancer screening is a “valuable and safe tool to assess individual risk profile and reduce unnecessary LDCT repeats in lung cancer screening,” Dr. Pastorino said.
“But what is more important for us [is that] the knowledge of individual biologic risk can improve the efficacy of screening, but can [also] guide prevention strategies because the problem in a heavy smoker is not to just detect lung cancer, it’s to reduce mortality,” he said at a press conference highlighting the findings. “And so, personalized prevention is a real option now, and that means diagnosis, but also preventive measures [such as] smoking cessation and chemoprevention.”
Invited discussant Harry J. de Koning, MD, PhD, professor of public health and screening evaluation at Erasmus Medical Center, Rotterdam, the Netherlands, noted that no other studies have evaluated screening intervals longer than 2 years, but he agreed that “reducing regular follow-up scans based on additional risk information is a way forward.”
However, the approach would increase costs, he said, adding that large, prospective, randomized, controlled trials are needed to confirm the safety of such approaches in nationwide programs.
Dr. Pastorino and Dr. de Koning each reported having no disclosures.
SOURCE: Pastorino U et al. WCLC 2019, Abstract PL02.04
REPORTING FROM WCLC 2019
MYSTIC trial analysis IDs mutations prognostic of mNSCLC outcomes
BARCELONA – Mutations in the tumor suppressor KEAP1 or STK11 genes in patients with metastatic non–small cell lung cancer (mNSCLC) in the randomized, phase 3 MYSTIC trial experienced poorer outcomes than did patients without the mutations, according to an exploratory analysis of trial data.
Mutations in ARID1a, however, were associated with improved overall survival (OS) among patients in the trial who were treated with durvalumab + tremelimumab.
Profiling of circulating tumor DNA from 943 evaluable baseline plasma specimens showed median OS of 7.4 vs. 12.9 months among 170 patients with KEAP1 mutations (m) vs. in 773 with KEAP1 wild type (hazard ratio, 1.64), and 6.8 vs. 12.6 months in patients with STK11m vs. 796 with STK11wt (HR, 1.52), Naiyer A. Rizvi, MD, the Price Family Professor of Medicine, director of Thoracic Oncology, and codirector of Cancer Immunotherapy at Columbia University Irving Medical Center, New York, reported at the World Conference on Lung Cancer.
Objective response rates (ORR) in the groups, respectively, were 17.6% vs. 27.7% for KEAP1m vs. KEAP1wt, and 16.3% vs. 27.6% for STK11m vs. STK11wt, Dr. Rizvi said at the conference, sponsored by the International Association for the Study of Lung Cancer.
This was regardless of MYSTIC trial treatment arm; the open-label, multicenter, global trial compared durvalumab monotherapy or durvalumab plus tremelimumab with platinum-based chemotherapy for the first-line treatment of patients with epidermal growth factor receptor and anaplastic lymphoma kinase wild-type, locally-advanced or metastatic NSCLC.
Mutations in the ARID1a gene, however, had no impact on OS (12.6 vs. 11.4 months in 114 vs. 829 patients with ARID1am vs. ARID1awt; HR, 0.94), and ORRs, respectively, were 35.1% vs. 24.6%.
When comparing outcomes by treatment arm, the ORRs with chemotherapy were 15.1% vs. 34% for KEAP1m vs. KEAP1wt, 12.2% vs. 33.6% for STK11m vs. STK1wt, and 28.1% vs. 31% for ARID1am vs. ARID1awt.
The ORRs in the durvalumab arm were 16.7% vs. 25.2% for KEAP1m vs. KEAP1st, 14.5% vs. 25.7% for STK11m vs. STK11wt and 25.6% vs. 23.4%, respectively, and in the durvalumab + tremelimumab arm they were 20.6% vs. 23.9% for KEAP1m vs. KEAP1wt, 21.6% vs. 23.6% for STK11m vs. STK11wt.
“The key finding here is really the ARID1a response,” Dr. Rizvi said, noting the “pretty impressive response rates” of 51.3% with ARID1am vs. 19.4% for ARID1awt.
The relationship between gene alterations and response to anti-programmed death-1 (PD-1) therapy with and without anti-CTLA-4 therapy is not well characterized. These findings, which suggest that KEAP1 and STK11 mutations are prognostic for OS in mNSCLC, and that ARID1am may be predictive of OS benefit in patients receiving durvalumab + tremelimumab, provide insights to the potential impact of specific mutations on response to immunotherapy, Dr. Rizvi said.
“STK11 and KEAP1 mutations ... are relatively common mutations – they are actually the third and fourth most common mutations in lung cancer after p53 and KRAS,” he said, adding that they influence outcomes and need to be factored in to analyses of outcomes in lung cancer. “ARID1am patients were about 10% of the population and they did particularly well with durvalumab and tremelimumab, and I think these exploratory analyses can help us think about how we use [tumor mutational burden] and outcomes among cancer patients in future trials.”
The MYSTIC trial was sponsored by AstraZeneca. Dr. Rizvi disclosed royalties related to intellectual property/patents filed by MSKCC and Personal Genome Diagnostics.
SOURCE: Rizvi N et al. WCLC 2019: Abstract OA04.07.
BARCELONA – Mutations in the tumor suppressor KEAP1 or STK11 genes in patients with metastatic non–small cell lung cancer (mNSCLC) in the randomized, phase 3 MYSTIC trial experienced poorer outcomes than did patients without the mutations, according to an exploratory analysis of trial data.
Mutations in ARID1a, however, were associated with improved overall survival (OS) among patients in the trial who were treated with durvalumab + tremelimumab.
Profiling of circulating tumor DNA from 943 evaluable baseline plasma specimens showed median OS of 7.4 vs. 12.9 months among 170 patients with KEAP1 mutations (m) vs. in 773 with KEAP1 wild type (hazard ratio, 1.64), and 6.8 vs. 12.6 months in patients with STK11m vs. 796 with STK11wt (HR, 1.52), Naiyer A. Rizvi, MD, the Price Family Professor of Medicine, director of Thoracic Oncology, and codirector of Cancer Immunotherapy at Columbia University Irving Medical Center, New York, reported at the World Conference on Lung Cancer.
Objective response rates (ORR) in the groups, respectively, were 17.6% vs. 27.7% for KEAP1m vs. KEAP1wt, and 16.3% vs. 27.6% for STK11m vs. STK11wt, Dr. Rizvi said at the conference, sponsored by the International Association for the Study of Lung Cancer.
This was regardless of MYSTIC trial treatment arm; the open-label, multicenter, global trial compared durvalumab monotherapy or durvalumab plus tremelimumab with platinum-based chemotherapy for the first-line treatment of patients with epidermal growth factor receptor and anaplastic lymphoma kinase wild-type, locally-advanced or metastatic NSCLC.
Mutations in the ARID1a gene, however, had no impact on OS (12.6 vs. 11.4 months in 114 vs. 829 patients with ARID1am vs. ARID1awt; HR, 0.94), and ORRs, respectively, were 35.1% vs. 24.6%.
When comparing outcomes by treatment arm, the ORRs with chemotherapy were 15.1% vs. 34% for KEAP1m vs. KEAP1wt, 12.2% vs. 33.6% for STK11m vs. STK1wt, and 28.1% vs. 31% for ARID1am vs. ARID1awt.
The ORRs in the durvalumab arm were 16.7% vs. 25.2% for KEAP1m vs. KEAP1st, 14.5% vs. 25.7% for STK11m vs. STK11wt and 25.6% vs. 23.4%, respectively, and in the durvalumab + tremelimumab arm they were 20.6% vs. 23.9% for KEAP1m vs. KEAP1wt, 21.6% vs. 23.6% for STK11m vs. STK11wt.
“The key finding here is really the ARID1a response,” Dr. Rizvi said, noting the “pretty impressive response rates” of 51.3% with ARID1am vs. 19.4% for ARID1awt.
The relationship between gene alterations and response to anti-programmed death-1 (PD-1) therapy with and without anti-CTLA-4 therapy is not well characterized. These findings, which suggest that KEAP1 and STK11 mutations are prognostic for OS in mNSCLC, and that ARID1am may be predictive of OS benefit in patients receiving durvalumab + tremelimumab, provide insights to the potential impact of specific mutations on response to immunotherapy, Dr. Rizvi said.
“STK11 and KEAP1 mutations ... are relatively common mutations – they are actually the third and fourth most common mutations in lung cancer after p53 and KRAS,” he said, adding that they influence outcomes and need to be factored in to analyses of outcomes in lung cancer. “ARID1am patients were about 10% of the population and they did particularly well with durvalumab and tremelimumab, and I think these exploratory analyses can help us think about how we use [tumor mutational burden] and outcomes among cancer patients in future trials.”
The MYSTIC trial was sponsored by AstraZeneca. Dr. Rizvi disclosed royalties related to intellectual property/patents filed by MSKCC and Personal Genome Diagnostics.
SOURCE: Rizvi N et al. WCLC 2019: Abstract OA04.07.
BARCELONA – Mutations in the tumor suppressor KEAP1 or STK11 genes in patients with metastatic non–small cell lung cancer (mNSCLC) in the randomized, phase 3 MYSTIC trial experienced poorer outcomes than did patients without the mutations, according to an exploratory analysis of trial data.
Mutations in ARID1a, however, were associated with improved overall survival (OS) among patients in the trial who were treated with durvalumab + tremelimumab.
Profiling of circulating tumor DNA from 943 evaluable baseline plasma specimens showed median OS of 7.4 vs. 12.9 months among 170 patients with KEAP1 mutations (m) vs. in 773 with KEAP1 wild type (hazard ratio, 1.64), and 6.8 vs. 12.6 months in patients with STK11m vs. 796 with STK11wt (HR, 1.52), Naiyer A. Rizvi, MD, the Price Family Professor of Medicine, director of Thoracic Oncology, and codirector of Cancer Immunotherapy at Columbia University Irving Medical Center, New York, reported at the World Conference on Lung Cancer.
Objective response rates (ORR) in the groups, respectively, were 17.6% vs. 27.7% for KEAP1m vs. KEAP1wt, and 16.3% vs. 27.6% for STK11m vs. STK11wt, Dr. Rizvi said at the conference, sponsored by the International Association for the Study of Lung Cancer.
This was regardless of MYSTIC trial treatment arm; the open-label, multicenter, global trial compared durvalumab monotherapy or durvalumab plus tremelimumab with platinum-based chemotherapy for the first-line treatment of patients with epidermal growth factor receptor and anaplastic lymphoma kinase wild-type, locally-advanced or metastatic NSCLC.
Mutations in the ARID1a gene, however, had no impact on OS (12.6 vs. 11.4 months in 114 vs. 829 patients with ARID1am vs. ARID1awt; HR, 0.94), and ORRs, respectively, were 35.1% vs. 24.6%.
When comparing outcomes by treatment arm, the ORRs with chemotherapy were 15.1% vs. 34% for KEAP1m vs. KEAP1wt, 12.2% vs. 33.6% for STK11m vs. STK1wt, and 28.1% vs. 31% for ARID1am vs. ARID1awt.
The ORRs in the durvalumab arm were 16.7% vs. 25.2% for KEAP1m vs. KEAP1st, 14.5% vs. 25.7% for STK11m vs. STK11wt and 25.6% vs. 23.4%, respectively, and in the durvalumab + tremelimumab arm they were 20.6% vs. 23.9% for KEAP1m vs. KEAP1wt, 21.6% vs. 23.6% for STK11m vs. STK11wt.
“The key finding here is really the ARID1a response,” Dr. Rizvi said, noting the “pretty impressive response rates” of 51.3% with ARID1am vs. 19.4% for ARID1awt.
The relationship between gene alterations and response to anti-programmed death-1 (PD-1) therapy with and without anti-CTLA-4 therapy is not well characterized. These findings, which suggest that KEAP1 and STK11 mutations are prognostic for OS in mNSCLC, and that ARID1am may be predictive of OS benefit in patients receiving durvalumab + tremelimumab, provide insights to the potential impact of specific mutations on response to immunotherapy, Dr. Rizvi said.
“STK11 and KEAP1 mutations ... are relatively common mutations – they are actually the third and fourth most common mutations in lung cancer after p53 and KRAS,” he said, adding that they influence outcomes and need to be factored in to analyses of outcomes in lung cancer. “ARID1am patients were about 10% of the population and they did particularly well with durvalumab and tremelimumab, and I think these exploratory analyses can help us think about how we use [tumor mutational burden] and outcomes among cancer patients in future trials.”
The MYSTIC trial was sponsored by AstraZeneca. Dr. Rizvi disclosed royalties related to intellectual property/patents filed by MSKCC and Personal Genome Diagnostics.
SOURCE: Rizvi N et al. WCLC 2019: Abstract OA04.07.
REPORTING FROM WCLC 2019
IASLC survey: Ongoing and intensified molecular testing education needed globally
BARCELONA – Molecular testing to guide treatment in patients with lung cancer remains underused, and awareness of related evidence-based guidelines is suboptimal, results of an international survey suggest.
Overall, 61% of the 2,537 respondents from 102 countries and across multiple relevant medical specialties reported that molecular testing rates in their country were less than 50%, with the lowest rates reported in Latin America. And 33% of those requesting molecular testing said they were unaware of the most updated guidelines supporting the use of such testing in lung cancer, Matthew Smeltzer, PhD, of the University of Memphis (Tenn.) reported during a press conference at the World Conference on Lung Cancer.
The findings from the International Association for the Study of Lung Cancer (IASLC) Global Survey on Molecular Testing in Lung Cancer also showed that 41% of respondents who perform or interpret molecular testing assays report being dissatisfied with the conditions of molecular testing in their country, 17% said they feel that patients are not satisfied, and 35% said they aren’t sure about the state of testing in their country.
Specific concerns reported by respondents included trouble understanding results, the time it takes to receive the results, and the reliability of samples.
The top five barriers to molecular testing included cost, quality, access, awareness, and time, Dr. Smeltzer said at the meeting which is sponsored by the IASLC.
“These five were the same five top barriers in each region of the world,” he said, noting that the ordering of the barriers differed somewhat among regions.
The survey included a seven-question introduction, with 32 additional questions for respondents who request tests and treat patients, 45 questions on performing and interpreting assays, and 24 questions on tissue acquisition. Additionally, all respondents were asked to list barriers that impede their country’s ability to offer molecular testing.
“I’d say we got a pretty good geographic distribution of responses; 56% of these responses were from developing countries, 44% from developed countries,” he said, noting that medical oncologists constituted the highest percentage of respondents, followed by pulmonologists, thoracic surgeons, pathologists, and other scientists.
When asked specifically what would prompt molecular testing, respondents most often listed adenocarcinoma, never-smoker status, female gender, and young age, Dr. Smeltzer said.
“Overall, we’re still finding that many in the lung cancer community are not satisfied with the current state of molecular testing. We’ve got suboptimal awareness of the evidence-based guidelines. We have barriers that remain to molecular testing, which we’ve identified, and [we’re] recommending continuous education around molecular testing, and that should be intensified on a national and international level to ensure that patients receive optimal therapy,” he concluded.
The IASLC survey was funded by AstraZeneca. Dr. Smeltzer reported receiving research support from the Bristol Myers Squibb Foundation.
BARCELONA – Molecular testing to guide treatment in patients with lung cancer remains underused, and awareness of related evidence-based guidelines is suboptimal, results of an international survey suggest.
Overall, 61% of the 2,537 respondents from 102 countries and across multiple relevant medical specialties reported that molecular testing rates in their country were less than 50%, with the lowest rates reported in Latin America. And 33% of those requesting molecular testing said they were unaware of the most updated guidelines supporting the use of such testing in lung cancer, Matthew Smeltzer, PhD, of the University of Memphis (Tenn.) reported during a press conference at the World Conference on Lung Cancer.
The findings from the International Association for the Study of Lung Cancer (IASLC) Global Survey on Molecular Testing in Lung Cancer also showed that 41% of respondents who perform or interpret molecular testing assays report being dissatisfied with the conditions of molecular testing in their country, 17% said they feel that patients are not satisfied, and 35% said they aren’t sure about the state of testing in their country.
Specific concerns reported by respondents included trouble understanding results, the time it takes to receive the results, and the reliability of samples.
The top five barriers to molecular testing included cost, quality, access, awareness, and time, Dr. Smeltzer said at the meeting which is sponsored by the IASLC.
“These five were the same five top barriers in each region of the world,” he said, noting that the ordering of the barriers differed somewhat among regions.
The survey included a seven-question introduction, with 32 additional questions for respondents who request tests and treat patients, 45 questions on performing and interpreting assays, and 24 questions on tissue acquisition. Additionally, all respondents were asked to list barriers that impede their country’s ability to offer molecular testing.
“I’d say we got a pretty good geographic distribution of responses; 56% of these responses were from developing countries, 44% from developed countries,” he said, noting that medical oncologists constituted the highest percentage of respondents, followed by pulmonologists, thoracic surgeons, pathologists, and other scientists.
When asked specifically what would prompt molecular testing, respondents most often listed adenocarcinoma, never-smoker status, female gender, and young age, Dr. Smeltzer said.
“Overall, we’re still finding that many in the lung cancer community are not satisfied with the current state of molecular testing. We’ve got suboptimal awareness of the evidence-based guidelines. We have barriers that remain to molecular testing, which we’ve identified, and [we’re] recommending continuous education around molecular testing, and that should be intensified on a national and international level to ensure that patients receive optimal therapy,” he concluded.
The IASLC survey was funded by AstraZeneca. Dr. Smeltzer reported receiving research support from the Bristol Myers Squibb Foundation.
BARCELONA – Molecular testing to guide treatment in patients with lung cancer remains underused, and awareness of related evidence-based guidelines is suboptimal, results of an international survey suggest.
Overall, 61% of the 2,537 respondents from 102 countries and across multiple relevant medical specialties reported that molecular testing rates in their country were less than 50%, with the lowest rates reported in Latin America. And 33% of those requesting molecular testing said they were unaware of the most updated guidelines supporting the use of such testing in lung cancer, Matthew Smeltzer, PhD, of the University of Memphis (Tenn.) reported during a press conference at the World Conference on Lung Cancer.
The findings from the International Association for the Study of Lung Cancer (IASLC) Global Survey on Molecular Testing in Lung Cancer also showed that 41% of respondents who perform or interpret molecular testing assays report being dissatisfied with the conditions of molecular testing in their country, 17% said they feel that patients are not satisfied, and 35% said they aren’t sure about the state of testing in their country.
Specific concerns reported by respondents included trouble understanding results, the time it takes to receive the results, and the reliability of samples.
The top five barriers to molecular testing included cost, quality, access, awareness, and time, Dr. Smeltzer said at the meeting which is sponsored by the IASLC.
“These five were the same five top barriers in each region of the world,” he said, noting that the ordering of the barriers differed somewhat among regions.
The survey included a seven-question introduction, with 32 additional questions for respondents who request tests and treat patients, 45 questions on performing and interpreting assays, and 24 questions on tissue acquisition. Additionally, all respondents were asked to list barriers that impede their country’s ability to offer molecular testing.
“I’d say we got a pretty good geographic distribution of responses; 56% of these responses were from developing countries, 44% from developed countries,” he said, noting that medical oncologists constituted the highest percentage of respondents, followed by pulmonologists, thoracic surgeons, pathologists, and other scientists.
When asked specifically what would prompt molecular testing, respondents most often listed adenocarcinoma, never-smoker status, female gender, and young age, Dr. Smeltzer said.
“Overall, we’re still finding that many in the lung cancer community are not satisfied with the current state of molecular testing. We’ve got suboptimal awareness of the evidence-based guidelines. We have barriers that remain to molecular testing, which we’ve identified, and [we’re] recommending continuous education around molecular testing, and that should be intensified on a national and international level to ensure that patients receive optimal therapy,” he concluded.
The IASLC survey was funded by AstraZeneca. Dr. Smeltzer reported receiving research support from the Bristol Myers Squibb Foundation.
REPORTING FROM WCLC 2019
New IASLC declaration targets tobacco use among cancer patients
BARCELONA – All cancer patients should be screened for tobacco use and advised about the benefits of tobacco cessation, and evidence-based tobacco cessation assistance should be provided to those who continue using tobacco, according to a new declaration from the International Association for the Study of Lung Cancer (IASLC).
Such assistance should be “routinely and integrally incorporated into multidisciplinary cancer care for the patients and their family members,” according to the declaration, which was developed by the IASLC Tobacco Control and Smoking Cessation Committee in part to increase physician involvement in tobacco control and was officially released at the World Conference on Lung Cancer.
“The consequences of smoking continuation by cancer patients and cancer survivors are many,” presenting author Jacek Jassem, MD, PhD, professor and head of the department of oncology and radiotherapy at the Medical University of Gdansk (Poland), said during a press conference at the meeting, which is sponsored by the IASLC.
Smoking after a cancer diagnosis increases cancer-related and overall mortality, the risk of developing additional cancers, and the risk of treatment toxicity, he explained.
“And of course [continued smoking is] associated with much higher treatment costs, mostly due to complications,” he added.
The IASLC addresses both the challenges and opportunities associated with tobacco cessation, including the fact that most cancer patients who smoke continue to do so during and after treatment and that health care providers often don’t provide patients with cessation assistance to help them quit.
In addition to the screening and tobacco cessation assistance recommendations, the declaration also states the following:
- Educational programs regarding cancer management should include tobacco cessation training, empathetic communication around the history of tobacco use and cessation, and utilization of existing evidence-based tobacco cessation resources.
- Smoking cessation counseling and treatment should be a reimbursable service.
- Smoking status, both initially and during the study, should be a required data element for all prospective clinical studies.
- Clinical trials of patients with cancer should consider designs that could also determine the most effective tobacco cessation interventions.
Dr. Jassem is on the speakers bureau for MSD, Takeda, BMS, Astra-Zeneca, and Pfizer.
BARCELONA – All cancer patients should be screened for tobacco use and advised about the benefits of tobacco cessation, and evidence-based tobacco cessation assistance should be provided to those who continue using tobacco, according to a new declaration from the International Association for the Study of Lung Cancer (IASLC).
Such assistance should be “routinely and integrally incorporated into multidisciplinary cancer care for the patients and their family members,” according to the declaration, which was developed by the IASLC Tobacco Control and Smoking Cessation Committee in part to increase physician involvement in tobacco control and was officially released at the World Conference on Lung Cancer.
“The consequences of smoking continuation by cancer patients and cancer survivors are many,” presenting author Jacek Jassem, MD, PhD, professor and head of the department of oncology and radiotherapy at the Medical University of Gdansk (Poland), said during a press conference at the meeting, which is sponsored by the IASLC.
Smoking after a cancer diagnosis increases cancer-related and overall mortality, the risk of developing additional cancers, and the risk of treatment toxicity, he explained.
“And of course [continued smoking is] associated with much higher treatment costs, mostly due to complications,” he added.
The IASLC addresses both the challenges and opportunities associated with tobacco cessation, including the fact that most cancer patients who smoke continue to do so during and after treatment and that health care providers often don’t provide patients with cessation assistance to help them quit.
In addition to the screening and tobacco cessation assistance recommendations, the declaration also states the following:
- Educational programs regarding cancer management should include tobacco cessation training, empathetic communication around the history of tobacco use and cessation, and utilization of existing evidence-based tobacco cessation resources.
- Smoking cessation counseling and treatment should be a reimbursable service.
- Smoking status, both initially and during the study, should be a required data element for all prospective clinical studies.
- Clinical trials of patients with cancer should consider designs that could also determine the most effective tobacco cessation interventions.
Dr. Jassem is on the speakers bureau for MSD, Takeda, BMS, Astra-Zeneca, and Pfizer.
BARCELONA – All cancer patients should be screened for tobacco use and advised about the benefits of tobacco cessation, and evidence-based tobacco cessation assistance should be provided to those who continue using tobacco, according to a new declaration from the International Association for the Study of Lung Cancer (IASLC).
Such assistance should be “routinely and integrally incorporated into multidisciplinary cancer care for the patients and their family members,” according to the declaration, which was developed by the IASLC Tobacco Control and Smoking Cessation Committee in part to increase physician involvement in tobacco control and was officially released at the World Conference on Lung Cancer.
“The consequences of smoking continuation by cancer patients and cancer survivors are many,” presenting author Jacek Jassem, MD, PhD, professor and head of the department of oncology and radiotherapy at the Medical University of Gdansk (Poland), said during a press conference at the meeting, which is sponsored by the IASLC.
Smoking after a cancer diagnosis increases cancer-related and overall mortality, the risk of developing additional cancers, and the risk of treatment toxicity, he explained.
“And of course [continued smoking is] associated with much higher treatment costs, mostly due to complications,” he added.
The IASLC addresses both the challenges and opportunities associated with tobacco cessation, including the fact that most cancer patients who smoke continue to do so during and after treatment and that health care providers often don’t provide patients with cessation assistance to help them quit.
In addition to the screening and tobacco cessation assistance recommendations, the declaration also states the following:
- Educational programs regarding cancer management should include tobacco cessation training, empathetic communication around the history of tobacco use and cessation, and utilization of existing evidence-based tobacco cessation resources.
- Smoking cessation counseling and treatment should be a reimbursable service.
- Smoking status, both initially and during the study, should be a required data element for all prospective clinical studies.
- Clinical trials of patients with cancer should consider designs that could also determine the most effective tobacco cessation interventions.
Dr. Jassem is on the speakers bureau for MSD, Takeda, BMS, Astra-Zeneca, and Pfizer.
REPORTING FROM WCLC 2019
High-dose vitamin D for bone health may do more harm than good
In fact, rather than a hypothesized increase in volumetric bone mineral density (BMD) with doses well above the recommended dietary allowance, a negative dose-response relationship was observed, Lauren A. Burt, PhD, of the McCaig Institute for Bone and Joint Health at the University of Calgary (Alta.) and colleagues found.
The total volumetric radial BMD was significantly lower in 101 and 97 study participants randomized to receive daily vitamin D3 doses of 10,000 IU or 4,000 IU for 3 years, respectively (–7.5 and –3.9 mg of calcium hydroxyapatite [HA] per cm3), compared with 105 participants randomized to a reference group that received 400 IU (mean percent changes, –3.5%, –2.4%, and –1.2%, respectively). Total volumetric tibial BMD was also significantly lower in the 10,000 IU arm, compared with the reference arm (–4.1 mg HA per cm3; mean percent change –1.7% vs. –0.4%), the investigators reported Aug. 27 in JAMA.
There also were no significant differences seen between the three groups for the coprimary endpoint of bone strength at either the radius or tibia.
Participants in the double-blind trial were community-dwelling healthy men and women aged 55-70 years (mean age, 62.2 years) without osteoporosis and with baseline levels of 25-hydroxyvitamin D (25[OH]D) of 30-125 nmol/L. They were enrolled from a single center between August 2013 and December 2017 and treated with daily oral vitamin D3 drops at the assigned dosage for 3 years and with calcium supplementation if dietary calcium intake was less than 1,200 mg daily.
Mean supplementation adherence was 99% among the 303 participants who completed the trial (out of 311 enrolled), and adherence was similar across the groups.
Baseline 25(OH)D levels in the 400 IU group were 76.3 nmol/L at baseline, 76.7 nmol/L at 3 months, and 77.4 nmol/L at 3 years. The corresponding measures for the 4,000 IU group were 81.3, 115.3, and 132.2 nmol/L, and for the 10,000 IU group, they were 78.4, 188.0, and 144.4, the investigators said, noting that significant group-by-time interactions were noted for volumetric BMD.
Bone strength decreased over time, but group-by-time interactions for that measure were not statistically significant, they said.
A total of 44 serious adverse events occurred in 38 participants (12.2%), and one death from presumed myocardial infarction occurred in the 400 IU group. Of eight prespecified adverse events, only hypercalcemia and hypercalciuria had significant dose-response effects; all episodes of hypercalcemia were mild and had resolved at follow-up, and the two hypercalcemia events, which occurred in one participant in the 10,000 IU group, were also transient. No significant difference in fall rates was seen in the three groups, they noted.
Vitamin D is considered beneficial for preventing and treating osteoporosis, and data support supplementation in individuals with 25(OH)D levels less than 30 nmol/L, but recent meta-analyses did not find a major treatment benefit for osteoporosis or for preventing falls and fractures, the investigators said.
Further, while most supplementation recommendations call for 400-2,000 IU daily, with a tolerable upper intake level of 4,000-10,000 IU, 3% of U.S. adults in 2013-2014 reported intake of at least 4,000 IU per day, but few studies have assessed the effects of doses at or above the upper intake level for 12 months or longer, they noted, adding that this study was “motivated by the prevalence of high-dose vitamin D supplementation among healthy adults.”
“It was hypothesized that a higher dose of vitamin D has a positive effect on high-resolution peripheral quantitative CT measures of volumetric density and strength, perhaps via suppression of parathyroid hormone (PTH)–mediated bone turnover,” they wrote.
However, based on the significantly lower radial BMD seen with both 4,000 and 10,000 IU, compared with 400 IU; the lower tibial BMD with 10,000 IU, compared with 400 IU; and the lack of a difference in bone strength at the radius and tibia, the findings do not support a benefit of high-dose vitamin D supplementation for bone health, they said, noting that additional study is needed to determine whether such doses are harmful.
“Because these results are in the opposite direction of the research hypothesis, this evidence of high-dose vitamin D having a negative effect on bone should be regarded as hypothesis generating, requiring confirmation with further research,” they concluded.
SOURCE: Burt L et al. JAMA. 2019 Aug 27;322(8):736-45.
In fact, rather than a hypothesized increase in volumetric bone mineral density (BMD) with doses well above the recommended dietary allowance, a negative dose-response relationship was observed, Lauren A. Burt, PhD, of the McCaig Institute for Bone and Joint Health at the University of Calgary (Alta.) and colleagues found.
The total volumetric radial BMD was significantly lower in 101 and 97 study participants randomized to receive daily vitamin D3 doses of 10,000 IU or 4,000 IU for 3 years, respectively (–7.5 and –3.9 mg of calcium hydroxyapatite [HA] per cm3), compared with 105 participants randomized to a reference group that received 400 IU (mean percent changes, –3.5%, –2.4%, and –1.2%, respectively). Total volumetric tibial BMD was also significantly lower in the 10,000 IU arm, compared with the reference arm (–4.1 mg HA per cm3; mean percent change –1.7% vs. –0.4%), the investigators reported Aug. 27 in JAMA.
There also were no significant differences seen between the three groups for the coprimary endpoint of bone strength at either the radius or tibia.
Participants in the double-blind trial were community-dwelling healthy men and women aged 55-70 years (mean age, 62.2 years) without osteoporosis and with baseline levels of 25-hydroxyvitamin D (25[OH]D) of 30-125 nmol/L. They were enrolled from a single center between August 2013 and December 2017 and treated with daily oral vitamin D3 drops at the assigned dosage for 3 years and with calcium supplementation if dietary calcium intake was less than 1,200 mg daily.
Mean supplementation adherence was 99% among the 303 participants who completed the trial (out of 311 enrolled), and adherence was similar across the groups.
Baseline 25(OH)D levels in the 400 IU group were 76.3 nmol/L at baseline, 76.7 nmol/L at 3 months, and 77.4 nmol/L at 3 years. The corresponding measures for the 4,000 IU group were 81.3, 115.3, and 132.2 nmol/L, and for the 10,000 IU group, they were 78.4, 188.0, and 144.4, the investigators said, noting that significant group-by-time interactions were noted for volumetric BMD.
Bone strength decreased over time, but group-by-time interactions for that measure were not statistically significant, they said.
A total of 44 serious adverse events occurred in 38 participants (12.2%), and one death from presumed myocardial infarction occurred in the 400 IU group. Of eight prespecified adverse events, only hypercalcemia and hypercalciuria had significant dose-response effects; all episodes of hypercalcemia were mild and had resolved at follow-up, and the two hypercalcemia events, which occurred in one participant in the 10,000 IU group, were also transient. No significant difference in fall rates was seen in the three groups, they noted.
Vitamin D is considered beneficial for preventing and treating osteoporosis, and data support supplementation in individuals with 25(OH)D levels less than 30 nmol/L, but recent meta-analyses did not find a major treatment benefit for osteoporosis or for preventing falls and fractures, the investigators said.
Further, while most supplementation recommendations call for 400-2,000 IU daily, with a tolerable upper intake level of 4,000-10,000 IU, 3% of U.S. adults in 2013-2014 reported intake of at least 4,000 IU per day, but few studies have assessed the effects of doses at or above the upper intake level for 12 months or longer, they noted, adding that this study was “motivated by the prevalence of high-dose vitamin D supplementation among healthy adults.”
“It was hypothesized that a higher dose of vitamin D has a positive effect on high-resolution peripheral quantitative CT measures of volumetric density and strength, perhaps via suppression of parathyroid hormone (PTH)–mediated bone turnover,” they wrote.
However, based on the significantly lower radial BMD seen with both 4,000 and 10,000 IU, compared with 400 IU; the lower tibial BMD with 10,000 IU, compared with 400 IU; and the lack of a difference in bone strength at the radius and tibia, the findings do not support a benefit of high-dose vitamin D supplementation for bone health, they said, noting that additional study is needed to determine whether such doses are harmful.
“Because these results are in the opposite direction of the research hypothesis, this evidence of high-dose vitamin D having a negative effect on bone should be regarded as hypothesis generating, requiring confirmation with further research,” they concluded.
SOURCE: Burt L et al. JAMA. 2019 Aug 27;322(8):736-45.
In fact, rather than a hypothesized increase in volumetric bone mineral density (BMD) with doses well above the recommended dietary allowance, a negative dose-response relationship was observed, Lauren A. Burt, PhD, of the McCaig Institute for Bone and Joint Health at the University of Calgary (Alta.) and colleagues found.
The total volumetric radial BMD was significantly lower in 101 and 97 study participants randomized to receive daily vitamin D3 doses of 10,000 IU or 4,000 IU for 3 years, respectively (–7.5 and –3.9 mg of calcium hydroxyapatite [HA] per cm3), compared with 105 participants randomized to a reference group that received 400 IU (mean percent changes, –3.5%, –2.4%, and –1.2%, respectively). Total volumetric tibial BMD was also significantly lower in the 10,000 IU arm, compared with the reference arm (–4.1 mg HA per cm3; mean percent change –1.7% vs. –0.4%), the investigators reported Aug. 27 in JAMA.
There also were no significant differences seen between the three groups for the coprimary endpoint of bone strength at either the radius or tibia.
Participants in the double-blind trial were community-dwelling healthy men and women aged 55-70 years (mean age, 62.2 years) without osteoporosis and with baseline levels of 25-hydroxyvitamin D (25[OH]D) of 30-125 nmol/L. They were enrolled from a single center between August 2013 and December 2017 and treated with daily oral vitamin D3 drops at the assigned dosage for 3 years and with calcium supplementation if dietary calcium intake was less than 1,200 mg daily.
Mean supplementation adherence was 99% among the 303 participants who completed the trial (out of 311 enrolled), and adherence was similar across the groups.
Baseline 25(OH)D levels in the 400 IU group were 76.3 nmol/L at baseline, 76.7 nmol/L at 3 months, and 77.4 nmol/L at 3 years. The corresponding measures for the 4,000 IU group were 81.3, 115.3, and 132.2 nmol/L, and for the 10,000 IU group, they were 78.4, 188.0, and 144.4, the investigators said, noting that significant group-by-time interactions were noted for volumetric BMD.
Bone strength decreased over time, but group-by-time interactions for that measure were not statistically significant, they said.
A total of 44 serious adverse events occurred in 38 participants (12.2%), and one death from presumed myocardial infarction occurred in the 400 IU group. Of eight prespecified adverse events, only hypercalcemia and hypercalciuria had significant dose-response effects; all episodes of hypercalcemia were mild and had resolved at follow-up, and the two hypercalcemia events, which occurred in one participant in the 10,000 IU group, were also transient. No significant difference in fall rates was seen in the three groups, they noted.
Vitamin D is considered beneficial for preventing and treating osteoporosis, and data support supplementation in individuals with 25(OH)D levels less than 30 nmol/L, but recent meta-analyses did not find a major treatment benefit for osteoporosis or for preventing falls and fractures, the investigators said.
Further, while most supplementation recommendations call for 400-2,000 IU daily, with a tolerable upper intake level of 4,000-10,000 IU, 3% of U.S. adults in 2013-2014 reported intake of at least 4,000 IU per day, but few studies have assessed the effects of doses at or above the upper intake level for 12 months or longer, they noted, adding that this study was “motivated by the prevalence of high-dose vitamin D supplementation among healthy adults.”
“It was hypothesized that a higher dose of vitamin D has a positive effect on high-resolution peripheral quantitative CT measures of volumetric density and strength, perhaps via suppression of parathyroid hormone (PTH)–mediated bone turnover,” they wrote.
However, based on the significantly lower radial BMD seen with both 4,000 and 10,000 IU, compared with 400 IU; the lower tibial BMD with 10,000 IU, compared with 400 IU; and the lack of a difference in bone strength at the radius and tibia, the findings do not support a benefit of high-dose vitamin D supplementation for bone health, they said, noting that additional study is needed to determine whether such doses are harmful.
“Because these results are in the opposite direction of the research hypothesis, this evidence of high-dose vitamin D having a negative effect on bone should be regarded as hypothesis generating, requiring confirmation with further research,” they concluded.
SOURCE: Burt L et al. JAMA. 2019 Aug 27;322(8):736-45.
FROM JAMA
Digital health and big data: New tools for making the most of real-world evidence
LAKE BUENA VISTA, FLA. – Digital health technology is vastly expanding the real-world data pool for clinical and comparative effectiveness research, according to Jeffrey Curtis, MD.
The trick is to harness the power of that data to improve patient care and outcomes, and that can be achieved in part through linkage of data sources and through point-of-care access, Dr. Curtis, professor of medicine in the division of clinical immunology and rheumatology at the University of Alabama at Birmingham (UAB), said at the annual meeting of the Florida Society of Rheumatology.
“We want to take care of patients, but probably what you and I also want is to have real-world evidence ... evidence relevant for people [we] take care of on a day-to-day basis – not people in highly selected phase 3 or even phase 4 trials,” he said.
Real-world data, which gained particular cachet through the 21st Century Cures Act permitting the Food and Drug Administration to consider real-world evidence as part of the regulatory process and in post-marketing surveillance, includes information from electronic health records (EHRs), health plan claims, traditional registries, and mobile health and technology, explained Dr. Curtis, who also is codirector of the UAB Pharmacoepidemiology and Pharmacoeconomics Unit.
“And you and I want it because patients are different, and in medicine we only have about 20% of patients where there is direct evidence about what we should do,” he added. “Give me the trial that describes the 75-year-old African American smoker with diabetes and how well he does on biologic du jour; there’s no trial like that, and yet you and I need to make those kinds of decisions in light of patients’ comorbidities and other features.”
Generating real-world evidence, however, requires new approaches and new tools, he said, explaining that efficiency is key for applying the data in busy practices, as is compatibility with delivering an intervention and with randomization.
Imagine using the EHR at the point of care to look up what happened to “the last 10 patients like this” based on how they were treated by you or your colleagues, he said.
“That would be useful information to have. In fact, the day is not so far in the future where you could, perhaps, randomize within your EHR if you had a clinically important question that really needed an answer and a protocol attached,” he added.
Real-world data collection
Pragmatic trials offer one approach to garnering real-world data by addressing a simple question – usually with a hard outcome – using very few inclusion and exclusion criteria, Dr. Curtis said, describing the recently completed VERVE Zoster Vaccine trial.
He and his colleagues randomized 617 patients from 33 sites to look at the safety of the live-virus Zostavax herpes zoster vaccine in rheumatoid arthritis patients over age 50 years on any anti–tumor necrosis factor (anti-TNF) therapy. Half of the patients received saline, the other half received the vaccine, and no cases of varicella zoster occurred in either group.
“So, to the extent that half of 617 people with zero cases was reassuring, we now have some evidence where heretofore there was none,” he said, noting that those results will be presented at the 2019 American College of Rheumatology annual meeting. “But the focus of this talk is not on vaccination, it’s really on how we do real-world effectiveness or safety studies in a way that doesn’t slow us way down and doesn’t require some big research operation.”
One way is through efficient recruitment, and depending on how complicated the study is, qualified patients may be easily identifiable through the EHR. In fact, numerous tools are available to codify and search both structured and unstructured data, Dr. Curtis said, noting that he and his colleagues used the web-based i2b2 Query Tool for the VERVE study.
The study sites that did the best with recruiting had the ability to search their own EHRs for patients who met the inclusion criteria, and those patients were then invited to participate. A short video was created to educate those who were interested, and a “knowledge review” quiz was administered afterward to ensure informed consent, which was provided via digital signature.
Health plan and other “big data” can also be very useful for answering certain questions. One example is how soon biologics should be stopped before elective orthopedic surgery? Dr. Curtis and colleagues looked at this using claims data for nearly 4,300 patients undergoing elective hip or knee arthroplasty and found no evidence that administering infliximab within 4 weeks of surgery increased serious infection risk within 30 days or prosthetic joint infection within 1 year.
“Where else are you going to go run a prospective study of 4,300 elective hips and knees,” he said, stressing that it wouldn’t be easy.
Other sources that can help generate real-world effectiveness data include traditional or single-center registries and EHR-based registries.
“The EHR registries are, I think, the newest that many are part of in our field,” he said, noting that “a number of groups are aggregating that,” including the ACR RISE registry and some physician groups, for example.
“What we’re really after is to have a clinically integrated network and a learning health care environment,” he explained, adding that the goal is to develop care pathways.
The approach represents a shift from evidence-based practice to practice-based evidence, he noted.
“When you and I practice, we’re generating that evidence and now we just need to harness that data to get smarter to take care of patients,” he said, adding that the lack of randomization for much of these data isn’t necessarily a problem.
“Do you have to randomize? I would argue that you don’t necessarily have to randomize if the source of variability in how we treat patients is very related to patients’ characteristics,” he said.
If the evidence for a specific approach is weak, or a decision is based on physician preference, physician practice, or insurance company considerations instead of patient characteristics, randomization may not be necessary, he explained.
In fact, insurance company requirements often create “natural experiments” that can be used to help identify better practices. For example, if one only covers adalimumab for first-line TNF inhibition, and another has a “different fail-first policy and that’s not first line and everybody gets some other TNF inhibitor, then I can probably compare those quite reasonably,” he said.
“That’s a great setting where you might not need randomization.”
Of note, “having more data sometimes trumps smarter algorithms,” but that means finding and linking more data that “exist in the wild,” Dr. Curtis said.
Linking data sources
When he and his colleagues wanted to assess the cost of not achieving RA remission, no single data source provided all of the information they needed. They used both CORRONA registry data and health claims data to look at various outcome measures across disease activity categories and with adjustment for comorbidity clusters. They previously reported on the feasibility and validity of the approach.
“We’re currently doing another project where one of the local Blue Cross plans said ‘I’m interested to support you to see how efficient you are; we will donate or loan you our claims data [and] let you link it to your practice so you can actually tell us ... cost conditional on [a patient’s] disease activity,’ ” he said.
Another example involves a recent study looking at biomarker-based cardiovascular disease risk prediction in RA using data from nearly 31,000 Medicare patients linked with multibiomarker disease activity (MBDA) test results, with which they “basically built and validated a risk prediction model,” he said.
The point is that such data linkage provided tools for use at the point of care that can predict CVD risk using “some simple things that you and I have in our EHR,” he said. “But you couldn’t do this if you had to assemble a prospective cohort of tens of thousands of arthritis patients and then wait years for follow-up.”
Patient-reported outcomes collected at the point of care and by patients at home between visits, such as digital data collected via wearable technology, can provide additional information to help improve patient care and management.
“My interest is not to think about [these data sources] in isolation, but really to think about how we bring these together,” he said. “I’m interested in maximizing value for both patients and clinicians, and not having to pick only one of these data sources, but really to harness several of them if that’s what we need to take better care of patients and to answer important questions.”
Doing so is increasingly important given the workforce shortage in rheumatology, he noted.
“The point is that we’re going to need to be a whole lot more efficient as a field because there are going to be fewer of us even at a time when more of us are needed,” he said.
It’s a topic in which the ACR has shown a lot of interest, he said, noting that he cochaired a preconference course on mobile health technologies at the 2018 ACR annual meeting and is involved with a similar course on “big data” ahead of the 2019 meeting.
The thought of making use of the various digital health and “big data” sources can be overwhelming, but the key is to start with the question that needs an answer or the problem that needs to be solved.
“Don’t start with the data,” he explained. “Start with [asking] ... ‘What am I trying to do?’ ”
Dr. Curtis reported funding from the National Institute on Arthritis and Musculoskeletal and Skin Diseases and the Patient-Centered Outcomes Research Institute. He has also consulted for or received research grants from Amgen, AbbVie, Bristol-Myers Squibb, CORRONA, Lilly, Janssen, Myriad, Novartis, Roche, Pfizer, and Sanofi/Regeneron.
LAKE BUENA VISTA, FLA. – Digital health technology is vastly expanding the real-world data pool for clinical and comparative effectiveness research, according to Jeffrey Curtis, MD.
The trick is to harness the power of that data to improve patient care and outcomes, and that can be achieved in part through linkage of data sources and through point-of-care access, Dr. Curtis, professor of medicine in the division of clinical immunology and rheumatology at the University of Alabama at Birmingham (UAB), said at the annual meeting of the Florida Society of Rheumatology.
“We want to take care of patients, but probably what you and I also want is to have real-world evidence ... evidence relevant for people [we] take care of on a day-to-day basis – not people in highly selected phase 3 or even phase 4 trials,” he said.
Real-world data, which gained particular cachet through the 21st Century Cures Act permitting the Food and Drug Administration to consider real-world evidence as part of the regulatory process and in post-marketing surveillance, includes information from electronic health records (EHRs), health plan claims, traditional registries, and mobile health and technology, explained Dr. Curtis, who also is codirector of the UAB Pharmacoepidemiology and Pharmacoeconomics Unit.
“And you and I want it because patients are different, and in medicine we only have about 20% of patients where there is direct evidence about what we should do,” he added. “Give me the trial that describes the 75-year-old African American smoker with diabetes and how well he does on biologic du jour; there’s no trial like that, and yet you and I need to make those kinds of decisions in light of patients’ comorbidities and other features.”
Generating real-world evidence, however, requires new approaches and new tools, he said, explaining that efficiency is key for applying the data in busy practices, as is compatibility with delivering an intervention and with randomization.
Imagine using the EHR at the point of care to look up what happened to “the last 10 patients like this” based on how they were treated by you or your colleagues, he said.
“That would be useful information to have. In fact, the day is not so far in the future where you could, perhaps, randomize within your EHR if you had a clinically important question that really needed an answer and a protocol attached,” he added.
Real-world data collection
Pragmatic trials offer one approach to garnering real-world data by addressing a simple question – usually with a hard outcome – using very few inclusion and exclusion criteria, Dr. Curtis said, describing the recently completed VERVE Zoster Vaccine trial.
He and his colleagues randomized 617 patients from 33 sites to look at the safety of the live-virus Zostavax herpes zoster vaccine in rheumatoid arthritis patients over age 50 years on any anti–tumor necrosis factor (anti-TNF) therapy. Half of the patients received saline, the other half received the vaccine, and no cases of varicella zoster occurred in either group.
“So, to the extent that half of 617 people with zero cases was reassuring, we now have some evidence where heretofore there was none,” he said, noting that those results will be presented at the 2019 American College of Rheumatology annual meeting. “But the focus of this talk is not on vaccination, it’s really on how we do real-world effectiveness or safety studies in a way that doesn’t slow us way down and doesn’t require some big research operation.”
One way is through efficient recruitment, and depending on how complicated the study is, qualified patients may be easily identifiable through the EHR. In fact, numerous tools are available to codify and search both structured and unstructured data, Dr. Curtis said, noting that he and his colleagues used the web-based i2b2 Query Tool for the VERVE study.
The study sites that did the best with recruiting had the ability to search their own EHRs for patients who met the inclusion criteria, and those patients were then invited to participate. A short video was created to educate those who were interested, and a “knowledge review” quiz was administered afterward to ensure informed consent, which was provided via digital signature.
Health plan and other “big data” can also be very useful for answering certain questions. One example is how soon biologics should be stopped before elective orthopedic surgery? Dr. Curtis and colleagues looked at this using claims data for nearly 4,300 patients undergoing elective hip or knee arthroplasty and found no evidence that administering infliximab within 4 weeks of surgery increased serious infection risk within 30 days or prosthetic joint infection within 1 year.
“Where else are you going to go run a prospective study of 4,300 elective hips and knees,” he said, stressing that it wouldn’t be easy.
Other sources that can help generate real-world effectiveness data include traditional or single-center registries and EHR-based registries.
“The EHR registries are, I think, the newest that many are part of in our field,” he said, noting that “a number of groups are aggregating that,” including the ACR RISE registry and some physician groups, for example.
“What we’re really after is to have a clinically integrated network and a learning health care environment,” he explained, adding that the goal is to develop care pathways.
The approach represents a shift from evidence-based practice to practice-based evidence, he noted.
“When you and I practice, we’re generating that evidence and now we just need to harness that data to get smarter to take care of patients,” he said, adding that the lack of randomization for much of these data isn’t necessarily a problem.
“Do you have to randomize? I would argue that you don’t necessarily have to randomize if the source of variability in how we treat patients is very related to patients’ characteristics,” he said.
If the evidence for a specific approach is weak, or a decision is based on physician preference, physician practice, or insurance company considerations instead of patient characteristics, randomization may not be necessary, he explained.
In fact, insurance company requirements often create “natural experiments” that can be used to help identify better practices. For example, if one only covers adalimumab for first-line TNF inhibition, and another has a “different fail-first policy and that’s not first line and everybody gets some other TNF inhibitor, then I can probably compare those quite reasonably,” he said.
“That’s a great setting where you might not need randomization.”
Of note, “having more data sometimes trumps smarter algorithms,” but that means finding and linking more data that “exist in the wild,” Dr. Curtis said.
Linking data sources
When he and his colleagues wanted to assess the cost of not achieving RA remission, no single data source provided all of the information they needed. They used both CORRONA registry data and health claims data to look at various outcome measures across disease activity categories and with adjustment for comorbidity clusters. They previously reported on the feasibility and validity of the approach.
“We’re currently doing another project where one of the local Blue Cross plans said ‘I’m interested to support you to see how efficient you are; we will donate or loan you our claims data [and] let you link it to your practice so you can actually tell us ... cost conditional on [a patient’s] disease activity,’ ” he said.
Another example involves a recent study looking at biomarker-based cardiovascular disease risk prediction in RA using data from nearly 31,000 Medicare patients linked with multibiomarker disease activity (MBDA) test results, with which they “basically built and validated a risk prediction model,” he said.
The point is that such data linkage provided tools for use at the point of care that can predict CVD risk using “some simple things that you and I have in our EHR,” he said. “But you couldn’t do this if you had to assemble a prospective cohort of tens of thousands of arthritis patients and then wait years for follow-up.”
Patient-reported outcomes collected at the point of care and by patients at home between visits, such as digital data collected via wearable technology, can provide additional information to help improve patient care and management.
“My interest is not to think about [these data sources] in isolation, but really to think about how we bring these together,” he said. “I’m interested in maximizing value for both patients and clinicians, and not having to pick only one of these data sources, but really to harness several of them if that’s what we need to take better care of patients and to answer important questions.”
Doing so is increasingly important given the workforce shortage in rheumatology, he noted.
“The point is that we’re going to need to be a whole lot more efficient as a field because there are going to be fewer of us even at a time when more of us are needed,” he said.
It’s a topic in which the ACR has shown a lot of interest, he said, noting that he cochaired a preconference course on mobile health technologies at the 2018 ACR annual meeting and is involved with a similar course on “big data” ahead of the 2019 meeting.
The thought of making use of the various digital health and “big data” sources can be overwhelming, but the key is to start with the question that needs an answer or the problem that needs to be solved.
“Don’t start with the data,” he explained. “Start with [asking] ... ‘What am I trying to do?’ ”
Dr. Curtis reported funding from the National Institute on Arthritis and Musculoskeletal and Skin Diseases and the Patient-Centered Outcomes Research Institute. He has also consulted for or received research grants from Amgen, AbbVie, Bristol-Myers Squibb, CORRONA, Lilly, Janssen, Myriad, Novartis, Roche, Pfizer, and Sanofi/Regeneron.
LAKE BUENA VISTA, FLA. – Digital health technology is vastly expanding the real-world data pool for clinical and comparative effectiveness research, according to Jeffrey Curtis, MD.
The trick is to harness the power of that data to improve patient care and outcomes, and that can be achieved in part through linkage of data sources and through point-of-care access, Dr. Curtis, professor of medicine in the division of clinical immunology and rheumatology at the University of Alabama at Birmingham (UAB), said at the annual meeting of the Florida Society of Rheumatology.
“We want to take care of patients, but probably what you and I also want is to have real-world evidence ... evidence relevant for people [we] take care of on a day-to-day basis – not people in highly selected phase 3 or even phase 4 trials,” he said.
Real-world data, which gained particular cachet through the 21st Century Cures Act permitting the Food and Drug Administration to consider real-world evidence as part of the regulatory process and in post-marketing surveillance, includes information from electronic health records (EHRs), health plan claims, traditional registries, and mobile health and technology, explained Dr. Curtis, who also is codirector of the UAB Pharmacoepidemiology and Pharmacoeconomics Unit.
“And you and I want it because patients are different, and in medicine we only have about 20% of patients where there is direct evidence about what we should do,” he added. “Give me the trial that describes the 75-year-old African American smoker with diabetes and how well he does on biologic du jour; there’s no trial like that, and yet you and I need to make those kinds of decisions in light of patients’ comorbidities and other features.”
Generating real-world evidence, however, requires new approaches and new tools, he said, explaining that efficiency is key for applying the data in busy practices, as is compatibility with delivering an intervention and with randomization.
Imagine using the EHR at the point of care to look up what happened to “the last 10 patients like this” based on how they were treated by you or your colleagues, he said.
“That would be useful information to have. In fact, the day is not so far in the future where you could, perhaps, randomize within your EHR if you had a clinically important question that really needed an answer and a protocol attached,” he added.
Real-world data collection
Pragmatic trials offer one approach to garnering real-world data by addressing a simple question – usually with a hard outcome – using very few inclusion and exclusion criteria, Dr. Curtis said, describing the recently completed VERVE Zoster Vaccine trial.
He and his colleagues randomized 617 patients from 33 sites to look at the safety of the live-virus Zostavax herpes zoster vaccine in rheumatoid arthritis patients over age 50 years on any anti–tumor necrosis factor (anti-TNF) therapy. Half of the patients received saline, the other half received the vaccine, and no cases of varicella zoster occurred in either group.
“So, to the extent that half of 617 people with zero cases was reassuring, we now have some evidence where heretofore there was none,” he said, noting that those results will be presented at the 2019 American College of Rheumatology annual meeting. “But the focus of this talk is not on vaccination, it’s really on how we do real-world effectiveness or safety studies in a way that doesn’t slow us way down and doesn’t require some big research operation.”
One way is through efficient recruitment, and depending on how complicated the study is, qualified patients may be easily identifiable through the EHR. In fact, numerous tools are available to codify and search both structured and unstructured data, Dr. Curtis said, noting that he and his colleagues used the web-based i2b2 Query Tool for the VERVE study.
The study sites that did the best with recruiting had the ability to search their own EHRs for patients who met the inclusion criteria, and those patients were then invited to participate. A short video was created to educate those who were interested, and a “knowledge review” quiz was administered afterward to ensure informed consent, which was provided via digital signature.
Health plan and other “big data” can also be very useful for answering certain questions. One example is how soon biologics should be stopped before elective orthopedic surgery? Dr. Curtis and colleagues looked at this using claims data for nearly 4,300 patients undergoing elective hip or knee arthroplasty and found no evidence that administering infliximab within 4 weeks of surgery increased serious infection risk within 30 days or prosthetic joint infection within 1 year.
“Where else are you going to go run a prospective study of 4,300 elective hips and knees,” he said, stressing that it wouldn’t be easy.
Other sources that can help generate real-world effectiveness data include traditional or single-center registries and EHR-based registries.
“The EHR registries are, I think, the newest that many are part of in our field,” he said, noting that “a number of groups are aggregating that,” including the ACR RISE registry and some physician groups, for example.
“What we’re really after is to have a clinically integrated network and a learning health care environment,” he explained, adding that the goal is to develop care pathways.
The approach represents a shift from evidence-based practice to practice-based evidence, he noted.
“When you and I practice, we’re generating that evidence and now we just need to harness that data to get smarter to take care of patients,” he said, adding that the lack of randomization for much of these data isn’t necessarily a problem.
“Do you have to randomize? I would argue that you don’t necessarily have to randomize if the source of variability in how we treat patients is very related to patients’ characteristics,” he said.
If the evidence for a specific approach is weak, or a decision is based on physician preference, physician practice, or insurance company considerations instead of patient characteristics, randomization may not be necessary, he explained.
In fact, insurance company requirements often create “natural experiments” that can be used to help identify better practices. For example, if one only covers adalimumab for first-line TNF inhibition, and another has a “different fail-first policy and that’s not first line and everybody gets some other TNF inhibitor, then I can probably compare those quite reasonably,” he said.
“That’s a great setting where you might not need randomization.”
Of note, “having more data sometimes trumps smarter algorithms,” but that means finding and linking more data that “exist in the wild,” Dr. Curtis said.
Linking data sources
When he and his colleagues wanted to assess the cost of not achieving RA remission, no single data source provided all of the information they needed. They used both CORRONA registry data and health claims data to look at various outcome measures across disease activity categories and with adjustment for comorbidity clusters. They previously reported on the feasibility and validity of the approach.
“We’re currently doing another project where one of the local Blue Cross plans said ‘I’m interested to support you to see how efficient you are; we will donate or loan you our claims data [and] let you link it to your practice so you can actually tell us ... cost conditional on [a patient’s] disease activity,’ ” he said.
Another example involves a recent study looking at biomarker-based cardiovascular disease risk prediction in RA using data from nearly 31,000 Medicare patients linked with multibiomarker disease activity (MBDA) test results, with which they “basically built and validated a risk prediction model,” he said.
The point is that such data linkage provided tools for use at the point of care that can predict CVD risk using “some simple things that you and I have in our EHR,” he said. “But you couldn’t do this if you had to assemble a prospective cohort of tens of thousands of arthritis patients and then wait years for follow-up.”
Patient-reported outcomes collected at the point of care and by patients at home between visits, such as digital data collected via wearable technology, can provide additional information to help improve patient care and management.
“My interest is not to think about [these data sources] in isolation, but really to think about how we bring these together,” he said. “I’m interested in maximizing value for both patients and clinicians, and not having to pick only one of these data sources, but really to harness several of them if that’s what we need to take better care of patients and to answer important questions.”
Doing so is increasingly important given the workforce shortage in rheumatology, he noted.
“The point is that we’re going to need to be a whole lot more efficient as a field because there are going to be fewer of us even at a time when more of us are needed,” he said.
It’s a topic in which the ACR has shown a lot of interest, he said, noting that he cochaired a preconference course on mobile health technologies at the 2018 ACR annual meeting and is involved with a similar course on “big data” ahead of the 2019 meeting.
The thought of making use of the various digital health and “big data” sources can be overwhelming, but the key is to start with the question that needs an answer or the problem that needs to be solved.
“Don’t start with the data,” he explained. “Start with [asking] ... ‘What am I trying to do?’ ”
Dr. Curtis reported funding from the National Institute on Arthritis and Musculoskeletal and Skin Diseases and the Patient-Centered Outcomes Research Institute. He has also consulted for or received research grants from Amgen, AbbVie, Bristol-Myers Squibb, CORRONA, Lilly, Janssen, Myriad, Novartis, Roche, Pfizer, and Sanofi/Regeneron.
EXPERT ANALYSIS FROM FSR 2019