On August 8, 2020 The Netherlands Cancer Institute reported that the combination of first-line nivolumab and ipilimumab demonstrated an improvement of overall survival for patients with unresectable malignant pleural mesothelioma compared to platinum-based chemotherapy (Press release, Checkmate Pharmaceuticals, AUG 8, 2020, View Source [SID1234563246]).
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The study is presented by Paul Baas, M.D., from The Netherlands Cancer Institute and The University of Leiden, in Amsterdam. Watch a video of Dr. Baas explaining his research here: View Source
Nivolumab is an immunotherapy that works as a checkpoint inhibitor, blocking a signal that prevents activation of T cells from attacking the cancer. Ipilimumab is a monoclonal antibody that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system. When administered in combination, this dual immunotherapy has shown clinical benefit in 6 different tumor types, including mesothelioma.
In this large phase III study, Dr. Baas and the global study investigators randomly assigned more than 600 patients: 303 to the nivolumab + ipilimumab arm and 302 to the chemotherapy arm. The study had a minimal follow up of close to two years. Two-year overall survival rates were 40.8% for the patients in the experimental treatment arm vs 27.0% in chemotherapy arm. Of the 30.3% of patients in the study-combination group who experienced grade 3-4 adverse events, 15% discontinued therapy compared with 7.4% of the 32.0% of patients in chemotherapy group.
"CheckMate 743 met its primary endpoint of statistically improved OS with nivolumab + ipilimumab vs standard of care chemotherapy in first-line treatment of patients with mesothelioma," said Dr. Baas. "These clinically meaningful data represent the first positive phase 3 trial of immunotherapy in first-line MPM and should be considered as a new standard of care."
Phase 3 eXalt3 Study Shows Significantly Longer Progression-Free Survival in Patients with ALK+ Lung Cancer with Ensartinib Versus Crizotinib
Patients with non-small cell lung cancer (NSCLC) carrying anaplastic lymphoma kinase (ALK) gene alterations who received ensartinib experienced substantially longer progression-free survival than a matched group of patients who received crizotinib.
The results were presented today by Leora Horn, MD, Ingram Associate Professor of Cancer Research in the Division of Hematology/Oncology and director of the Thoracic Oncology Program at Vanderbilt-Ingram Cancer Center, Nashville, Tenn. View a video interview of Dr. Horn discussing the trial here: View Source
Ensartinib (X-396) is a novel next-generation ALK tyrosine kinase inhibitor (TKI). According to Dr. Horn, in Phase 1 and 2 studies, ensartinib showed promising activity in patients with ALK+ NSCLC who were ALK TKI treatment naive or received prior crizotinib or second-generation ALK TKIs, including strong activity in patients with brain metastases.
Crizotinib is an anti-cancer drug acting as an ALK, MET, and ROS1 inhibitor, approved for treatment of some subtypes of patients with NSCLC (including ALK+) in the United States and other countries worldwide.
Dr. Horn and her colleagues at the participating cancer centers randomized 290 patients with ALK+ NSCLC to either ensartinib or crizotinib—the prespecified intent to treat (ITT) population with locally determined ALK+ NSCLC. Patients were stratified by prior chemotherapy, Eastern Cooperative Oncology Group performance status, brain metastases, and geographic region. Baseline characteristics were well balanced between the two groups: median age was 54.1; 26% of patients had prior chemotherapy, and 36% of patients had baseline brain metastases (5% had prior brain radiotherapy). The modified ITT population (the prespecified patient population that was ALK+ as confirmed by central Abbott FISH test) included 247 patients, of which 121 received ensartinib and 126 received crizotinib.
At the July 1, 2020 data cutoff, based on a pre-planned interim analysis design (at 75% of progression-free survival events) treatment was ongoing in 64 ensartinib-treated patients (45%) and 25 crizotinib-treated patients (17%). There were 139 patients who experienced disease progression (as assessed by blinded independent review committee, BIRC) or death, which represented 73% of progression events in the ITT population and 119 BIRC-events or deaths (63%) in the mITT population.
According to Dr. Horn, the trial’s analysis demonstrated a statistically significant difference between patients who received ensartinib, with a median progression-free survival of 25.8 months compared with 12.7 months with crizotinib, with a median follow-up of 23.8 and 20.2 months, respectively (HR, 0.52; 95% CI, 0.36-0.75; P=.0003 by log-rank test). In the mITT population, the median progression-free survival has not been reached yet for the ensartinib arm vs. 12.7 months for the crizotinib arm (HR, 0.48; 95% CI, 0.32-0.71; P=.0002 by log-rank test).
The overall response rate was 75% versus 67% with crizotinib; among patients with measurable brain metastases, the BIRC-assessed intracranial overall response rate was 64% with ensartinib versus 21% with crizotinib.
The time-to-treatment-failure rate in the brain in patients with no baseline brain metastases was also significantly lower with ensartinib compared to crizotinib (4% vs 24% at 12 months).
"In patients with ALK-positive NSCLC, ensartinib significantly prolonged progression-free survival over crizotinib with a favorable safety profile, representing a new option in the first-line setting," Dr. Horn concluded.
Addition of Sintilimab to Pemetrexed and Platinum Improved Progression-Free Survival in Patients with Nonsquamous Non-Small Cell Lung Cancer—Results of ORIENT-11 Presented at IASLC Virtual Presidential Symposium
The interim analysis of ORIENT-11, a phase III double-blind randomized trial has shown a nearly two-fold increase in progression-free survival with addition of sintilimab to chemotherapy in patients with advanced or metastatic non-squamous non-small cell lung cancer without EGFR or ALK genomic aberrations, according to research data presented today at the International Association for the Study of Lung Cancer Virtual Presidential Symposium.
The research findings are also published simultaneously in the Journal of Thoracic Oncology, the journal of the International Association for the Study of Lung Cancer.
Previously, sintilimab in combination with pemetrexed and a platinum-based chemotherapy had shown promising activity for nonsquamous non small cell lung cancer in a phase 1b study, according to Li Zhang, M.D., of Sun Yat-sen University Cancer Center, Guangzhou, China.
Dr. Zhang and investigators from centers in China enrolled 397 patients in the study. Of these, 266 and 131 patients were randomly assigned to the sintilimab combination and to placebo combination, respectively. Patients with all ranges of PD-L1 expression (by tumor proportion score, TPS) were included. The median progression free survival per was significantly improved in sintilimab-combination group compared to placebo combination group (8.9 vs. 5.0 months).
Dr. Zhang reported that sintilimab-combination group showed a nominally significant improvement of overall survival The overall response rate also was improved for the sintilimab-combination group (51.9% versus 29%). The safety signal for the sintilimab combination was similar to that found in other studies, but rates of occurrence of grade > 3 adverse events were slightly higher in the sintilimab-combination group (61.7% versus 58.8%).
"This study demonstrated that the addition of sintilimab to chemotherapy significantly improved progression-free survival and a nominally improved overall survival, with an acceptable safety profile in [patients with] first-line non-squamous non small cell lung cancer," said Dr. Zhang. "In this study, we collected tumor samples at baseline of treatment. So, our next work will focus on biomarker exploration. By RNA sequencing of tumor samples, we look forward to searching a potential biomarker which can predict the survival benefit from PD-1 combination with chemotherapy."