Abstract
Background: Approved systemic treatments for malignant pleural mesothelioma (MPM) have been limited to chemotherapy regimens that have moderate survival benefit with poor outcomes. Nivolumab plus ipilimumab has shown clinical benefit in other tumour types, including first-line non-small-cell lung cancer. We hypothesised that this regimen would improve overall survival in MPM. Methods: This open-label, randomised, phase 3 study (CheckMate 743) was run at 103 hospitals across 21 countries. Eligible individuals were aged 18 years and older, with previously untreated, histologically confirmed unresectable MPM, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to nivolumab (3 mg/kg intravenously once every 2 weeks) plus ipilimumab (1 mg/kg intravenously once every 6 weeks) for up to 2 years, or platinum plus pemetrexed chemotherapy (pemetrexed [500 mg/m2 intravenously] plus cisplatin [75 mg/m2 intravenously] or carboplatin [area under the concentration-time curve 5 mg/mL per min intravenously]) once every 3 weeks for up to six cycles. The primary endpoint was overall survival among all participants randomly assigned to treatment, and safety was assessed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT02899299, and is closed to accrual. Findings: Between Nov 29, 2016, and April 28, 2018, 713 patients were enrolled, of whom 605 were randomly assigned to either nivolumab plus ipilimumab (n=303) or chemotherapy (n=302). 467 (77%) of 605 participants were male and median age was 69 years (IQR 64–75). At the prespecified interim analysis (database lock April 3, 2020; median follow-up of 29·7 months [IQR 26·7–32·9]), nivolumab plus ipilimumab significantly extended overall survival versus chemotherapy (median overall survival 18·1 months [95% CI 16·8–21·4] vs 14·1 months [12·4–16·2]; hazard ratio 0·74 [96·6% CI 0·60–0·91]; p=0·0020). 2-year overall survival rates were 41% (95% CI 35·1–46·5) in the nivolumab plus ipilimumab group and 27% (21·9–32·4) in the chemotherapy group. Grade 3–4 treatment-related adverse events were reported in 91 (30%) of 300 patients treated with nivolumab plus ipilimumab and 91 (32%) of 284 treated with chemotherapy. Three (1%) treatment-related deaths occurred in the nivolumab plus ipilimumab group (pneumonitis, encephalitis, and heart failure) and one (<1%) in the chemotherapy group (myelosuppression). Interpretation: Nivolumab plus ipilimumab provided significant and clinically meaningful improvements in overall survival versus standard-of-care chemotherapy, supporting the use of this first-in-class regimen that has been approved in the USA as of October, 2020, for previously untreated unresectable MPM. Funding: Bristol Myers Squibb.
Original language | English |
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Pages (from-to) | 375-386 |
Number of pages | 12 |
Journal | The Lancet |
Volume | 397 |
Issue number | 10272 |
DOIs | |
Publication status | Published - 30 Jan 2021 |
Bibliographical note
Funding Information:This study was funded by Bristol Myers Squibb. We thank the patients and families who participated for making this trial possible, and the investigators (appendix p 2) and clinical study teams who participated in the trial. We also thank Ama Day for contributions as protocol manager of this trial; Dako for collaborative development of the PD-L1 IHC 28-8 pharmDx assay; and Mhairi Laird, of Caudex (Oxford, UK), for her assistance in the preparation of the manuscript. The NCCN guidelines were cited with the permission of NCCN. NCCN makes no warranties of any kind whatsoever regarding their content, use, or application, and disclaims any responsibility for their application or use in any way.
Funding Information:
PB has received institutional grant funding from Bristol Myers Squibb and MSD and has a consultancy or advisory role for Bristol Myers Squibb, MSD, Roche, Beigene, Epizyme, Takeda, Trizell, and Daichii-Sankyo (all honoraria are paid to his institute). AS has received grant funding and personal fees from Bristol Myers Squibb (for provided work on advisory boards, consultancy, service on the speaker's bureau, provision of expert testimony, and for travel or accommodation expenses) and their institution has also received support from Bristol Myers Squibb (payment for work as a principal investigator or coprincipal investigator in clinical trials); has received personal fees from AstraZeneca and MSD (for provided work on advisory boards, consultancy, service on the speaker's bureau, provision of expert testimony, and for travel or accommodation expenses) and their institution also received support from AstraZeneca and MSD (payment for work as a principal investigator or coprincipal investigator in clinical trials); and has received personal fees from Roche (for provided work on advisory boards, consultancy, service on the speaker's bureau, provision of expert testimony, and for travel or accommodation expenses) and their institution also received support from Roche (payment for work as a principal investigator or coprincipal investigator in clinical trials). AKN has received grant funding from Atara Biotherapeutics and Douglas Pharmaceuticals; received non-financial, travel support, and grant funding from AstraZeneca; received personal fees from Bayer Pharmaceuticals, Pharmabcine, and Trizell (honoraria and provided consulting); received personal fees, non-financial, and travel support from Boehringer Ingelheim (honoraria, served on the advisory board and travel funding); received personal fees from Douglas Pharmaceuticals, Merck Sharp Dohme, and Roche Pharmaceuticals (served on the advisory board and honoraria); and received personal fees from Atara Biotherapeutics (served on the advisory board). NF has received personal fees from Bristol Myers Squibb and Daiichi Sankyo (honoraria) and received grant funding and personal fees from ONO pharmaceutical (honoraria, and provided advice and consulting). SPe has received personal fees and non-financial support from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, F Hoffmann-La Roche, MSD, Novartis, and Pfizer (served on the advisory board, gave talks, honoraria, and investigation in trials); received personal fees from Amgen, Clovis, Illumina, and Merck Serono (served on the advisory board, honoraria, and investigation in trials); received personal fees from Takeda (gave talks, and honorarium); received personal fees from Eli Lilly and Sanofi (served on the advisory board, honoraria, and gave talks); received personal fees from AbbVie, Bayer, Biocartis, Biovent, Daiichi Sankyo, Debiopharm, Foundation Medicine, Janssen, Merrimack, Pharma Mar, Regeneron, Seattle Genetics, and Takeda (served on the advisory board and honoraria). AST has received personal fees from Bristol Myers Squibb, Eli Lilly, Genentech, Roche, Novartis, Ariad, EMD Serono, Merck, Seattle Genetics, AstraZeneca, Boehringer Ingelheim, Sellas Life Science, and Takeda (for advisory boards); and has received grant support from Millenium, Polaris, Epizyme, EMD Serono, and Seattle Genetics (for research grants). ASM's institution received support from AbbVie, AstraZeneca, Bristol Myers Squibb, and Genentech/Roche (paid honoraria to the institution); received grant funding from Novartis and Verily (paid to institution); and ASM has received travel expenses from Roche; and ASM has acted as a non-remunerated director for the Mesothelioma Applied Research Foundation. SPo received personal fees from AbbVie, AstraZeneca, Bayer, Beigene, Blueprint, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, EMD Serono, Eli Lilly, GlaxoSmithKline, Guardant Health, Incyte, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Seattle Genetics, Takeda, and Tesaro (served on the advisory board and provided consulting); received personal fees from Elsevier (employment); and received personal fees from Paradox (provided consulting). TJ has received personal fees from Atara Pharmaceuticals; grant funding from AstraZeneca, Eli Lilly, Epizyme, Polaris, Springworks, and Trizell; and retired during manuscript development. SA has received personal fees from Bristol Myers Squibb (consulting or advisory role); personal fees from Achilles Biotech, Celcius Therapeutics, Memgen, Rapt Therapeutics, Venn Therapeutics, Glympse, and Samyang (for advisory boards); personal fees from AstraZeneca, Caris Life Science, G1 Therapeutics, GlaxoSmithKline, Merck, and Nektar (as an advisor); personal fees and non-financial support from Amgen (as an advisor and for travel fees); grant support from Cellular Biomedicine Group (for clinical trial support); and personal fees from EMD Serono (for a data review committee). YO has received personal fees from AstraZeneca, Bristol Myers Squibb, and MSD (served on the advisory board). RC has received personal fees from MSD and Roche (served on the advisory board), and personal fees from Bristol Myers Squibb, Pfizer, and Roche (served on the speaker's bureau). LG has received personal fees from AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, MSD, Novartis, Pfizer, Roche, and Takeda (advisory board). FG has received grant funding from Bristol Myers Squibb; personal fees from AstraZeneca, Bristol Myers Squibb, Eli Lilly, MSD, and Roche (served on the advisory board and served on the speaker's bureau); personal fees from Amgen, Boehringer Ingelheim, Pierre Fabre, and Pfizer (served on the speaker's bureau); and personal fees from Takeda and Bayer (served on the advisory board). DK has received personal fees from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Merck, Merck Sharp & Dome, Pfizer, Roche, and Takeda (served on the advisory board and provided consulting). JR-C has received other funding (sponsored research) from Bristol Myers Squibb; grant support, personal fees, and non-financial support (for advisory boards, as a speaker and in a research role) from Bristol Myers Squibb, MSD, and Roche; grant support and personal fees (for advisory boards, as a speaker and in a research role) from Takeda, Novartis, Pfizer, and AstraZeneca; personal fees (for advisory boards, as a speaker and in a research role) for Beigene; personal fees (for a research role) from Celltrion and Janssen; grant support and personal fees (for advisory boards and as a speaker) from Merck and Bayer; and grant support, personal fees, and non-financial support (for advisory boards and as a speaker) from Boehringer Ingelheim. PA was an employee of Bristol Myers Squibb. AO and CB are employees of and hold stocks in Bristol Myers Squibb. GZ has received grant funding from Inventiva and Roche; personal fees and reimbursement for attendance of international meetings from AbbVie, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Pfizer, and Roche (travel or accommodation expenses); personal fees from AstraZeneca, Bristol Myers Squibb, and Roche (served on the advisory board and honoraria); personal fees from Bristol Myers Squibb and Inventiva (provided consulting); and personal fees from MSD and Da Volterra (served on the advisory board). YB declares no competing interests.
Funding Information:
This study was funded by Bristol Myers Squibb. We thank the patients and families who participated for making this trial possible, and the investigators ( appendix p 2 ) and clinical study teams who participated in the trial. We also thank Ama Day for contributions as protocol manager of this trial; Dako for collaborative development of the PD-L1 IHC 28-8 pharmDx assay; and Mhairi Laird, of Caudex (Oxford, UK), for her assistance in the preparation of the manuscript. The NCCN guidelines were cited with the permission of NCCN. NCCN makes no warranties of any kind whatsoever regarding their content, use, or application, and disclaims any responsibility for their application or use in any way.
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