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Clinical Trial
. 2022 Oct;23(10):1274-1286.
doi: 10.1016/S1470-2045(22)00518-6. Epub 2022 Sep 12.

Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial

Mary O'Brien  1 , Luis Paz-Ares  2 , Sandrine Marreaud  3 , Urania Dafni  4 , Kersti Oselin  5 , Libor Havel  6 , Emilio Esteban  7 , Dolores Isla  8 , Alex Martinez-Marti  9 , Martin Faehling  10 , Masahiro Tsuboi  11 , Jong-Seok Lee  12 , Kazuhiko Nakagawa  13 , Jing Yang  14 , Ayman Samkari  14 , Steven M Keller  14 , Murielle Mauer  3 , Nitish Jha  3 , Rolf Stahel  15 , Benjamin Besse  16 , Solange Peters  17 ; EORTC-1416-LCG/ETOP 8-15 – PEARLS/KEYNOTE-091 Investigators
Affiliations
Clinical Trial

Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial

Mary O'Brien et al. Lancet Oncol. 2022 Oct.

Abstract

Background: Pembrolizumab is a standard-of-care for advanced non-small-cell lung cancer (NSCLC). We assessed pembrolizumab as adjuvant therapy for completely resected stage IB-IIIA NSCLC.

Methods: In this randomised, triple-blind, phase 3 trial (PEARLS/KEYNOTE-091), patients were recruited from 196 medical centres in 29 countries. Eligible patients were aged 18 years or older, with completely resected, pathologically confirmed stage IB (tumours of ≥4 cm in diameter), II, or IIIA NSCLC per the American Joint Committee on Cancer staging system (7th edition) of any histology or PD-L1 expression level, and an Eastern Cooperative Oncology Group performance status of 0 or 1; adjuvant chemotherapy was to be considered for stage IB disease and was strongly recommended for stage II and IIIA disease, according to national and local guidelines. Using a central interactive voice-response system, eligible participants were randomly assigned (1:1), using a minimisation technique and stratified by disease stage, previous adjuvant chemotherapy, PD-L1 expression, and geographical region, to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks for up to 18 cycles. Participants, investigators, and analysts were masked to treatment assignment. Dual primary endpoints were disease-free survival in the overall population and in the population with PD-L1 tumour proportion score (TPS) of 50% or greater. Efficacy was assessed in the intention-to-treat (ITT) population (ie, all participants randomly assigned to a treatment group). Safety was assessed in all participants randomly assigned to treatment who received at least one dose of study treatment. Here we report results of the second interim analysis, prespecified to occur when approximately 118 disease-free survival events had occurred in the PD-L1 TPS of 50% or greater population. This study is registered with ClinicalTrials.gov, NCT02504372, and is active but not recruiting.

Findings: Between Jan 20, 2016, and May 6, 2020, 1177 (60%) of 1955 screened participants were randomly assigned to pembrolizumab (n=590, including n=168 with PD-L1 TPS of ≥50%) or placebo (n=587; including n=165 with PD-L1 TPS of ≥50%) and included in the ITT population. Median follow-up as of data cutoff (Sept 20, 2021) for this interim analysis was 35·6 months (IQR 27·1-45·5). In the overall population, median disease-free survival was 53·6 months (95% CI 39·2 to not reached) in the pembrolizumab group versus 42·0 months (31·3 to not reached) in the placebo group (HR 0·76 [95% CI 0·63-0·91], p=0·0014). In the PD-L1 TPS of 50% or greater population, median disease-free survival was not reached in either the pembrolizumab group (95% CI 44·3 to not reached) or the placebo group (95% CI 35·8 to not reached; HR 0·82 [95% CI 0·57-1·18]; p=0·14). Grade 3 or worse adverse events occurred in 198 (34%) of 580 participants who received pembrolizumab and 150 (26%) of 581 participants who received placebo. Grade 3 or worse events that occurred in at least ten participants in either treatment group were hypertension (35 [6%]) and pneumonia (12 [2%]) with pembrolizumab and hypertension (32 [6%]) with placebo. Serious adverse events occurred in 142 (24%) participants in the pembrolizumab group and 90 (15%) in the placebo group; serious adverse events that occurred in more than 1% of participants were pneumonia (13 [2%]), pneumonitis (12 [2%]), and diarrhoea (seven [1%]) with pembrolizumab and pneumonia (nine [2%]) with placebo. Treatment-related adverse events led to death in four (1%) participants treated with pembrolizumab (one due to both cardiogenic shock and myocarditis, one due to both septic shock and myocarditis, one due to pneumonia, and one due to sudden death) and in no participants treated with placebo.

Interpretation: Pembrolizumab significantly improved disease-free survival compared with placebo and was not associated with new safety signals in completely resected, PD-L1-unselected, stage IB-IIIA NSCLC. Pembrolizumab is potentially a new treatment option for stage IB-IIIA NSCLC after complete resection and, when recommended, adjuvant chemotherapy, regardless of PD-L1 expression.

Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co.

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Conflict of interest statement

Declaration of interests MO, LP-A, SM, UD, KO, LH, EE, DI, AM-M, MF, MT, J-SL, KN, MM, NJ, RS, BB, and SP report funding to their institutions from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co (Rahway, NJ, USA; MSD) to support conduct of this study. All authors received medical writing support for the preparation of this manuscript from MSD. MO additionally reports consulting fees for serving on advisory boards for MSD, Merck, Pierre Fabre, Amgen, Puma, Iteos, and PharmaMar; honoraria from Roche and Lilly in China; travel support from MSD; payment for serving as a member of an independent data monitoring committee for PharmaMar; and payment from ALPI (Sweden) for an academic review. LP-A additionally reports institutional grants or contracts from MSD, AstraZeneca, Pfizer, and Bristol Myers Squibb (BMS); consulting fees from Lilly, MSD, Roche, PharmaMar, Merck, AstraZeneca, Novartis, Servier, Amgen, Pfizer, Sanofi, Bayer, BMS, Mirati, GSK, Janssen, and Takeda; honoraria from AstraZeneca, Janssen, Merck, and Mirati; participation on a data safety monitoring board for Altum Sequencing and Genomica; and serving as a principal investigator on trials for Alkermes, Amgen, AstraZeneca, BMS, Daiichi Sankyo, IO Biotech, Janssen-Cilag, Lilly, MSD, Novartis, Pfizer, PharmaMar, Roche, Sanofi, Takeda, and Tesaro. UD additionally reports consulting fees from Roche. KO additionally reports institutional grants or contracts from Pfizer and Takeda; consulting fees from Amgen, Takeda, MSD, Janssen, Roche, and AstraZeneca; and travel support from MSD. DI additionally reports consulting fees from MSD, Roche, AstraZeneca, Amgen, Pfizer, Sanofi, Bayer, BMS, GSK, Janssen, and Takeda; honoraria from MSD, Roche, AstraZeneca, Amgen, Pfizer, Sanofi, Bayer, BMS, and Takeda; and travel support from AstraZeneca. AM-M additionally reports consulting fees for advisory board membership from AstraZeneca/MedImmune, BMS, F Hoffmann-La Roche AG, MSD, and Pfizer; honoraria from AstraZeneca/MedImmune, BMS, F Hoffmann-La Roche AG, MSD, and Pfizer; serving as a steering committee member for AstraZeneca/MedImmune; and travel support from AstraZeneca/MedImmune, BMS, F Hoffmann-La Roche AG, MSD, Pfizer, and Lilly. MF additionally reports honoraria from Roche and Sanofi; travel support from AstraZeneca; and serving as an advisory board member for MSD, Roche, and AstraZeneca. MT additionally reports institutional grants or contracts from Boehringer-Ingelheim Japan, MSD, AstraZeneca KK, Ono Pharmaceutical, and Novartis; consulting fees from AstraZeneca KK, Chugai Pharmaceutical, and MSD KK; honoraria from Johnson & Johnson Japan, AstraZeneca KK, Eli Lilly Japan, Chugai Pharmaceutical, Taiho Pharma, Medtronic Japan, Ono Pharmaceutical, MSD KK, BMS KK, Daiichi Sankyo KK, and Teijin Pharma; serving as a data safety monitoring committee member for Chugai Pharmaceutical; and serving as an advisory board member for AstraZeneca KK, MSD, Novartis, and Eli Lilly. KN additionally reports institutional grants or contracts from AstraZeneca KK, MSD KK, Ono Pharmaceutical, Nippon Boehringer Ingelheim, Novartis Pharma KK, Pfizer Japan, BMS, Eli Lilly Japan KK, Chugai Pharmaceutical, Daiichi Sankyo, Merck Biopharma, Parexel International, PRA Health Sciences, EPS Corporation, Kissei Pharmaceutical, Taiho Pharmaceutical, PPD-SNBL KK, SymBio Pharmaceutical, IQVIA Services Japan KK, Syneos Health Clinical KK, Nippon Kayaku, EP-CRSU, Mebix, Janssen Pharmaceutical KK, AbbVie, Bayer Yakuhin, Eiasi, Mochida Pharmaceutical, Covance Japan, Japan Clinical Research Operations, Takeda Pharmaceutical, GSK KK, Sanofi KK, Sysmex Corporation, Medical Research Support, Otsuka Pharmaceutical, SRL, Pfizer R&D Japan GK, and Amgen; consulting fees from Eli Lilly Japan KK, Kyorin Pharmaceutical, Ono Pharmaceutical, and Pfizer Japan; honoraria from Ono Pharmaceutical, Amgen, Nippon Kayaku, AstraZeneca KK, Chugai Pharmaceutical, Eli Lilly Japan KK, MSD KK, Pfizer Japan, Nippon Boehringer Ingelheim, Taiho Pharmaceutical, Bayer Yakuhin, CMIC ShiftZero KK, Life Technologies Japan, Neo Communication, Roche Diagnostics KK, AbbVie, Merck Biopharma, Kyowa Kirin, Takeda Pharmaceutical, 3H Clinical Trial, CareNet, Medical Review, Yodosha, Nikkei Business Publications, Japan Clinical Research Operations, CMIC, Novartis Pharma KK, Taiyo Pharma, Kyorin Pharmaceutical, BMS KK; and patents with Daiichi Sankyo. RS additionally reports institutional grants or contracts from AstraZeneca, BMS, Daiichi Sankyo, Celgene, Ipsen, Janssen, Mirati, MSD, Novartis, Pfizer, Pierre Fabre, and Roche; consulting fees from AstraZeneca, BMS, Boehringer Ingelheim, GSK, Janssen, MSD, Pfizer, Roche, Sandoz, Seagen, and Takeda; honoraria from Amgen, AstraZeneca, Blueprint Medicines, BMS, Boehringer Ingelheim, GSK, MSD, Novartis, and Roche; data safety monitoring or advisory board participation with Roche and Takeda; and a leadership role with the European Thoracic Oncology Platform International Breast Cancer Study Group (ETOP IBCSG) Partners Foundation. BB additionally reports institutional grants or contracts from 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Chugai Pharmaceutical, Cristal Therapeutics, Daiichi Sankyo, Eli Lilly, Eisai, Genzyme Corporation, GSK, Inivata, Ipsen, Janssen, Onxeo, OSE Immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals, and Turning Point Therapeutics. SP additionally reports institutional grants or contracts from Amgen, AstraZeneca, BeiGene, BMS, GSK, MSD, and Roche/Genentech; consulting fees paid to their institution from AbbVie, AiCME, Amgen, Arcus, AstraZeneca, Bayer, BeiGene, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, BMS, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, F-Star, Fishawack, Foundation Medicine, Genzyme, Gilead, GSK, Illumina, Imedex, IQVIA, Incyte, iTeos, Janssen, Medscape, MSD, Merck Serono, Merrimack, Novartis, Novocure, Oncology Education, PharmaMar, PeerView, PER, Phosplatin Therapeutics, Pfizer, Prime, Regeneron, RMEI, Roche/Genentech, RTP, Sanofi, Seagen, Takeda, and Vaccibody; honoraria paid to their institution from AiCME, AstraZeneca, Boehringer Ingelheim, BMS, ecancer, Eli Lilly, Foundation Medicine, Illumina, Imedex, Medscape, MSD, Mirati, Novartis, PeerView, PER, Pfizer, Prime, Roche/Genentech, RTP, Sanofi, and Takeda; travel support from AstraZeneca, BMS, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Pfizer, Roche/Genentech, and Takeda; and participation on a data safety monitoring or advisory board, with all fees paid to their institution, from AbbVie, Amgen, Arcus, AstraZeneca, Bayer, BeiGene, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, BMS, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F-Star, Foundation Medicine, Genzyme, Gilead, GSK, Illumina, Incyte, iTeos, Janssen, MSD, Merck Serono, Merrimack, Novartis, Novocure, PharmaMar, Phosplatin Therapeutics, Pfizer, Regeneron, Roche/Genentech, Sanofi, Seagen, Takeda, and Vaccibody. JY, AS, and SMK report salary for full-time employment from MSD; AS and SMK also own stock in Merck & Co, Rahway, NJ, USA.

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