VP3-2022: Pembrolizumab (pembro) versus placebo for early-stage non-small cell lung cancer (NSCLC) following complete resection and adjuvant chemotherapy (chemo) when indicated: Randomized, triple-blind, phase III EORTC-1416-LCG/ETOP 8-15 – PEARLS/KEYNOTE-091 study

BackgroundPembro is a standard of care for advanced NSCLC. PEARLS/KEYNOTE-091 (NCT02504372) evaluated adjuvant pembro vs placebo for patients (pts) with completely resected early-stage NSCLC.MethodsEligible pts with completely resected stage IB (T ≥4 cm), II, or IIIA NSCLC per AJCC v7 followed by adjuvant chemo as indicated per guidelines, ECOG PS 0-1, and any PD-L1 expression were randomized 1:1 to pembro 200 mg or placebo Q3W for 18 doses (∼1 year). Dual primary end points are DFS in the all-comers and PD-L1 TPS ≥50% populations. Secondary end points are DFS in the TPS ≥1% population, OS in the all-comers, TPS ≥50% and ≥1% populations, and safety. Data are from the protocol-specified second interim analysis (IA2; 20 September 2021, data cutoff).Results1177 pts were randomized to pembro (N = 590) or placebo (N = 587), including 168 and 165, respectively, who had TPS ≥50%. Baseline characteristics were generally balanced between arms. Median time from randomization to data cutoff for IA2 was 35.6 mo (range 16.5-68.0). DFS was significantly improved with pembro in the all-comers population (median 53.6 vs 42.0 mo; HR 0.76; 95% CI 0.63-0.91; P = 0.0014); the significance boundary was not crossed for the TPS ≥50% population (median not reached in either arm; HR 0.82; 95% CI 0.57-1.18; P = 0.14). With only 209 events, the significance boundary for OS in the all-comers population was not crossed (18-mo rate 91.7% vs 91.3%; HR 0.87; 95% CI 0.67-1.15; P = 0.17). Median number of doses was 17 for pembro vs 18 for placebo. AEs were grade ≥3 in 34.1% of pts in the pembro arm vs 25.8% in the placebo arm and led to discontinuation in 19.8% vs 5.9%; treatment-related AEs led to death in 0.7% vs 0%.ConclusionsAdjuvant pembro provided a statistically significant, clinically meaningful DFS improvement following complete resection and, when indicated, adjuvant chemo in pts with stage IB (T ≥4 cm)-IIIA NSCLC, regardless of PD-L1 expression. The pembro safety profile was as expected. DFS in the PD-L1-defined populations and OS will be tested at future analyses according to the analysis plan.Clinical trial identificationNCT02504372, first posted 21 July 2015.Editorial acknowledgementMedical writing and editorial assistance was provided by Melanie Leiby of Merck & Co., Inc., Kenilworth, NJ, USA. This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.Legal entity responsible for the studyEORTC Lung Cancer Group and ETOP.FundingMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.DisclosureL. Paz-Ares: Financial Interests, Personal, Advisory Board: Roche, MSD, Merck Serono, BMS, AstraZeneca, Lilly, Pfizer, PharmaMar, Bayer, Amgen, Janssen, GSK, Novartis, Ipsen, Takeda, Sanofi, Tesaro, Mirati; Financial Interests, Personal, Invited Speaker: Altum Sequencing, Amgen; Financial Interests, Institutional, Invited Speaker: Daiichi Sankyo, AstraZeneca, Merck Sharp & Dohme Corp., BMS, Janssen-Cilag International NV, Novartis, Roche, Sanofi, Tesaro, Alkermes, Lilly, Takeda, Pfizer, IO Biotech, PharmaMar. M.E.R. O'Brien: Financial Interests, Personal, Advisory Board, Virtual Ad Board: Puma, Sanofi; Financial Interests, Personal, Advisory Board: iTeos, Amgen, MSD, Pierre Fabre; Financial Interests, Institutional, Invited Speaker, we host clinical trials, PI for MSD PEARLS trial: MSD; Non-Financial Interests, Advisory Role: Eisai; Other: Chair this UK Research Group NCRI CSG LORD Subgroup. U. Dafni: Financial Interests, Personal, Other, Member of the Tumor Agnostic Evidence Generation Working Group: Roche. K. Oselin: Financial Interests, Personal, Advisory Board: MSD, Takeda, AstraZeneca; Financial Interests, Personal and Institutional, Invited Speaker: MSD; Financial Interests, Institutional, Research Grant: Takeda, Roche, Pfizer. D. Isla: Financial Interests, Institutional, Research Grant: GSK; Financial Interests, Personal, Advisory Role: MSD, Roche, AstraZeneca, Amgen, Pfizer, Sanofi, Bayer, BMS, GSK, Janssen, Takeda, BI; Financial Interests, Personal, Speaker’s Bureau: Amgen, AstraZeneca, Bayer, BMS, Roche, MSD, Pfizer, Takeda. A. Martinez-Marti: Financial Interests, Personal, Advisory Board, Speaker's Bureau: Bristol Myers Squibb, F. Hoffman La Roche AG, Merck Sharp & Dohme Corp., MSD Oncology, AstraZeneca/MedImmune; Financial Interests, Personal, Speaker’s Bureau: Pfizer. M. Faehling: Financial Interests, Institutional, Principal Investigator: MSD, Roche, AstraZeneca; Financial Interests, Personal, Advisory Board: MSD, Roche, AstraZeneca, BMS; Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, Sanofi, BMS. M. Tsuboi: Financial Interests, Personal, Invited Speaker, Lecture: Johnson & Johnson Japan; Financial Interests, Personal, Advisory Board, Lectures, Advisory boards: AstraZeneca KK, Chugai Pharmaceutical Co., Ltd., MSD; Financial Interests, Personal, Invited Speaker, Lectures: Eli Lilly Japan, Bristol Myers Squibb KK, Teijin Pharma, Taiho Pharma, Medtronic Japan, Ono Pharmaceutical Co., Ltd.; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo Company Limited, MSD, AstraZeneca, Novartis; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim Japan, MSD, AstraZeneca KK, Ono Pharmaceutical Co., Ltd., Bristol Myers Squibb KK, Novartis; Financial Interests, Institutional, Invited Speaker: Eli Lilly Japan. K. Nakagawa: Financial Interests, Personal and Institutional, Research Grant, Consulting and Advisor Role: Astellas Pharma Inc., Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Eli Lilly Japan K.K.; Financial Interests, Personal and Institutional, Research Grant: AstraZeneca K.K., MSD K.K., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K.K., Bristol Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Merck Serono Co., Ltd./Merck Biopharma Co., Ltd.; Financial Interests, Personal and Institutional, Invited Speaker, Consulting and Advisor Role: Pfizer Japan Inc.; Financial Interests, Personal, Writing Engagements: Medicus Shuppan Publishers Co., Ltd., Care Net, Inc., Medical Mobile Communications Co., Ltd., Yodosha Co., Ltd., Nikkei Business Publications, Inc., Yomiuri Telecasting Corporation; Financial Interests, Personal, Invited Speaker: Kyorin Pharmaceutical Co., Ltd., Roche Diagnostics K.K., 3H Clinical Trial Inc., Nichi-Iko Pharmaceutical Co., Ltd., Thermo Fisher Scientific K.K., Nippon Kayaku Co., Ltd., Hisamitsu Pharmaceutical Co., Inc., Nanzando Co., Ltd., Amgen Inc.; Financial Interests, Personal, Advisory Board: Medical Review Co., Ltd.; Financial Interests, Personal and Institutional, Research Grant, Invited Speaker: Taiho Pharmaceutical Co., Ltd., AbbVie Inc., Bayer Yakuhin, Ltd.; Financial Interests, Institutional, Research Grant: SymBio Pharmaceuticals Limited, ICON Japan K.K., Parexel International Corp, Kissei Pharmaceutical Co., Ltd., EPS Corporation, Syneos Health, Pfizer R&D Japan G.K., A2 Healthcare Corp., IQVIA Services Japan K.K., Eisai Co., Ltd., CMIC Shift Zero K.K., EPS International Co., Ltd., Otsuka Pharmaceutical Co., Ltd., PRA Healthsciences, Covance Japan Inc., Medical Research Support, Sanofi K.K., PPD-SNBL K.K., Japan Clinical Research Operations, Sysmex Corporation, Mochida Pharmaceutical Co., Ltd., GlaxoSmithKline K.K. J. Yang: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme Corp. S.M. Keller: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme Corp., Financial Interests, Personal, Stocks/Shares: Merck Sharp & Dohme Corp. R.A. Stahel: Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Blueprint, Boehringer Ingelheim, GSK, MSD, Novartis, Roche, BMS; Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Janssen, MSD, Pfizer, Roche, Sandoz, Seattle Genetics, Takeda, GSK, Boehringer Ingelheim; Financial Interests, Personal, Other, DMC: Takeda; Financial Interests, Personal, Other, Editor in Chief: Lung Cancer; Financial Interests, Personal, Other, Editor: CTR; Financial Interests, Institutional, Research Grant, ETOP study: Roche, AstraZeneca, BMS, MSD, Pfizer, Mirati, Janssen; Financial Interests, Institutional, Research Grant, IBCSG study: Novartis, Ipsen, Pierre Fabre, MSD, Pfizer, Roche, AstraZeneca, Celgene; Non-Financial Interests, Invited Speaker, President Foundation Council: IBCSG, ETOP. S. Peters: Consultation / Advisory role: AbbVie, Amgen, AstraZeneca, Bayer, Beigene, Biocartis, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, Fishawack, Foundation Medicine, Illumina, Imedex, IQVIA, Incyte, Janssen, Medscape, Merck Sharp & Dohme, Merck Serono, Merrimack, Novartis, OncologyEducation, PharmaMar, Phosplatin Therapeutics, PER, Pfizer, PRIME, Regeneron, RMEI, Roche/Genentech, RTP, Sanofi, Seattle Genetics, Takeda, Talk in a company’s organized public event: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, ecancer, Eli Lilly, Illumina, Imedex, Medscape, Merck Sharp & Dohme, Novartis, PER, Pfizer, Prime, Roche/Genentech, RTP, Sanofi, Takeda, Receipt of grants/research supports: (Sub)investigator in trials (institutional financial support for clinical trials) sponsored by Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, GSK, Illumina, Lilly, Merck Sharp & Dohme, Merck Serono, Mirati, Novartis, Pfizer, Phosplatin Therapeutics, Roche/Genentech. B. Besse: Financial Interests, Institutional, Funding: 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, BMS, Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi Sankyo, Eli Lilly, GSK, Janssen, Onxeo, OSE Immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals. All other authors have declared no conflicts of interest.NoteThis abstract is presented as part of the ESMO Virtual Plenaries programme (https://www.esmo.org/meetings/esmo-virtual-plenaries) and eligible for encore presentation at the ESMO Congress 2022. BackgroundPembro is a standard of care for advanced NSCLC. PEARLS/KEYNOTE-091 (NCT02504372) evaluated adjuvant pembro vs placebo for patients (pts) with completely resected early-stage NSCLC. Pembro is a standard of care for advanced NSCLC. PEARLS/KEYNOTE-091 (NCT02504372) evaluated adjuvant pembro vs placebo for patients (pts) with completely resected early-stage NSCLC. MethodsEligible pts with completely resected stage IB (T ≥4 cm), II, or IIIA NSCLC per AJCC v7 followed by adjuvant chemo as indicated per guidelines, ECOG PS 0-1, and any PD-L1 expression were randomized 1:1 to pembro 200 mg or placebo Q3W for 18 doses (∼1 year). Dual primary end points are DFS in the all-comers and PD-L1 TPS ≥50% populations. Secondary end points are DFS in the TPS ≥1% population, OS in the all-comers, TPS ≥50% and ≥1% populations, and safety. Data are from the protocol-specified second interim analysis (IA2; 20 September 2021, data cutoff). Eligible pts with completely resected stage IB (T ≥4 cm), II, or IIIA NSCLC per AJCC v7 followed by adjuvant chemo as indicated per guidelines, ECOG PS 0-1, and any PD-L1 expression were randomized 1:1 to pembro 200 mg or placebo Q3W for 18 doses (∼1 year). Dual primary end points are DFS in the all-comers and PD-L1 TPS ≥50% populations. Secondary end points are DFS in the TPS ≥1% population, OS in the all-comers, TPS ≥50% and ≥1% populations, and safety. Data are from the protocol-specified second interim analysis (IA2; 20 September 2021, data cutoff). Results1177 pts were randomized to pembro (N = 590) or placebo (N = 587), including 168 and 165, respectively, who had TPS ≥50%. Baseline characteristics were generally balanced between arms. Median time from randomization to data cutoff for IA2 was 35.6 mo (range 16.5-68.0). DFS was significantly improved with pembro in the all-comers population (median 53.6 vs 42.0 mo; HR 0.76; 95% CI 0.63-0.91; P = 0.0014); the significance boundary was not crossed for the TPS ≥50% population (median not reached in either arm; HR 0.82; 95% CI 0.57-1.18; P = 0.14). With only 209 events, the significance boundary for OS in the all-comers population was not crossed (18-mo rate 91.7% vs 91.3%; HR 0.87; 95% CI 0.67-1.15; P = 0.17). Median number of doses was 17 for pembro vs 18 for placebo. AEs were grade ≥3 in 34.1% of pts in the pembro arm vs 25.8% in the placebo arm and led to discontinuation in 19.8% vs 5.9%; treatment-related AEs led to death in 0.7% vs 0%. 1177 pts were randomized to pembro (N = 590) or placebo (N = 587), including 168 and 165, respectively, who had TPS ≥50%. Baseline characteristics were generally balanced between arms. Median time from randomization to data cutoff for IA2 was 35.6 mo (range 16.5-68.0). DFS was significantly improved with pembro in the all-comers population (median 53.6 vs 42.0 mo; HR 0.76; 95% CI 0.63-0.91; P = 0.0014); the significance boundary was not crossed for the TPS ≥50% population (median not reached in either arm; HR 0.82; 95% CI 0.57-1.18; P = 0.14). With only 209 events, the significance boundary for OS in the all-comers population was not crossed (18-mo rate 91.7% vs 91.3%; HR 0.87; 95% CI 0.67-1.15; P = 0.17). Median number of doses was 17 for pembro vs 18 for placebo. AEs were grade ≥3 in 34.1% of pts in the pembro arm vs 25.8% in the placebo arm and led to discontinuation in 19.8% vs 5.9%; treatment-related AEs led to death in 0.7% vs 0%. ConclusionsAdjuvant pembro provided a statistically significant, clinically meaningful DFS improvement following complete resection and, when indicated, adjuvant chemo in pts with stage IB (T ≥4 cm)-IIIA NSCLC, regardless of PD-L1 expression. The pembro safety profile was as expected. DFS in the PD-L1-defined populations and OS will be tested at future analyses according to the analysis plan. Adjuvant pembro provided a statistically significant, clinically meaningful DFS improvement following complete resection and, when indicated, adjuvant chemo in pts with stage IB (T ≥4 cm)-IIIA NSCLC, regardless of PD-L1 expression. The pembro safety profile was as expected. DFS in the PD-L1-defined populations and OS will be tested at future analyses according to the analysis plan.