Final analysis of the phase III KEYNOTE-042 study: Pembrolizumab (Pembro) versus platinum-based chemotherapy (Chemo) as first-line therapy for patients (Pts) with PD-L1–positive locally advanced/metastatic NSCLC
Authors: T.S.K Mok, Y.-L. Wu, I. Kudaba, D.M. Kowalski, B.C. Cho, H.Z. Turna, G. de Castro, V. Srimuninnimit, K.K. Laktionov, I. Bondarenko, K. Kubota, C. Caglevic, B. Karaszewska, T. Dang, L. Yin, J. Penrod, G. Lopes
Journal: Annals of Oncology (2019)

Background: Pembro significantly improved OS vs chemo as first-line therapy in pts with PD-L1–positive locally advanced/metastatic NSCLC without EGFR/ALK alterations after median follow-up of 12.8 mo based on interim analysis of KEYNOTE-042 (NCT02220894). We present the final protocol-specified analysis with an additional 6 mo of follow-up. Methods: Pts were randomized 1:1 to 35 cycles of pembro 200 mg Q3W or chemo (6 cycles of paclitaxel/pemetrexed [pem] + carboplatin with optional pem maintenance [nonsquamous only]), stratified by region (east Asia/non-east Asia), ECOG PS (0/1), histology (squamous/nonsquamous), and PD-L1 tumor proportion score (TPS; ≥50%/1%–49%). No α was allocated to OS in this analysis as the primary hypotheses for OS were met at the interim analysis. PFS differences (secondary endpoints) were assessed sequentially in pts with TPS ≥50%, ≥20%, and ≥1% using the stratified log-rank test (one-sided P = 0.01977, 0.02022, and 0.02065, respectively). Other secondary endpoints were ORR and safety. Duration of response (DOR) was an exploratory endpoint. Results: 1274 pts were randomized, 637 per arm. As of September 4, 2018 (median follow-up, 14 mo), 6% were receiving pembro and 3% were receiving pem maintenance. OS benefit with pembro vs chemo was maintained with longer follow-up (Table). PFS was not significantly improved with pembro vs chemo in pts with TPS ≥50%, therefore secondary efficacy hypotheses were not formally tested beyond TPS ≥50%. DOR was longer with pembro vs chemo (Table). Grade 3–5 treatment-related AEs were less frequent with pembro (18%) vs chemo (41%).Table102O OS, PFS, and DOR by PD-L1 TPSnOSPFSDORMedian, mo (95% CI)HR (95% CI)Median, mo (95% CI)HR (95% CI)P*PFS differences were assessed sequentially in pts with TPS≥50%, ≥20%, and ≥1% using the stratified log-rank test (one-sided P=0.01977, 0.02022, and 0.02065, respectively).Responders, n (95% CI)Median, mo (range)PD-L1 TPS ≥50%Pembro29920.0 (15.9–24.2)0.70 (0.58–0.86)6.5 (5.9–8.5)0.83 (0.69–1.00)0.026011722.0 (–2.1+ to 36.5+)Chemo30012.2 (10.4–14.6)6.4 (6.2–7.2)9610.8 1.8+ to 30.4+)PD-L1 TPS ≥20%Pembro41318.0 (15.4–21.9)0.77 (0.65–0.91)6.2 (5.1–7.4)0.94 (0.80–1.10)–13720.2 (2.1+ to 36.5+)Chemo40513.0 (11.6–15.3)6.7 (6.3–8.0)11710.8 (1.8+ to 30.4+)PD-L1 TPS ≥1%Pembro63716.4 (14.0–19.7)0.82 (0.71–0.93)5.4 (4.3–6.2)1.05 (0.93–1.19)–17320.2 (2.1+ to 37.0+)Chemo63712.1 (11.3–13.3)6.6 (6.3–7.3)1698.4 (1.8+ to 30.4+)PD-L1 TPS 1%–49%†Exploratory analysis.Pembro33813.4 (10.7–16.9)0.91 (0.77–1.09)4.2 (4.1–5.2)1.27 (1.08–1.50)–5617.4 (2.2 to 37.0+)Chemo33712.1 (11.0–14.0)7.0 (6.4–8.1)738.1 (1.9+ to 28.2)* PFS differences were assessed sequentially in pts with TPS≥50%, ≥20%, and ≥1% using the stratified log-rank test (one-sided P = 0.01977, 0.02022, and 0.02065, respectively).† Exploratory analysis. Open table in a new tab Conclusions: With an additional 6 mo follow-up, pembro demonstrated continued OS benefit vs chemo as first-line therapy in pts with locally advanced/metastatic PD-L1–positive NSCLC without EGFR/ALK alterations. Clinical trial identification: NCT02220894. Editorial acknowledgement: Medical writing and editorial assistance was provided by Rozena Varghese, PharmD, of C4 MedSolutions, LLC (Yardley, PA), a CHC Group company. This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Legal entity responsible for the study: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure: T.S.K. Mok: Grants or research support: AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, Merck Sharp & Dohme, Novartis, Pfizer, Roche, SFJ Pharmaceuticals, XCovery; Speakers' fees: AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, Boehringer Ingelheim, Merck Sharp & Dohme, Novartis, Bristol-Myers Squibb, Taiho, Takeda Oncology; Honoraria: AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, Boehringer Ingelheim, Merck Serono, Merck Sharp & Dohme, Novartis, SFJ Pharmaceuticals, ACEA Biosciences, Inc., Vertex Pharmaceuticals, Bristol-Myers Squibb, OncoGenex Pharmaceuticals, Inc., Celgene, Ignyta, Inc., Fishawack Facilitate Ltd, Takeda Oncology, Janssen; Major stockholder: Sanomics Ltd.; Advisory board member: AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, Boehringer Ingelheim, Clovis Oncology, Merck Serono, Merck Sharp & Dohme, Novartis, SFJ Pharmaceuticals, ACEA Biosciences, Inc., Vertex Pharmaceuticals, Bristol-Myers Squibb, geneDecode Co., Ltd., OncoGenex Technologies Inc., Celgene, Ignyta, Inc., Cirina, Fishawack Facilitate Ltd., Janssen, Takeda, ChiMed. Y-L. Wu: Honoraria: AstraZeneca, Eli Lilly, Roche, Pierre Fabre, Pfizer, Sanofi; Consulting, advisory role: AstraZeneca, Roche, Merck, Boehringer Ingelheim; Research funding to institution: Boehringer Ingelheim, Roche. B.C. Cho: Honoraria: AstraZeneca, Roche, Boehringer Ingelheim; Consultant/advisor: AstraZeneca, Roche, Boehringer Ingelheim; Speakers' bureau: AstraZeneca, BMS, Merck Sharp & Dohme, Novartis; Research funding: Bayer, AstraZeneca, Yuhan, Novartis. G. de Castro Jr: Consulting, advisory role: AstraZeneca, MSD, BMS, Roche, Novartis, Boehringer Ingelheim; Speakers' bureau: MSD, BMS, Novartis, AstraZeneca; Travel, accommodation, expenses: MSD, BMS, Roche, Bayer, Novartis, Boehringer Ingelheim, AstraZeneca. K. Kubota: Research funding: Boehringer Ingelheim, Taiho, Ono; Speakers' fees: Chugai, Taiho, MSD, Boehringer Ingelheim, AstraZeneca, BMS, Eli-Lilly, Daiichi Sankyo, Novartis, Ono, Dainippon-Sumitomo, Kyowa-Kirin, Eisai; Advisory role: Taiho. C. Caglevic: Consultant/advisor: BMS, MSD, Bayer, AZ; Speakers' bureau: BMS, MSD, Bayer, Lilly, Roche; Research funding: MSD, Boehringer Ingelheim, GSK, Bayer, AZ, Medivation, Astellas Pharma, BMS; Travel, accommodation expenses: Boehringer Ingelheim, MSD. T. Dang, L. Yin, J. Penrod: Employee: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. G. Lopes: Research funding to institution: Merck & Co., Inc., EMD Serono, AstraZeneca. All other authors have declared no conflicts of interest.