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Clinical Trial
. 2025 Feb;20(2):219-232.
doi: 10.1016/j.jtho.2024.10.026. Epub 2024 Nov 7.

The Phase 3 KEYLYNK-006 Study of Pembrolizumab Plus Olaparib Versus Pembrolizumab Plus Pemetrexed as Maintenance Therapy for Metastatic Nonsquamous NSCLC

Jhanelle E Gray  1 , Michael Schenker  2 , Mehmet Ali Nahit Şendur  3 , Viktoriya Leonova  4 , Dariusz Kowalski  5 , Terufumi Kato  6 , Rashida Orlova  7 , James Chih-Hsin Yang  8 , Adrian Langleben  9 , Arnold Pilz  10 , Andrei Ungureanu  11 , Milena Perez Mak  12 , Flavia De Angelis  13 , Himani Aggarwal  14 , Zachary Zimmer  14 , Bin Zhao  14 , Mark Shamoun  14 , Tae Min Kim  15
Affiliations
Free article
Clinical Trial

The Phase 3 KEYLYNK-006 Study of Pembrolizumab Plus Olaparib Versus Pembrolizumab Plus Pemetrexed as Maintenance Therapy for Metastatic Nonsquamous NSCLC

Jhanelle E Gray et al. J Thorac Oncol. 2025 Feb.
Free article

Abstract

Introduction: Poly (adenosine diphosphate-ribose) inhibitors, including olaparib, upregulate programmed cell death ligand 1, which may increase the efficacy of anti-programmed cell death protein 1 and anti-programmed cell death ligand 1 therapies.

Methods: In the phase 3 KEYLYNK-006 trial (NCT03976323), eligible adults with previously untreated metastatic nonsquamous NSCLC without targetable genetic alterations who had complete response, partial response, or stable disease after induction therapy with four cycles of pembrolizumab 200 mg every three weeks, pemetrexed 500 mg/m2, and carboplatin area under the concentration-time curve 5 mg/mL/min or cisplatin 75 mg/m2 were randomized in a one-to-one ratio to olaparib 300 mg orally twice daily or pemetrexed every three weeks, both given with up to 31 cycles of pembrolizumab every three weeks. Dual primary endpoints were progression-free survival (PFS) and overall survival (OS). Progression-free survival was tested at interim analysis 2 (i.e., final PFS analysis) and OS at final analysis (FA).

Results: Of 1003 patients who received induction therapy, 672 (67.0%) were randomized to pembrolizumab plus olaparib (n = 337) or pembrolizumab plus pemetrexed (n = 335) in the intention-to-treat population. Median follow-up at FA was 39.9 (range: 28.1-51.5) months. At interim analysis 2, the median (95% confidence interval [CI]) PFS was 7.1 (5.6-8.7) months versus 8.3 (6.9-11.5) months in the olaparib versus pemetrexed groups (hazard ratio = 1.12, 95% CI: 0.92-1.36, p = 0.87). At FA, the median (95% CI) OS was 20.7 (18.0-24.8) months versus 23.0 (19.0-26.4) months (hazard ratio = 1.04, 95% CI: 0.87-1.25, p = 0.6649). Grade 3 to 5 maintenance treatment-related adverse events occurred in 26.1% versus 30.1% of patients, respectively.

Conclusion: Pembrolizumab plus maintenance olaparib did not improve PFS or OS versus pembrolizumab plus pemetrexed in previously untreated metastatic nonsquamous NSCLC without targetable genetic alterations.

Keywords: KEYLYNK-006; Non-squamous non‒small-cell lung cancer; Olaparib; Pembrolizumab; Pemetrexed.

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Conflict of interest statement

Disclosure Dr. Gray received grants or funding from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, EMD Serono – Merck KGaA, Genentech, Gilead Sciences, G1 Therapeutics, Ludwig Institute of Cancer Research, Merck & Co, Inc, Novartis, Panbela Therapeutics, Pfizer, and Regeneron; holds consultant or advisor positions in AbbVie, AstraZeneca, Blueprint Medicines, Coherus, Daiichi Sankyo, EMD Serono, Gilead Sciences, Inc, IDEOlogy Health, Janssen Scientific Affairs, LLC, Jazz Pharmaceuticals, Loxo Oncology Inc, Merck & Co, Inc, Novartis, OncoCyte Biotechnology, Regeneron, Spectrum ODAC, Takeda Pharmaceuticals, Triptych Health Partners, and Zai Lab (US) LLC; received honoraria from AbbVie, AstraZeneca, Blueprint Medicines, Coherus, Daiichi Sankyo, EMD Serono, Gilead Sciences, Inc, IDEOlogy Health, Janssen Scientific Affairs, LLC, Jazz Pharmaceuticals, Loxo Oncology Inc, Merck & Co, Inc, Novartis, OncoCyte Biotechnology, Regeneron, Spectrum ODAC, Takeda Pharmaceuticals, Triptych Health Partners, and Zai Lab (US) LLC; and holds the following director or committee member positions: SWOG Lung Committee Chair (ASCO Board of Directors Member), IASLC Board of Directors Member, and ASCO Education Committee Ex-Chair. Dr. Schenker received research grants from AbbVie, Amgen, Astellas, AstraZeneca, Bayer, BeiGene, Clovis, Daiichi Sankyo, EISAI, Eli Lilly, Five Prime, Gilead, GSK, Mylan, Novartis, Pfizer, Pharma Mar, Samsung, and Takeda. Dr. Şendur holds consultant or advisor positions in Roche, AstraZeneca, Pfizer, Novartis, Astellas, BMS, MSD, Lilly, Gilead, Takeda; Honoraria: Roche, AstraZeneca, Pfizer, Novartis, Astellas, BMS, MSD, Lilly, Gilead, and Takeda. Dr. Leonova received grants or funding from Bio-Thera Solutions, Ltd., Roche, Shanghai Henlius Biotech, Incyte Corporation, Ipsen Bioscience, Merck Serono, and Janssen Research & Development. Dr. Kowalski reports participation on a data safety monitoring board or advisory boards of MSD, BMS, Takeda, Pfizer, AstraZeneca, Amgen, Roche, Medison, and Johnson & Johnson. Dr. Kato received grants or funding to the institution from AbbVie, Amgen, Arrivent, AstraZeneca, Bayer, BeiGene, BluePrint, Bristol-Meyers Squibb, Chugai, Daiichi-Sankyo, Eli Lilly, Gilead, GlaxoSmithKline, Haihe, Janssen, Merck KGaA, MSD, Novartis, Pfizer, Regeneron, and Takeda; received honoraria from Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol-Meyers Squibb, Chugai, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Janssen, Merck KGaA, MSD, Novartis, Ono, Pfizer, Taiho, and Takeda; reports participation on a data safety monitoring board or advisory boards of AstraZeneca, BeiGene, Chugai, Daiichi-Sankyo, Janssen, Merck KGaA, MSD, Novartis, and Pfizer; and reports Eli Lilly as spouse’s employer. Dr. Yang received research grants from AstraZeneca and Roche/Genentech; received institutional fees for advisory or consultancy services from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Merck KGaA, MSD, Novartis, Pfizer, Roche/Genentech, Takeda Oncology, Yuhan Pharmaceuticals, Janssen Pharmaceuticals, Gilead Sciences Inc, GSK, BeiGene, Regeneron Pharmaceutical, ArriVent, and AnHeart Therapeutics; received travel grant to major meetings from AstraZeneca, Dizal Pharmaceuticals. Dr. Aggarwal is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, United States, a shareholder of Merck & Co., Inc., Rahway, New Jersey, United States, and a Stockholder of Eli Lilly and Company. Dr. Angelis received honoraria from Merck, Pfizer, AstraZeneca, BMS, and GSK. Dr. Kim received clinical trial funding to institution from AbbVie, Amgen, AstraZeneca/Medimmune, Bayer, Black Diamond Therapeutics, Blueprint Medicines, Boryung, Bristol Myers Squibb, Celgene, Dizal, EMD Serono Inc, Enliven Therapeutics, F. Hoffmann-La Roche Ltd/Genentech, Inc, Fore Biotherapeutics, Hanmi, Genmab, Janssen, Merck & Co. Inc., Novartis, Pfizer, RAPT Therapeutics, Regeneron, Sanofi, Takeda, Taiho, and Yuhan; holds consultant or advisor positions in AstraZeneca, Daiichi-Sankyo, HK inno.N, IMBDx. Inc., Janssen, Regeneron, Roche/Genentech, Samsung Bioepis, and Takeda; reports participation on a data safety monitoring board or advisory boards of AstraZeneca, Janssen, Regeneron, Roche/Genentech, Samsung Bioepis, and Takeda. Dr. Mak received honoraria from Merck KGaA, Sanofi, Lilly, Bristol-Myers Squibb, and Johnson & Johnson/Janssen. Dr. Pilz holds consultant/advisor positions in MSD, Roche, and Janssen Pharmaceutical; received honoraria from AstraZeneca, Roche, MSD, and Bristol Myers Squibb; received support for attending meetings or travel from Roche and AstraZeneca. Dr. Shamoun is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, United States, and a shareholder of Merck & Co., Inc., Rahway, New Jersey, United States. Dr. Ungureanu received honoraria from AstraZeneca, MSD, BMS, and Gilead; received support for attending meetings or travel from MSD, AstraZeneca, Pfizer, and Gilead; reports participation on a data safety monitoring board or advisory boards of MSD, BMS, AstraZeneca, Takeda, Pfizer, Gilead, and Merck. Dr. Zhao is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, United States, and a shareholder of Merck & Co., Inc., Rahway, New Jersey, United States. Dr. Zimmer is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, United States, and a shareholder of Merck & Co., Inc., Rahway, New Jersey, United States. The remaining authors declare no conflict of interest.

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