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Randomized Controlled Trial
. 2021 Jul 20;39(21):2327-2338.
doi: 10.1200/JCO.20.03579. Epub 2021 Jan 29.

Pembrolizumab Plus Ipilimumab or Placebo for Metastatic Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50%: Randomized, Double-Blind Phase III KEYNOTE-598 Study

Michael Boyer  1 , Mehmet A N Şendur  2 , Delvys Rodríguez-Abreu  3 , Keunchil Park  4 , Dae Ho Lee  5 , Irfan Çiçin  6 , Perran Fulden Yumuk  7 , Francisco J Orlandi  8 , Ticiana A Leal  9 , Olivier Molinier  10 , Nopadol Soparattanapaisarn  11 , Adrian Langleben  12 , Raffaele Califano  13 , Balazs Medgyasszay  14 , Te-Chun Hsia  15 , Gregory A Otterson  16 , Lu Xu  17 , Bilal Piperdi  17 , Ayman Samkari  17 , Martin Reck  18 ; KEYNOTE-598 Investigators
Affiliations
Randomized Controlled Trial

Pembrolizumab Plus Ipilimumab or Placebo for Metastatic Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50%: Randomized, Double-Blind Phase III KEYNOTE-598 Study

Michael Boyer et al. J Clin Oncol. .

Abstract

Purpose: Pembrolizumab monotherapy is standard first-line therapy for metastatic non-small-cell lung cancer (NSCLC) with programmed death ligand 1 (PD-L1) tumor proportion score (TPS) ≥ 50% without actionable driver mutations. It is not known whether adding ipilimumab to pembrolizumab improves efficacy over pembrolizumab alone in this population.

Methods: In the randomized, double-blind, phase III KEYNOTE-598 trial (ClinicalTrials.gov identifier: NCT03302234), eligible patients with previously untreated metastatic NSCLC with PD-L1 TPS ≥ 50% and no sensitizing EGFR or ALK aberrations were randomly allocated 1:1 to ipilimumab 1 mg/kg or placebo every 6 weeks for up to 18 doses; all participants received pembrolizumab 200 mg every 3 weeks for up to 35 doses. Primary end points were overall survival and progression-free survival.

Results: Of the 568 participants, 284 were randomly allocated to each group. Median overall survival was 21.4 months for pembrolizumab-ipilimumab versus 21.9 months for pembrolizumab-placebo (hazard ratio, 1.08; 95% CI, 0.85 to 1.37; P = .74). Median progression-free survival was 8.2 months for pembrolizumab-ipilimumab versus 8.4 months for pembrolizumab-placebo (hazard ratio, 1.06; 95% CI, 0.86 to 1.30; P = .72). Grade 3-5 adverse events occurred in 62.4% of pembrolizumab-ipilimumab recipients versus 50.2% of pembrolizumab-placebo recipients and led to death in 13.1% versus 7.5%. The external data and safety monitoring committee recommended that the study be stopped for futility and that participants discontinue ipilimumab and placebo.

Conclusion: Adding ipilimumab to pembrolizumab does not improve efficacy and is associated with greater toxicity than pembrolizumab monotherapy as first-line treatment for metastatic NSCLC with PD-L1 TPS ≥ 50% and no targetable EGFR or ALK aberrations. These data do not support use of pembrolizumab-ipilimumab in place of pembrolizumab monotherapy in this population.

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Conflict of interest statement

Michael BoyerHonoraria: AstraZenecaConsulting or Advisory Role: Merck Sharp & Dohme, AstraZeneca, Bristol-Myers Squibb, JanssenResearch Funding: Merck Sharp & Dohme, Pfizer, Boehringer Ingelheim, Lilly, Genentech/Roche, AstraZeneca, Bristol-Myers Squibb, Amgen, Ascentage Pharma, Novartis, Janssen, Merck SeronoTravel, Accommodations, Expenses: Merck Sharp & Dohme, Genentech/Roche Mehmet A. N. ŞendurResearch Funding: Merck Sharp & Dohme Delvys Rodríguez-AbreuConsulting or Advisory Role: Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, AstraZeneca Spain, NovartisResearch Funding: Merck Sharp & DohmeSpeakers' Bureau: Roche, Bristol-Myers Squibb, Merck Sharp & DohmeTravel, Accommodations, Expenses: Roche, Bristol-Myers Squibb, Merck Sharp & Dohme Keunchil ParkConsulting or Advisory Role: AstraZeneca, Lilly, Ono Pharmaceutical, Bristol-Myers Squibb, Merck Sharp & Dohme, Blueprint Medicines, Amgen, Merck KGaA, LOXO, Abbvie, Daiichi Sankyo, Boehringer Ingelheim, Johnson & Johnson, Eisai, Puma BiotechnologySpeakers' Bureau: Boehringer Ingelheim, AZDResearch Funding: AstraZeneca, Merck Sharp & Dohme Dae Ho LeeHonoraria: AstraZeneca/MedImmune, Boehringer Ingelheim, Bristol-Myers Squibb, Chong Kun Dang Pharmaceutical, CJ Healthcare, Lilly, Janssen, Merck, Merck Sharp & Dohme, Mundipharma, Novartis, Ono Pharmaceutical, Pfizer, Roche/Genentech, Samyang, ST Cube, Takeda, Abbvie, Menarini, Green CrossConsulting or Advisory Role: ST CubeResearch Funding: Merck Sharp & DohmeTravel, Accommodations, Expenses: Takeda, Blueprint Medicines Irfan ÇiçinConsulting or Advisory Role: Pfizer, Merck Sharp & Dohme, Roche, Novartis/Ipsen, Lilly, Bristol-Myers Squibb, SERVIER, Abdi Ibrahim, Nobelpharma, Abbvie, Teva, Janssen OncologyResearch Funding: Merck Sharp & DohmeSpeakers' Bureau: Novartis, Roche, Bristol-Myers Squibb, Pfizer, Abdi Ibrahim Perran Fulden YumukConsulting or Advisory Role: Takeda, Roche, Bristol-Myers SquibbSpeakers' Bureau: Novo Nordisk, Nestle Health Science, Bristol-Myers Squibb, Roche, AstraZenecaResearch Funding: Roche, Merck, Merck Sharp & Dohme, Novartis Francisco J. OrlandiHonoraria: Roche/GenentechConsulting or Advisory Role: AstraZeneca, Roche/Genentech, Bristol-Myers Squibb, Merck Sharp & Dohme, Lilly, Pfizer, Novartis, SanofiSpeakers' Bureau: AstraZeneca/MedImmune, RocheResearch Funding: AstraZeneca/MedImmune, Amgen, Genentech/Roche, Boehringer Ingelheim, Astellas Medivation, Merck Sharp & Dohme, Bristol-Myers Squibb, Celltrion, Pfizer, mAbxience, Nektar, SanofiTravel, Accommodations, Expenses: Pfizer, Merck Sharp & Dohme, AstraZeneca/MedImmune, Roche, Bristol-Myers Squibb, Genentech/Roche Ticiana A. LealConsulting or Advisory Role: Takeda, Abbvie, AstraZeneca, Genentech, Bayer, BeyondSpring Pharmaceuticals, Bristol-Myers Squibb, Merck & Co, InvisionFirst Lung, NovocureTravel, Accommodations, Expenses: Takeda, Abbvie, Bristol-Myers Squibb, Genentech, Mirati Therapeutics, AstraZeneca, Merck & Co Olivier MolinierConsulting or Advisory Role: AstraZeneca, Bristol-Myers Squibb, TakedaResearch Funding: Merck Sharp & DohmeTravel, Accommodations, Expenses: Boehringer Ingelheim Nopadol SoparattanapaisarnResearch Funding: Merck Sharp & Dohme Adrian LanglebenResearch Funding: Merck Sharp & Dohme Raffaele CalifanoStock and Other Ownership Interests: The Christie Private CareHonoraria: AstraZeneca, Boehringer Ingelheim, Lilly Oncology, Roche, Pfizer, Merck Sharp & Dohme, BMS, Takeda, NovartisConsulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Lilly Oncology, Roche, Pfizer, Merck Sharp & Dohme, BMS, Takeda, NovartisSpeakers' Bureau: AstraZeneca, Roche, Pfizer, Merck Sharp & Dohme, BMS, Takeda, and NovartisResearch Funding: Roche, AstraZeneca, Pfizer, Clovis, Lilly Oncology, Merck Sharp & Dohme, BMS, Abbvie, Takeda, and NovartisTravel, Accommodations, Expenses: Roche, Lilly Oncology, Merck Sharp & Dohme, Takeda Balazs MedgyasszayResearch Funding: Merck Sharp & Dohme Te-Chun HsiaResearch Funding: Merck Sharp & Dohme Gregory A. OttersonConsulting or Advisory Role: Takeda, Novocure, Guardant Health, Bristol-Myers Squibb, AstraZenecaResearch Funding: Genentech/Roche, Pfizer, Bristol-Myers Squibb, Novartis, Merck, AstraZeneca, Celgene Lu XuEmployment: Merck Sharp & DohmeStock and Other Ownership Interests: Merck & Co, Inc, Kenilworth, NJ, USA Bilal PiperdiEmployment: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USAStock and Other Ownership Interests: Merck & Co, Inc, Kenilworth, NJ, USA Ayman SamkariEmployment: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USAStock and Other Ownership Interests: Merck & Co, Inc, Kenilworth, NJ, USA Martin ReckConsulting or Advisory Role: Lilly, Merck Sharp & Dohme, Merck Serono, Bristol-Myers Squibb, AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, Roche/Genentech, Abbvie, Amgen, Mirati Therapeutics, Samsung BioepisResearch Funding: Merck Sharp & DohmeSpeakers' Bureau: Roche/Genentech, Lilly, Merck Sharp & Dohme, Merck Serono, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Pfizer, Novartis, Amgen, Mirati TherapeuticsNo other potential conflicts of interest were reported.

Comment in

  • Ipilimumab can be safely omitted.
    Sidaway P. Sidaway P. Nat Rev Clin Oncol. 2021 Apr;18(4):194. doi: 10.1038/s41571-021-00483-3. Nat Rev Clin Oncol. 2021. PMID: 33594254 No abstract available.

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