Study of Pemetrexed+Platinum Chemotherapy With or Without Pembrolizumab (MK-3475) in Participants With First Line Metastatic Nonsquamous Non-small Cell Lung Cancer (MK-3475-189/KEYNOTE-189)
Summary
This is an efficacy and safety study of pembrolizumab (MK-3475) combined with pemetrexed/platinum chemotherapy versus pemetrexed/platinum chemotherapy alone in participants with advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) who have not previously received systemic therapy for advanced disease. Participants will be randomly assigned to receive pembrolizumab combined with pemetrexed/platinum (Investigators choice of cisplatin or carboplatin), OR pemetrexed/platinum (Investigators choice of cisplatin or carboplatin). With Amendment 10 (effective date 23-Dec-2019), active participants, investigator, and sponsor personnel or delegate(s) involved in the treatment administration or clinical evaluation of the participants will be unblinded, and all participants in the 'control' arm will discontinue saline placebo. With Amendment 11 (effective date 31-Jan-2022), once the study objectives have been met or the study has ended, participants will be discontinued from this study and will be enrolled in an extension study to continue protocol-defined assessments and treatment. The primary hypothesis is that pembrolizumab in combination with pemetrexed/platinum chemotherapy prolongs Progression-Free Survival (PFS) and Overall Survival (OS) compared to pemetrexed/platinum chemotherapy alone.
Timeline
- Start
- 2016-01-15
- Primary completion
- 2017-11-08
- Completion
- 2023-06-22
Outcome
Met primary endpoint
registry analysis (superiority test); Pembrolizumab+Pemetrexed+Platinum Chemotherapy Followed by Pembrolizumab+Pemetrexed vs Control; p <0.00001; Hazard Ratio (HR) 0.52 (95% CI 0.43 to 0.64); Log Rank NCT02578680 ↗
registry analysis (superiority test); Pembrolizumab+Pemetrexed+Platinum Chemotherapy Followed by Pembrolizumab+Pemetrexed vs Control; p <0.00001; Hazard Ratio (HR) 0.49 (95% CI 0.38 to 0.64); Log Rank NCT02578680 ↗
Publications
- Garassino MC, Cheng Y, Rodriguez-Abreu D, Novello S, Mazieres J, Robinson AG, Powell SF, Halmos B, Gray JE, Wang M, Chen C, Yang J, Souza F, Schwarzenberger P, Paz-Ares L. Impact of Tumor Response and Response Duration on Survival Among Participants Receiving Pembrolizumab Plus Chemotherapy as First-Line Therapy for Non-Small-Cell Lung Cancer. Oncol Ther. 2025 Sep;13(3):667-681. doi: 10.1007/s40487-025-00350-6. Epub 2025 Jun 11.
- Gadgeel SM, Rodriguez-Abreu D, Halmos B, Garassino MC, Kurata T, Cheng Y, Jensen E, Shamoun M, Rajagopalan K, Paz-Ares L. Pembrolizumab Plus Chemotherapy for Metastatic NSCLC With Programmed Cell Death Ligand 1 Tumor Proportion Score Less Than 1%: Pooled Analysis of Outcomes After Five Years of Follow-Up. J Thorac Oncol. 2024 Aug;19(8):1228-1241. doi: 10.1016/j.jtho.2024.04.011. Epub 2024 Apr 18.
- Cheng Y, Yang JC, Okamoto I, Zhang L, Hu J, Wang D, Hu C, Zhou J, Wu L, Cao L, Liu J, Zhang H, Sun H, Wang Z, Gao H, Yan Y, Xiao S, Lin J, Pietanza MC, Kurata T. Pembrolizumab plus chemotherapy for advanced non-small-cell lung cancer without tumor PD-L1 expression in Asia. Immunotherapy. 2023 Sep;15(13):1029-1044. doi: 10.2217/imt-2023-0043. Epub 2023 Jul 19.
- Garassino MC, Gadgeel S, Speranza G, Felip E, Esteban E, Domine M, Hochmair MJ, Powell SF, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Kurata T, Gray JE, Schwarzenberger P, Jensen E, Pietanza MC, Rodriguez-Abreu D. Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non-Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study. J Clin Oncol. 2023 Apr 10;41(11):1992-1998. doi: 10.1200/JCO.22.01989. Epub 2023 Feb 21.
- Garassino MC, Gadgeel S, Novello S, Halmos B, Felip E, Speranza G, Hui R, Garon EB, Horinouchi H, Sugawara S, Rodriguez-Abreu D, Reck M, Cristescu R, Aurora-Garg D, Loboda A, Lunceford J, Kobie J, Ayers M, Piperdi B, Pietanza MC, Paz-Ares L. Associations of Tissue Tumor Mutational Burden and Mutational Status With Clinical Outcomes With Pembrolizumab Plus Chemotherapy Versus Chemotherapy For Metastatic NSCLC. JTO Clin Res Rep. 2022 Nov 8;4(1):100431. doi: 10.1016/j.jtocrr.2022.100431. eCollection 2023 Jan.
- Garon EB, Aerts J, Kim JS, Muehlenbein CE, Peterson P, Rizzo MT, Gadgeel SM. Safety of pemetrexed plus platinum in combination with pembrolizumab for metastatic nonsquamous non-small cell lung cancer: A post hoc analysis of KEYNOTE-189. Lung Cancer. 2021 May;155:53-60. doi: 10.1016/j.lungcan.2021.02.021. Epub 2021 Feb 19.
- Gadgeel S, Rodriguez-Abreu D, Speranza G, Esteban E, Felip E, Domine M, Hui R, Hochmair MJ, Clingan P, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Garon EB, Novello S, Rubio-Viqueira B, Boyer M, Kurata T, Gray JE, Yang J, Bas T, Pietanza MC, Garassino MC. Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 May 10;38(14):1505-1517. doi: 10.1200/JCO.19.03136. Epub 2020 Mar 9.
- Garassino MC, Gadgeel S, Esteban E, Felip E, Speranza G, Domine M, Hochmair MJ, Powell S, Cheng SY, Bischoff HG, Peled N, Reck M, Hui R, Garon EB, Boyer M, Wei Z, Burke T, Pietanza MC, Rodriguez-Abreu D. Patient-reported outcomes following pembrolizumab or placebo plus pemetrexed and platinum in patients with previously untreated, metastatic, non-squamous non-small-cell lung cancer (KEYNOTE-189): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2020 Mar;21(3):387-397. doi: 10.1016/S1470-2045(19)30801-0. Epub 2020 Feb 6.
- Gandhi L, Rodriguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. doi: 10.1056/NEJMoa1801005. Epub 2018 Apr 16.
Drugs
| Evaluation | Drug | Modality | Dose | Route |
|---|---|---|---|---|
| Subject | Carboplatin | Small molecule | 5 unknown | Intravenous |
| Subject | Cisplatin | Other / unclassified | 75 mg/m2 | Intravenous |
| Subject | Pembrolizumab | Monoclonal antibody | 200 mg | Intravenous |
| Background | Dexamethasone | Small molecule | 4 mg | Oral |
| Background | Pemetrexed | Small molecule | 500 mg/m2 | Intravenous |