Study of Pemetrexed + Platinum Chemotherapy With or Without Pembrolizumab (MK-3475) in Adults With Tyrosine Kinase Inhibitor- (TKI)-Resistant Epidermal Growth Factor Receptor- (EGFR)-Mutated Metastatic Non-squamous Non-small Cell Lung Cancer (NSCLC) (MK-3475-789/KEYNOTE-789)

Summary

The purpose of this study is to evaluate the efficacy and safety of pemetrexed plus platinum chemotherapy (carboplatin or cisplatin) with or without pembrolizumab (MK-3475; KEYTRUDA®) in the treatment of adults with the following types of tyrosine kinase inhibitor (TKI)-resistant, epidermal growth factor receptor (EGFR)-mutated, metastatic non-squamous non-small cell lung cancer (NSCLC) tumors: 1) TKI-failures (including osimertinib \[TAGRISSO®\] failure) with T790M-negative mutation tumors, 2) T790M-positive mutation tumors with prior exposure to osimertinib, and 3) first-line osimertinib failure regardless of T790M mutation status. The primary study hypotheses are that the combination of pembrolizumab plus chemotherapy has superior efficacy compared to saline placebo plus chemotherapy in terms of: 1) Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) based on blinded independent central review, and 2) Overall Survival (OS). This study will be considered to have met its success criteria if the combination of pembrolizumab plus chemotherapy is superior to saline placebo plus chemotherapy in terms of PFS or OS. Upon study completion, participants are discontinued and may be enrolled in a pembrolizumab extension study, if available.

Timeline

Start

2018-06-29

Primary completion

2023-01-17

Completion

2023-10-02

Outcome

Missed primary endpoint

paper CONCLUSION: Addition of pembrolizumab to chemotherapy in patients with TKI-resistant, EGFR-mutant, metastatic nonsquamous NSCLC did not significantly prolong PFS or OS versus placebo plus chemotherapy in KEYNOTE-789. PMID 39173098 ↗

paper At IA2, the median PFS was 5.6 months for pembrolizumab plus chemotherapy versus 5.5 months for placebo plus chemotherapy (hazard ratio [HR], 0.80 [95% CI, 0.65 to 0.97]; P = .0122). PMID 39173098 ↗

paper At FA, the median OS was 15.9 versus 14.7 months, respectively (HR, 0.84 [95% CI, 0.69 to 1.02]; P = .0362). PMID 39173098 ↗

Publications

• Results Yang JC, Lee DH, Lee JS, Fan Y, de Marinis F, Iwama E, Inoue T, Rodriguez-Cid J, Zhang L, Yang CT, de la Mora Jimenez E, Zhou J, Perol M, Lee KH, Vicente D, Ichihara E, Riely GJ, Luo Y, Chirovsky D, Pietanza MC, Bhagwati N, Lu S. Phase III KEYNOTE-789 Study of Pemetrexed and Platinum With or Without Pembrolizumab for Tyrosine Kinase Inhibitor-Resistant, EGFR-Mutant, Metastatic Nonsquamous Non-Small Cell Lung Cancer. J Clin Oncol. 2024 Dec;42(34):4029-4039. doi: 10.1200/JCO.23.02747. Epub 2024 Aug 22.

Drugs

Evaluation	Drug	Modality	Dose	Route
Subject	Pembrolizumab	Monoclonal antibody	200 mg	—
Background	Carboplatin	Small molecule	5 unknown	Intravenous
Background	Cisplatin	Other / unclassified	75 mg/m2	Intravenous
Background	Pemetrexed	Small molecule	500 mg/m2	Intravenous

Indications