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

Abstract

Purpose: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard first-line therapy for EGFR-mutant, metastatic non-small cell lung cancer (NSCLC); however, most patients experience disease progression. We report results from the randomized, double-blind, phase III KEYNOTE-789 study of pemetrexed and platinum-based chemotherapy with or without pembrolizumab for TKI-resistant, EGFR-mutant, metastatic nonsquamous NSCLC (ClinicalTrials.gov identifier: NCT03515837).

Methods: Adults with pathologically confirmed stage IV nonsquamous NSCLC, documented DEL19 or L858R EGFR mutation, and progression after EGFR-TKI treatment were randomly assigned 1:1 to 35 cycles of pembrolizumab 200 mg or placebo once every 3 weeks plus four cycles of pemetrexed and carboplatin or cisplatin once every 3 weeks and then maintenance pemetrexed. Dual primary end points were progression-free survival (PFS) and overall survival (OS). Final PFS testing was completed at the second interim analysis (IA2; data cutoff, December 3, 2021); OS was tested at final analysis (FA; data cutoff, January 17, 2023). Efficacy boundaries were one-sided P = .0117 for PFS and OS.

Results: Four hundred ninety-two patients were randomly assigned to pembrolizumab plus chemotherapy (n = 245) or placebo plus chemotherapy (n = 247). 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). 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). Grade ≥3 treatment-related adverse events occurred in 43.7% of pembrolizumab plus chemotherapy recipients versus 38.6% of placebo plus chemotherapy recipients.

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.

FIG 1.

Patient disposition. ITT, intention to treat.

FIG 2.

PFS and OS. (A) Kaplan-Meier estimates of PFS tested at IA2 according to RECIST version 1.1 by blinded independent central review. (B) Analysis of PFS in key subgroups. (C) Kaplan-Meier estimates of OS tested at protocol-specified final analysis. (D) Analysis of OS in key subgroups. ^aFor the overall population, analysis was based on the Cox regression model with treatment as a covariate stratified by PD-L1 TPS (≥50% or <50%), treatment history (osimertinib or no osimertinib), and geographic region (East Asia or not East Asia). For subgroups, analysis was based on the unstratified Cox regression model with treatment as a covariate. ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; HR, hazard ratio; IA2, second interim analysis; OS, overall survival; PFS, progression-free survival; TKI, tyrosine kinase inhibitor; TPS, tumor proportion score.

FIG 3.

Kaplan-Meier analysis of PFS at IA2 and OS at protocol-specified FA by PD-L1 TPS. (A) PFS in patients with PD-L1 TPS ≥1%. (B) PFS in patients with PD-L1 TPS <1%. (C) OS in patients with PD-L1 TPS ≥1%. (D) OS in patients with PD-L1 TPS <1%. FA, final analysis; HR, hazard ratio; IA2, second interim analysis; OS, overall survival; PFS, progression-free survival; TPS, tumor proportion score.

FIG 4.

Kaplan-Meier estimate of time to true deterioration for the composite end point of cough, chest pain, and dyspnea at the protocol-specified final analysis. HR, hazard ratio; NR, not reached.

FIG A1.

Multiplicity diagram for type I error control. The initial α allocated to each hypothesis is represented in the green boxes with the weights for reallocation from each hypothesis to others represented in the white boxes. If both the PFS and OS hypotheses are rejected, the reallocation strategy allows retesting of ORR at α = .025 on the basis of the P value at IA1. The actual boundaries were updated on the basis of the actual number of events observed and calculated using the Lan-DeMets O'Brien-Fleming spending function with the information fraction on the basis of the minimum of the expected information fraction and the actual information fraction at each analysis. ORR, objective response rate; OS, overall survival; PFS, progression-free survival.

FIG A2.

Kaplan-Meier analysis of progression-free survival per RECIST version 1.1 by BICR at IA2 and OS at the final analysis in PD-L1 TPS subgroups. (A) PFS in patients with PD-L1 TPS 1%-49%. (B) PFS in patients with PD-L1 TPS ≥50%. (C) OS in patients with PD-L1 1%-49%. (D) OS in patients with PD-L1 TPS ≥50%. BICR, blinded independent central review; HR, hazard ratio; IA2, second interim analysis; OS, overall survival; PFS, progression-free survival; TPS, tumor proportion score.