Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non-Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study

Abstract

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically on the based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We present 5-year outcomes from the phase 3 KEYNOTE-189 study (ClinicalTrials.gov identifier: NCT02578680). Eligible patients with previously untreated metastatic nonsquamous non-small-cell lung cancer without EGFR/ALK alterations were randomly assigned 2:1 to pembrolizumab 200 mg or placebo once every 3 weeks for up to 35 cycles with pemetrexed and investigator's choice of carboplatin/cisplatin for four cycles, followed by maintenance pemetrexed until disease progression or unacceptable toxicity. Primary end points were overall survival (OS) and progression-free survival (PFS). Among 616 randomly assigned patients (n = 410, pembrolizumab plus pemetrexed-platinum; n = 206, placebo plus pemetrexed-platinum), median time from random assignment to data cutoff (March 8, 2022) was 64.6 (range, 60.1-72.4) months. Hazard ratio (95% CI) for OS was 0.60 (0.50 to 0.72) and PFS was 0.50 (0.42 to 0.60) for pembrolizumab plus platinum-pemetrexed versus placebo plus platinum-pemetrexed. 5-year OS rates were 19.4% versus 11.3%. Toxicity was manageable. Among 57 patients who completed 35 cycles of pembrolizumab, objective response rate was 86.0% and 3-year OS rate after completing 35 cycles (approximately 5 years after random assignment) was 71.9%. Pembrolizumab plus pemetrexed-platinum maintained OS and PFS benefits versus placebo plus pemetrexed-platinum, regardless of programmed cell death ligand-1 expression. These data continue to support pembrolizumab plus pemetrexed-platinum as a standard of care in previously untreated metastatic non-small-cell lung cancer without EGFR/ALK alterations.

FIG 1.

Kaplan-Meier estimates of OS in the (A) ITT, (B) PD-L1 TPS ≥ 50%, (C) PD-L1 TPS 1%-49%, and (D) PD-L1 TPS < 1% populations and PFS by RECIST version 1.1 by blinded independent central review in the (E) ITT, (F) PD-L1 TPS ≥ 50%, (G) PD-L1 TPS 1%-49%, and (H) PD-L1 TPS < 1% populations. Chemo, chemotherapy; ITT, intention-to-treat; OS, overall survival; PD-L1, programmed cell death ligand 1; PFS, progression-free survival; TPS, tumor proportion score.

FIG 2.

(A) Duration of response in the ITT population and (B) treatment duration and time to response in patients who completed 35 cycles of pembrolizumab. Response assessments are shown per RECIST version 1.1 by BICR. Median PFS was not reached (95% CI, 14.7 months to not reached). PFS rate 3 years after completion of 35 cycles was 56.2% (95% CI, 39.7 to 69.8). BICR, blinded independent central review; chemo, chemotherapy; CR, complete response; ITT, intention-to-treat; PD, progressive disease; PFS, progression-free survival; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease.

FIG A1.

Kaplan-Meier estimates of (A) OS and (B) PFS per Response Evaluation Criteria in Solid Tumors version 1.1 by blinded independent central review in patients with PD-L1 TPS ≥ 1%. Chemo, chemotherapy; OS, overall survival; PD-L1, programmed cell death ligand 1; pembro, pembrolizumab; PFS, progression-free survival; TPS, tumor proportion score.