Pembrolizumab plus pemetrexed‐platinum for metastatic nonsquamous non–small‐cell lung cancer: KEYNOTE‐189 Japan Study

Abstract

Pembrolizumab plus pemetrexed‐platinum significantly improved overall survival (OS) and progression‐free survival (PFS) with manageable safety compared with placebo plus pemetrexed‐platinum in patients with previously untreated metastatic nonsquamous non–small‐cell lung cancer (NSCLC) without EGFR/ALK alterations in the global, randomized, double‐blind, phase 3 KEYNOTE‐189 study. We present results of Japanese patients enrolled in the KEYNOTE‐189 global and Japan extension studies. Patients were randomized 2:1 to intravenous pembrolizumab 200 mg or placebo every 3 weeks (Q3W) for up to 35 cycles. All patients received pemetrexed 500 mg/m2 plus the investigator’s choice of cisplatin or carboplatin Q3W for four cycles, followed by maintenance pemetrexed 500 mg/m2 Q3W (all intravenous). Co–primary endpoints were OS and PFS. Forty Japanese patients enrolled (pembrolizumab, n = 25; placebo, n = 15). At data cutoff (20 May 2019; median time from randomization to data cutoff, 18.5 [range, 14.7‒38.2] months), the median OS was not reached in the pembrolizumab plus pemetrexed‐platinum arm; the median OS was 25.9 (95% confidence interval [CI], 11.9‒29.0) months in the placebo plus pemetrexed‐platinum arm (hazard ratio [HR] .29; 95% CI, .07‒1.15). The median (95% CI) PFS was 16.5 (8.8‒21.1) compared with 7.1 (4.7‒21.4) months (HR, .62; 95% CI, .27‒1.42), respectively. There were no grade 5 adverse events (AE). Grade 3/4 AE occurred in 72% vs 60% of patients in the pembrolizumab vs placebo arms; 40% vs 20% had immune‐mediated AE, and 4% vs 0% had infusion reactions. Efficacy and safety outcomes were similar to those from the global study and support first‐line therapy with pembrolizumab plus pemetrexed‐platinum in Japanese patients with nonsquamous NSCLC without EGFR/ALK alterations.

First-line nivolumab + ipilimumab in advanced NSCLC: CheckMate 227 subpopulation analyses in Asian patients

“…The consistent findings across subgroups and all randomized patients in this study are in line with prior studies that compared clinical outcomes of first-line immunotherapy for NSCLC between Asian and global populations. 27 , 28 , 29 , 30 , 31 , 32 , 33 In a subanalysis of Asian patients enrolled in CheckMate 9LA, first-line nivolumab plus ipilimumab in combination with two cycles of chemotherapy showed survival benefit over chemotherapy, consistent with results in all randomized patients. 30 , 31 Subanalyses of the KEYNOTE-407 study in East Asian patients and the KEYNOTE-189 study in Japanese patients showed clinical benefits of first-line pembrolizumab plus chemotherapy over chemotherapy for metastatic squamous or nonsquamous NSCLC, respectively, consistent with results in the all randomized population of each study.…”

“… 30 , 31 Subanalyses of the KEYNOTE-407 study in East Asian patients and the KEYNOTE-189 study in Japanese patients showed clinical benefits of first-line pembrolizumab plus chemotherapy over chemotherapy for metastatic squamous or nonsquamous NSCLC, respectively, consistent with results in the all randomized population of each study. 27 , 28 , 32 , 33 Similarly, in a subgroup analysis of the KEYNOTE-024 study in Japanese patients with metastatic NSCLC and PD-L1 tumor proportion score ≥50%, pembrolizumab monotherapy showed survival benefit over platinum-based chemotherapy, consistent with the outcomes for all randomized patients in the study. 34 , 35 Cross-study comparisons should be made with caution, however, due to differences in patient populations, study design, and other key elements.…”

First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in advanced non-small cell lung cancer: a subanalysis of Asian patients in CheckMate 9LA

“…versus 45%, respectively), consistent with OS improvements observed in the all randomized population[29]. Subanalyses of the KEYNOTE-407 study in East Asian patients and the KEYNOTE-189 study in Japanese patients also favored first-line combination immunotherapy with pembrolizumab plus chemotherapy over chemotherapy in Asian/Japanese patients with metastatic squamous or nonsquamous NSCLC, respectively, consistent with findings in the all randomized population of each study[2,3,27,28].…”

“…Chemotherapy for NSCLC is associated with interethnic differences in survival outcomes [ 23 ]; however, data directly comparing the efficacy of immunotherapy between Asian and global populations are limited. Some studies have shown clinical benefits of first-line immunotherapy combinations in both all randomized patients and the Asian subpopulation [ 27 – 29 ]. In a subanalysis of the phase 3 CheckMate 227 study in Asian patients with tumor PD-L1 expression ≥ 1% or < 1%, first-line treatment with nivolumab plus ipilimumab combination therapy demonstrated durable long-term survival and clinical benefits versus chemotherapy (median OS not reached versus 22.9 months; 2-year OS rate, 53% versus 45%, respectively), consistent with OS improvements observed in the all randomized population [ 29 ].…”

“…randomized patients and the Asian subpopulation[27][28][29]. In a subanalysis of the phase 3 CheckMate 227 study in Asian patients with tumor PD-L1 expression ≥ 1% or < 1%, first-line treatment with nivolumab plus ipilimumab combination therapy demonstrated durable long-term survival and clinical benefits versus chemotherapy (median OS not reached versus 22.9 months; 2-year OS rate, 53% On the other hand, in the IMpower132 trial, atezolizumab plus chemotherapy as first-line treatment for nonsquamous NSCLC showed apparent OS improvement versus chemotherapy in the Japanese subpopulation [median OS, 30.8 versus 22.2 months; HR 0.63 (95% CI 0.36-1.14)], but OS difference in the global population was not statistically significant between the treatment arms (median OS, 17.5 versus 13.6 months; p = 0.1546)…”