As reported in The Lancet by Tony S.K. Mok, MD, of Chinese University of Hong Kong, and colleagues, the KEYNOTE-042 trial has shown an improvement in overall survival with pembrolizumab vs standard chemotherapy in previously untreated patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) without a sensitizing EGFR mutation or ALK translocation who have a programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS) ≥ 1%.1 The study supported the recent expansion of the indication for pembrolizumab in this setting from a TPS threshold of ≥ 50% in patients with metastatic disease to ≥ 1% expression in patients with stage III NSCLC who are not candidates for surgical resection or definitive chemoradiation as well as patients with metastatic NSCLC.
In the open-label trial, 1,274 patients from 213 sites in 32 countries with a PD-L1 TPS ≥ 1% were randomly assigned between December 2014 and March 2017 to receive pembrolizumab at 200 mg every 3 weeks for up to 35 cycles (n = 637) or investigator’s choice of platinum-based chemotherapy (carboplatin at AUC 5–6 plus paclitaxel at 200 mg/m2 or pemetrexed at 500 mg/m2 every 3 weeks for four to six cycles (n = 637). Maintenance therapy with pemetrexed at 500 mg/m2 every 3 weeks was optional but encouraged in patients in the chemotherapy group who had nonsquamous histology.
The benefit-to-risk profile suggests that pembrolizumab monotherapy can be extended as first-line therapy to patients with locally advanced or metastatic non–small-cell lung cancer without sensitizing EGFR or ALK alterations and with low PD-L1 TPS.— Tony S.K. Mok, MD
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Randomization was stratified by region (East Asia vs the rest of the world), Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1), histology (squamous vs nonsquamous), and PD-L1 TPS (≥ 50% vs 1%–49%). Primary endpoints were overall survival in patients with TPS ≥ 50%, ≥ 20%, and ≥ 1% (one-sided significance thresholds of P = .0122, P = .0120, and P = .0124, respectively) in the intention-to-treat population, assessed sequentially if findings in the previous TPS population were significant.
For the pembrolizumab vs chemotherapy groups, baseline characteristics were similar. Overall, 599 patients (47%) had a TPS ≥ 50% and 818 (64%) had a TPS ≥ 20%.
Median follow-up was 12.8 months. Median overall survival in the pembrolizumab vs chemotherapy group was 20.0 months vs 12.2 months among patients with a TPS score ≥ 50% (hazard ratio [HR] = 0.69, P = .0003), 17.7 months vs 13.0 months among those with a TPS ≥ 20% (HR = 0.77, P = .0020), and 16.7 months vs 12.1 months among those with TPS ≥ 1% (HR = 0.81, P = .0018).
In an exploratory analysis, the hazard ratio for pembrolizumab vs chemotherapy was 0.82 (95% confidence interval [CI] =0.77–1.11) among patients with a TPS of 1% to 49% (median = 13.4 months vs 12.1 months). Hazard ratios favored pembrolizumab in most subgroups in the three TPS populations.
Objective response rates in the three TPS populations were 39% vs 32%, 33% vs 29%, and 27% vs 27%, with median durations of response of 20.2 months in the pembrolizumab group in all TPS populations vs 10.8, 8.3, and 8.3 months in the chemotherapy group. Median progression-free survival durations in the three TPS populations were 7.1 months vs 6.4 months, 6.2 months vs 6.6 months, and 5.4 months vs 6.5 months (significance was not formally tested in the ≥ 20% or ≥ 1% population since the superiority boundary was not met in the ≥ 50% population). At least one subsequent anticancer therapy was received by 38% of the pembrolizumab group and 44% of the chemotherapy group, including immunotherapy in 3% and 20%.
Treatment-related adverse events of any grade occurred in 63% of the pembrolizumab group vs 90% of the chemotherapy group. Grade ≥ 3 treatment-related adverse events occurred in 18% vs 41%, with those occurring in at least 20 patients consisting of pneumonitis (3%) in the pembrolizumab group and anemia (13%), decreased neutrophil count (9%), neutropenia (7%), decreased white blood cell count (5%), and decreased platelet count (3%) in the chemotherapy group.
Treatment-related adverse events led to treatment discontinuation in 9% of patients in both groups. Death was considered related to treatment in 2% of patients in both groups.
Immune-mediated adverse events or infusion reactions occurred in 28% (8% grade ≥ 3) vs 7% (1% grade ≥ 3). Grade ≥ 3 immune-mediated events occurring in at least 5 patients in the pembrolizumab group were pneumonitis (3%), severe skin reactions (2%), and hepatitis (1%).
The investigators concluded: “The benefit-to-risk profile suggests that pembrolizumab monotherapy can be extended as first-line therapy to patients with locally advanced or metastatic non–small-cell lung cancer without sensitizing EGFR or ALK alterations and with low PD-L1 TPS.” ■
DISCLOSURE: Dr. Mok has a leadership role in Sanomics Limited, Hutchison MediPharma, and AstraZeneca; has stock/other ownership interests in Sanomics Limited and Hutchison MediPharma; has received honoraria from AstraZeneca, Roche/Genentech, Lilly, Bristol-Myers Squibb, Boehringer Ingelheim, Novartis, Merck Sharp & Dohme, Pfizer, Merck Serono, SFJ Pharmaceuticals Group, ACEA Biosciences, Vertex, Celgene, Ignyta, Fishawack Facilitate, Takeda, Janssen, and Hutchison MediPharma; is a consultant/advisor for AstraZeneca, Roche/Genentech, Lilly, Merck Serono, Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, Novartis, Clovis Oncology, Vertex, SFJ Pharmaceuticals Group, ACEA Biosciences, Merck Sharp & Dohme, GeneDecode, OncoGenex, Celgene, Ignyta, Cirina, and Hutchison MediPharma; and has received institutional research funding from AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, SFJ Pharmaceuticals Group, Roche, Merck Sharp & Dohme, Clovis Oncology, Bristol-Myers Squibb, and Xcovery. The study was funded by Merck Sharp & Dohme.
1. Mok TSK, Wu Y-L, Kudaba I, et al: Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): A randomised, open-label, controlled, phase 3 trial. Lancet 393:1819-1830, 2019.