KEYNOTE-042: Pembrolizumab vs Chemotherapy in Previously Untreated Locally Advanced or Metastatic NSCLC With PD-L1 Expression ≥ 1%


Key Points

  • Pembrolizumab improved overall survival vs chemotherapy among patients with PD-L1 TPS ≥ 1%.
  • The effect was greatest among patients with PD-L1 TPS ≥ 50%.

As reported in The Lancet by Mok et al, 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%. The study supported the April 11th 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, and patients with metastatic NSCLC. 

Study Details

The open-label trial included 1,274 patients from 213 sites in 32 countries with PD-L1 TPS ≥1%. Patients 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 AUC of 5–6 plus paclitaxel at 200 mg/m² or pemetrexed at 500 mg/m² every 3 weeks for 4 to 6 cycles [n = 637]). Maintenance therapy with pemetrexed at 500 mg/m² every 3 weeks was optional but encouraged in chemotherapy group patients with nonsquamous histology. Randomization was stratified by region (East Asia vs rest of world), Eastern Cooperative Oncology Group 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. Overall, 599 patients (47%) had a TPS of ≥ 50% and 818 (64%) had a TPS of ≥ 20%, with 35% vs 36% having a TPS of 1% to 19%, 18% vs 16% having a TPS of 20% to 49%, and 47% vs 47% having a TPS ≥ 50%.

Overall Survival

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 ≥ 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 a 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 3 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 3 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 not formally tested in ≥ 20% or ≥ 1% population, since the superiority boundary was not met in ≥ 50% population). At least 1 subsequent anticancer therapy was received by 38% of the pembrolizumab group and 44% of the chemotherapy group, including immunotherapy in 3% and 20%, respectively.

Adverse Events

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 ≥ 20 patients being 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% vs 9% of patients. Death was considered related to treatment in 2% vs 2% of patients. 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 ≥ 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 sensitising EGFR or ALK alterations and with low PD-L1 TPS.”

Tony S.K. Mok, MD, of the State Key Laboratory of South China, Chinese University of Hong Kong, is the corresponding author for The Lancet article.

Disclosure: The study was funded by Merck Sharp & Dohme. For full disclosures of the study authors, visit


The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.