Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer¶
Why this mattered¶
Before KEYNOTE-189, first-line treatment for metastatic nonsquamous NSCLC without actionable EGFR or ALK alterations was still organized around platinum-doublet chemotherapy, with pembrolizumab monotherapy reserved mainly for tumors with high PD-L1 expression. This trial changed that logic. By showing a large overall-survival benefit from adding pembrolizumab to pemetrexed-platinum chemotherapy, despite permitted crossover to pembrolizumab after progression in the control group, it established that immunotherapy could improve outcomes when used upfront with chemotherapy rather than saved for later. Just as important, the benefit appeared across the evaluated PD-L1 subgroups, making first-line immunotherapy relevant even for patients whose tumors did not meet the high PD-L1 threshold used for pembrolizumab monotherapy.
The paper mattered because it turned chemoimmunotherapy from an experimental combination into a new default treatment architecture for a major lung-cancer population. Chemotherapy was no longer simply a cytotoxic fallback; in combination with PD-1 blockade, it became part of a regimen that could extend survival early in metastatic disease. The similar rates of grade 3 or higher adverse events between groups also helped make the result clinically actionable: the survival gain did not depend on a dramatic increase in severe toxicity compared with chemotherapy alone.
KEYNOTE-189 also helped define the next phase of lung-cancer oncology. Subsequent advances increasingly built around molecular stratification and immune-context selection: targeted therapies for driver mutations, immunotherapy combinations for patients without such drivers, and later trials testing perioperative or earlier-stage use of checkpoint blockade. In that sequence, this study was a hinge point: it moved PD-1 inhibition from a biomarker-restricted or later-line strategy toward broad first-line integration, making metastatic NSCLC treatment less a choice between chemotherapy and immunotherapy than a platform for combining systemic modalities according to tumor biology.
Abstract¶
BACKGROUND: First-line therapy for advanced non-small-cell lung cancer (NSCLC) that lacks targetable mutations is platinum-based chemotherapy. Among patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line treatment of choice. The addition of pembrolizumab to chemotherapy resulted in significantly higher rates of response and longer progression-free survival than chemotherapy alone in a phase 2 trial. METHODS: In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) 616 patients with metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations who had received no previous treatment for metastatic disease to receive pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance therapy. Crossover to pembrolizumab monotherapy was permitted among the patients in the placebo-combination group who had verified disease progression. The primary end points were overall survival and progression-free survival, as assessed by blinded, independent central radiologic review. RESULTS: After a median follow-up of 10.5 months, the estimated rate of overall survival at 12 months was 69.2% (95% confidence interval [CI], 64.1 to 73.8) in the pembrolizumab-combination group versus 49.4% (95% CI, 42.1 to 56.2) in the placebo-combination group (hazard ratio for death, 0.49; 95% CI, 0.38 to 0.64; P<0.001). Improvement in overall survival was seen across all PD-L1 categories that were evaluated. Median progression-free survival was 8.8 months (95% CI, 7.6 to 9.2) in the pembrolizumab-combination group and 4.9 months (95% CI, 4.7 to 5.5) in the placebo-combination group (hazard ratio for disease progression or death, 0.52; 95% CI, 0.43 to 0.64; P<0.001). Adverse events of grade 3 or higher occurred in 67.2% of the patients in the pembrolizumab-combination group and in 65.8% of those in the placebo-combination group. CONCLUSIONS: In patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to standard chemotherapy of pemetrexed and a platinum-based drug resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by Merck; KEYNOTE-189 ClinicalTrials.gov number, NCT02578680 .).
Related¶
- cite → Pembrolizumab for the Treatment of Non–Small-Cell Lung Cancer — The 2018 trial extends early pembrolizumab NSCLC efficacy findings by testing PD-1 blockade combined with platinum chemotherapy in metastatic disease.
- cite → Nivolumab versus Docetaxel in Advanced Nonsquamous Non–Small-Cell Lung Cancer — The 2018 trial cites nivolumab evidence showing PD-1 blockade improves survival versus docetaxel in previously treated nonsquamous NSCLC.
- cite → Nivolumab versus Docetaxel in Advanced Squamous-Cell Non–Small-Cell Lung Cancer — The 2018 trial cites nivolumab evidence that PD-1 inhibition improves outcomes in advanced squamous NSCLC.
- cite → Pembrolizumab versus Chemotherapy for PD-L1–Positive Non–Small-Cell Lung Cancer — The 2018 trial builds on pembrolizumab monotherapy superiority in PD-L1-positive NSCLC by adding chemotherapy in first-line metastatic treatment.