First-Line Pembrolizumab vs Chemotherapy in Advanced PD-L1–Positive NSCLC Without EGFR/ALK Alterations

Overall Survival at 5 Years in the KEYNOTE-042 Trial

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As reported in the Journal of Clinical Oncology by Gilberto de Castro, Jr, MD, PhD, and colleagues, 5-year follow-up of the KEYNOTE-042 trial showed a maintained overall survival benefit with first-line pembrolizumab vs chemotherapy in patients with non–small cell lung cancer (NSCLC) with a PD-L1 tumor proportion score (TPS) ≥ 1% and no EGFR/ALK alterations.

The trial supported the April 2019 expansion of labeling for pembrolizumab as monotherapy in the first-line treatment of patients with stage III NSCLC who are not candidates for surgical resection or definitive chemoradiation, or those with metastatic NSCLC whose tumors have TPS ≥ 1% with no EGFR/ALK alterations.

Gilberto de Castro, Jr, MD, PhD

Gilberto de Castro, Jr, MD, PhD

Study Details

In the open-label trial, 1,274 patients with locally advanced or metastatic disease with TPS ≥ 1% were randomly assigned to receive pembrolizumab at 200 mg every 3 weeks for 35 cycles (n = 637) or chemotherapy with carboplatin plus paclitaxel or pemetrexed for four to six cycles with optional pemetrexed maintenance (n = 637). Patients completing 35 cycles of pembrolizumab with ≥ stable disease could begin a second course of pembrolizumab upon disease progression. 

Primary endpoints were overall survival in the total population (TPS ≥ 1%), the TPS ≥ 20% population (413 patients in pembrolizumab group and 405 in chemotherapy group), and the TPS ≥ 50% population (299 and 300 patients). 

Key Findings 

Median follow-up was 61.1 months (range = 50.0–76.3 months). For the pembrolizumab group vs chemotherapy group, median overall survival was: 16.4 vs 12.1 months in the total population (hazard ratio [HR] = 0.79, 95% confidence interval [CI] = 0.70–0.89); 18.0 vs 13.0 months in the TPS ≥ 20% population (HR = 0.75, 95% CI = 0.64–0.87); and 20.0 vs 12.2 months in the TPS ≥ 50% population (HR = 0.68, 95% CI= 0.57–0.81). Overall survival at 5 years was 16.6% vs 8.5%, 19.4% vs 10.1%, and 21.9% vs 9.8%, in the three TPS populations, respectively. 

Progression-free survival at 5 years was 6.9% vs 1.2% in the total population, 7.8% vs 1.6% in the TPS ≥ 20% population, and 9.2% vs 2.1% in the TPS ≥ 50% population.

Among 102 patients receiving pembrolizumab who completed 35 cycles of treatment, the objective response rate was 84.3%; median overall survival was not reached, with a 5-year rate of 61.8%; and median progression-free survival was 31.9 months. Among 33 patients who received second-course pembrolizumab, the objective response rate was 15.2%.

No new toxicities were identified. No new fatal treatment-related adverse events occurred in either treatment group. Exposure-adjusted treatment-related adverse events, immune-mediated adverse events, and infusion reaction rates generally decreased over time in both groups.

The investigators concluded, “First-line pembrolizumab monotherapy continued to show durable clinical benefit vs chemotherapy after 5 years of follow-up in [patients with] PD-L1–positive, locally advanced/metastatic NSCLC without EGFR/ALK alterations and remains a standard of care.”

Dr. de Castro, of Medical Oncology, Instituto do Câncer do Estado de São Paulo, Brazil, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc. For full disclosures of the study authors, visit

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