The KEYNOTE-042 investigators reported on 28 October 2022 in the Journal of Clinical Oncology the study outcomes after approximately 5 years of follow-up and ad hoc analyses in patients who completed 35 cycles of pembrolizumab and in those who began a second course of pembrolizumab monotherapy. First-line pembrolizumab monotherapy continues to show long-term overall survival (OS) benefit and durable responses versus chemotherapy, regardless of PD-L1 tumour proportion score (TPS) in patients with PD-L1–positive locally advanced/metastatic non-small cell lung cancer (NSCLC) without EGFR/ALK alterations. According to Dr. Gilberto de Castro Jr of the Instituto do Câncer do Estado de São Paulo in São Paulo, Brazil and study colleagues, with 5-year OS rates of up to 22%, the data support the continued use of pembrolizumab monotherapy as a standard-of-care treatment for previously untreated PD-L1–positive advanced/metastatic NSCLC.

In KEYNOTE-042, a randomised phase III study, patients with locally advanced/metastatic NSCLC without EGFR/ALK alterations and with PD-L1 TPS ≥ 1% received pembrolizumab 200 mg once every 3 weeks for 35 cycles or chemotherapy (carboplatin plus paclitaxel or pemetrexed) for 4-6 cycles with optional maintenance pemetrexed. Patients who completed 35 cycles of pembrolizumab with at least stable disease could begin second-course pembrolizumab upon progression. In total, 1274 patients were randomly assigned, 637 to pembrolizumab and 637 to chemotherapy.

Primary endpoints were OS in PD-L1 TPS ≥ 50%, ≥ 20%, and ≥ 1% groups. Secondary endpoints were progression-free survival (PFS, defined as a time from random assignment to documented progression of disease or death due to any cause) and objective response rate (ORR, defined as a proportion of patients with radiologically confirmed complete response or partial response), both assessed per RECIST v1.1 by blinded independent central review, and safety. Exploratory endpoints included PFS2 (defined as a time from random assignment to second/subsequent progression of disease on next-line treatment or death from any cause).

Previously reported data from this study showed significantly longer OS with pembrolizumab monotherapy versus platinum-based chemotherapy in patients with previously untreated locally advanced or metastatic NSCLC with PD-L1 TPS ≥ 50%, ≥ 20%, and ≥ 1%.

In the latest report published in the JCO, median follow-up time was 61.1 months (range, 50.0-76.3). OS outcomes favoured pembrolizumab versus chemotherapy regardless of PD-L1 TPS (hazard ratio for TPS ≥ 50%, 0.68; TPS ≥ 20%, 0.75; TPS ≥ 1%, 0.79), with estimated 5-year OS rates with pembrolizumab of 21.9%, 19.4%, and 16.6%, respectively.

Longer-term follow-up continues to show a manageable safety profile of pembrolizumab with fewer treatment-related adverse events than chemotherapy and no new safety signals.

ORR was 84.3% among 102 patients who completed 35 cycles of pembrolizumab and 15.2% among 33 patients who received second-course pembrolizumab.

The authors concluded that with more than 5 years of follow-up, first-line pembrolizumab monotherapy was associated with substantially longer OS, durable response, and prolonged PFS2 compared with platinum-based chemotherapy in patients with PD-L1–positive locally advanced/metastatic NSCLC with no EGFR/ALK alterations. More than half of the patients who completed 35 cycles of pembrolizumab were alive 4 years after completing treatment (approximately 6 years after random assignment), and a high disease control rate was observed in patients who received a second course of pembrolizumab.

The latest study data were previously presented in part at the 36th Annual Meeting of the Society for Immunotherapy of Cancer in Washington, DC, US from 10 to 14 November 2021 and the 62nd Annual Meeting of the Japan Lung Cancer Society in Yokohama, Japan from 26 to 28 November 2021.

The study was supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ.


de Castro Jr G, Kudaba I, Wu Y-L et al. Five-Year Outcomes With Pembrolizumab Versus Chemotherapy as First-Line Therapy in Patients With Non–Small-Cell Lung Cancer and Programmed Death Ligand-1 Tumor Proportion Score ≥ 1% in the KEYNOTE-042 Study. JCO; Published online 28 October 2022. DOI: 10.1200/JCO.21.02885