Pembrolizumab versus Chemotherapy for PD-L1–Positive Non–Small-Cell Lung Cancer¶
Why this mattered¶
Before KEYNOTE-024, platinum-based chemotherapy was still the default first-line treatment for most patients with advanced non–small-cell lung cancer without targetable EGFR or ALK alterations. This trial showed that, in the biologically defined subgroup whose tumors expressed PD-L1 on at least 50% of cells, blocking PD-1 with pembrolizumab was not merely an option after chemotherapy failure but superior to chemotherapy as initial treatment. The magnitude and consistency of benefit mattered: longer progression-free survival, an early overall-survival advantage despite permitted crossover, higher response rate, longer response duration, and substantially fewer severe treatment-related adverse events.
The paper helped move lung cancer treatment from histology-centered chemotherapy selection toward biomarker-directed immunotherapy. PD-L1 expression became a practical clinical stratifier for choosing first-line therapy, analogous in treatment-decision importance, though biologically distinct, to oncogenic driver testing. It also established that immune checkpoint blockade could produce durable disease control in a major solid tumor population at the first treatment decision point, rather than being reserved for later lines of therapy.
Subsequent advances built directly on this shift. Later trials extended checkpoint inhibition into broader NSCLC populations, combinations with chemotherapy, dual-immunotherapy strategies, locally advanced disease, and perioperative settings. KEYNOTE-024 was therefore pivotal not because it introduced PD-1 blockade itself, but because it demonstrated that immunotherapy could displace chemotherapy as the preferred first-line standard for a molecularly selected group of patients with advanced lung cancer.
Abstract¶
BACKGROUND: Pembrolizumab is a humanized monoclonal antibody against programmed death 1 (PD-1) that has antitumor activity in advanced non-small-cell lung cancer (NSCLC), with increased activity in tumors that express programmed death ligand 1 (PD-L1). METHODS: In this open-label, phase 3 trial, we randomly assigned 305 patients who had previously untreated advanced NSCLC with PD-L1 expression on at least 50% of tumor cells and no sensitizing mutation of the epidermal growth factor receptor gene or translocation of the anaplastic lymphoma kinase gene to receive either pembrolizumab (at a fixed dose of 200 mg every 3 weeks) or the investigator's choice of platinum-based chemotherapy. Crossover from the chemotherapy group to the pembrolizumab group was permitted in the event of disease progression. The primary end point, progression-free survival, was assessed by means of blinded, independent, central radiologic review. Secondary end points were overall survival, objective response rate, and safety. RESULTS: Median progression-free survival was 10.3 months (95% confidence interval [CI], 6.7 to not reached) in the pembrolizumab group versus 6.0 months (95% CI, 4.2 to 6.2) in the chemotherapy group (hazard ratio for disease progression or death, 0.50; 95% CI, 0.37 to 0.68; P<0.001). The estimated rate of overall survival at 6 months was 80.2% in the pembrolizumab group versus 72.4% in the chemotherapy group (hazard ratio for death, 0.60; 95% CI, 0.41 to 0.89; P=0.005). The response rate was higher in the pembrolizumab group than in the chemotherapy group (44.8% vs. 27.8%), the median duration of response was longer (not reached [range, 1.9+ to 14.5+ months] vs. 6.3 months [range, 2.1+ to 12.6+]), and treatment-related adverse events of any grade were less frequent (occurring in 73.4% vs. 90.0% of patients), as were grade 3, 4, or 5 treatment-related adverse events (26.6% vs. 53.3%). CONCLUSIONS: In patients with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells, pembrolizumab was associated with significantly longer progression-free and overall survival and with fewer adverse events than was platinum-based chemotherapy. (Funded by Merck; KEYNOTE-024 ClinicalTrials.gov number, NCT02142738 .).
Related¶
- cite → Pembrolizumab for the Treatment of Non–Small-Cell Lung Cancer — The 2016 pembrolizumab trial extends earlier NSCLC evidence by testing pembrolizumab as first-line therapy in PD-L1-positive disease.
- cite → Improved Survival with Ipilimumab in Patients with Metastatic Melanoma — The pembrolizumab NSCLC trial cites ipilimumab melanoma survival gains as clinical evidence that immune checkpoint blockade can improve cancer outcomes.
- cite → Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation — The pembrolizumab NSCLC trial cites vemurafenib to contrast immune checkpoint therapy with genotype-targeted therapy in modern oncology.
- cite → Pembrolizumab versus Ipilimumab in Advanced Melanoma — The pembrolizumab NSCLC trial cites pembrolizumab-versus-ipilimumab melanoma results as prior evidence of PD-1 blockade efficacy.
- cite → Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer — The pembrolizumab NSCLC trial builds on early anti-PD-1 safety, activity, and immune-correlate evidence across cancers.
- cite ← Pembrolizumab plus Chemotherapy in Metastatic 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.
- enables ← Improved Survival with Ipilimumab in Patients with Metastatic Melanoma — The ipilimumab trial proved that immune checkpoint blockade can improve survival in metastatic cancer, supporting later PD-1 blockade testing with pembrolizumab in lung cancer.
- enables ← Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation — The vemurafenib trial established mutation-selected targeted therapy as a survival-improving oncology strategy, contrasting with and motivating biomarker-selected immunotherapy trials such as pembrolizumab in PD-L1-positive lung cancer.