FDA Expands Pembrolizumab Indication for NSCLC in First-Line Setting

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On April 14, the U.S. Food and Drug Administration (FDA) approved pembrolizumab (Keytruda) for the first-line treatment of patients with stage III non–small cell lung cancer (NSCLC) who are not candidates for surgical resection or definitive chemoradiation, or those with metastatic NSCLC. Patients’ tumors must have no EGFR or ALK genomic aberrations and express programmed cell death ligand 1 (tumor proportion score [TPS] ≥ 1%), as determined by an FDA-approved test. Pembrolizumab was previously approved as a single agent for the first-line treatment of patients with metastatic NSCLC whose tumors express PD-L1 TPS ≥ 50%.


Approval was based on KEYNOTE-042, a randomized, multicenter, open-label, active-controlled trial conducted in 1,274 patients with stage III or IV NSCLC who had not received prior systemic treatment for metastatic NSCLC and whose tumors expressed PD-L1 (TPS ≥ 1%). PD-L1 expression was determined by an immunohistochemistry assay using the PD-L1 IHC 22C3 pharmDx Kit.

Patients were randomly assigned 1:1 to receive pembrolizumab at 200 mg intravenously every 3 weeks or investigator’s choice of a carboplatin-containing regimen with either pemetrexed or paclitaxel. Randomization was stratified by Eastern Cooperative Oncology Group performance status, histology, geographic region, and PD-L1 expression (TPS ≥ 50% vs TPS 1%–49%).

Overall survival in the TPS ≥ 50% NSCLC subgroup, the TPS ≥ 20% NSCLC subgroup, and the overall population (TPS ≥ 1%) were the major efficacy measures.

Trial Results

The trial demonstrated statistically significant improvements in overall survival for those randomly assigned to pembrolizumab compared with chemotherapy in all three populations.

In the TPS ≥ 1% population (overall population), the median overall survival was 16.7 and 12.1 months for the pembrolizumab and chemotherapy arms, respectively (hazard ratio [HR] = 0.81, 95% confidence interval [CI] = 0.71–0.93; = .0036). For the TPS ≥ 20% subgroup, the median overall survival was 17.7 months for the pembrolizumab arm and 13.0 months for the chemotherapy arm (HR = 0.77, 95% CI = 0.64–0.92; = .004). For the TPS ≥ 50% subgroup, the estimated median overall survival was 20 months and 12.2 months for those receiving pembrolizumab and chemotherapy, respectively (HR = 0.69, 95% CI = 0.56–0.85; = .0006). There were no significant differences in progression-free survival or overall response rate between the arms in any population. 

The most common adverse reactions reported in at least 10% of patients who received pembrolizumab as a single agent in KEYNOTE-042 include fatigue, decreased appetite, dyspnea, cough, rash, constipation, diarrhea, nausea, hypothyroidism, pneumonia, pyrexia, and weight loss.

The recommended pembrolizumab dose for NSCLC is 200 mg as an intravenous infusion over 30 minutes every 3 weeks.