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.— Martin Reck, MD, PhD, and colleagues
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In the phase III KEYNOTE-024 trial reported in The New England Journal of Medicine by Martin Reck, MD, PhD, of the German Center of Lung Research, Grosshansdorf, and colleagues, pembrolizumab (Keytruda) significantly improved progression-free and overall survival vs platinum-based chemotherapy in patients with previously untreated advanced non–small cell lung cancer (NSCLC) with ≥ 50% programmed cell death ligand 1 (PD-L1) expression and no sensitizing epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) translocations.1
In this open-label study, 305 patients from 102 sites in 16 countries were randomized between September 2014 and October 2015 to receive pembrolizumab at 200 mg every 3 weeks for 35 cycles (n = 154) or investigator choice from among 5 platinum-based regimens for 4 to 6 cycles (n = 151). Patients had to have stage IV NSCLC with no sensitizing EGFR mutations or ALK translocations, PD-L1 expression on at least 50% of tumor cells, no previous systemic therapy for metastatic disease, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
Platinum-based regimens consisted of carboplatin plus pemetrexed (Alimta), cisplatin plus pemetrexed, carboplatin plus gemcitabine, cisplatin plus gemcitabine, or carboplatin plus paclitaxel. The most common platinum regimen was carboplatin plus pemetrexed (67 patients, 44%). Crossover from the chemotherapy group to the pembrolizumab group was permitted after disease progression. The primary endpoint was progression-free survival on blinded independent central radiologic review in the intent-to-treat population.
For the pembrolizumab and chemotherapy groups: median age was 64.5 and 66.0 years; 60% and 63% were male; 14% and 13% were from East Asia and 86% and 87% were from non-East Asian regions; 35% had an ECOG performance status of 0; smoking status was current for 22% and 21%, former for 75% and 67%, and never for 3% and 13%; histology was nonsquamous in 81% and 82%; brain metastases were present in 12% and 7%; 2% and 1% had received systemic neoadjuvant therapy; and 4% and 2% had received systemic adjuvant therapy.
Improved Progression-Free and Overall Survival
At second interim analysis, with a cutoff date in May 2016, pembrolizumab was superior to chemotherapy in terms of overall survival on prespecified criteria; the external data and safety monitoring committee recommended that the trial be stopped early, with patients in the chemotherapy group given the opportunity to receive pembrolizumab. All data discussed here are from the second interim analysis.
Median of follow-up was 11.2 months (range = 6.3–19.7 months) at data cutoff. Median progression-free survival was 10.3 months (95% confidence interval [CI] = 6.7 months to not reached) in the pembrolizumab group vs 6.0 months (95% CI = 4.2–6.2 months) in the chemotherapy group (hazard ratio [HR] = 0.50, P < .001). Hazard ratios favored pembrolizumab in all subgroups examined. A total of 43.7% of the chemotherapy group crossed over to pembrolizumab after disease progression; of them, 57.6% were still receiving pembrolizumab at the time of data cutoff.
The estimated overall survival rate at 6 months was 80.2% vs 72.4% (HR = 0.60, P = .005). Median overall survival was not reached in either group. Response rates were 44.8% vs 27.8%, and median duration of response was not reached (range = 1.9+ to 14.5+ months) vs 6.3 months (range = 2.1+ to 12.6+ months). Median time to response was 2.2 months in both groups.
Treatment-related adverse events of any grade occurred in 73.4% of the pembrolizumab group vs 90.0% of the chemotherapy group, and treatment-related adverse events of grade ≥ 3 occurred in 26.6% vs 53.3%. The most common treatment-related adverse events of any grade were diarrhea (14.3%), fatigue (10.4%), and pyrexia (10.4%) in the pembrolizumab group and anemia (44.0%), nausea (43.3%), and fatigue (28.7%) in the chemotherapy group; the most common grade ≥ 3 events were diarrhea (3.9%) and pneumonitis (2.6%) in the pembrolizumab group and anemia (19.3%), neutropenia (13.3%), decreased platelet count (6.0%), thrombocytopenia (5.3%), decreased neutrophil count (4.0%), fatigue (3.3%), and decreased appetite (2.7%) in the chemotherapy group.
Serious treatment-related adverse events occurred in 21.4% vs 20.7%. Treatment was discontinued due to treatment-related adverse events in 7.1% vs 10.7%. Death due to adverse events considered related to treatment occurred in 1 pembrolizumab patient (sudden death of unknown cause on day 2) and 3 chemotherapy patients (pulmonary sepsis on day 25, pulmonary alveolar hemorrhage on day 112, and unknown cause on day 8).
Immune-mediated adverse events of any grade irrespective of causal attribution occurred in 29.2% of the pembrolizumab group vs 4.7% of the chemotherapy group; grade 3 or 4 events occurred in 9.7% vs 0.7%, with the most common in the pembrolizumab group being severe skin reactions (3.9%), pneumonitis (2.6%), and colitis (1.3%).
The investigators concluded: “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.” ■
Disclosure: The study was funded by Merck. For full disclosures of the study authors, visit www.nejm.org.
Deborah B. Doroshow, MD, PhD
Roy S. Herbst, MD, PhD
We are in the midst of a paradigm shift in lung cancer. In the past 2 years, the anti–programmed cell death protein 1 (anti–PD-1) inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) were found to improve overall survival in the...