2018 ASCO: Pembrolizumab Plus Chemotherapy as First-Line Treatment of Metastatic Squamous NSCLC: KEYNOTE-407 Study
Results from KEYNOTE-407, a randomized, double-blind, placebo-controlled, phase III study evaluating pembrolizumab (Keytruda) in combination with carboplatin/paclitaxel or carboplatin/nab-paclitaxel (Abraxane) as first-line treatment for metastatic squamous non–small cell lung cancer (NSCLC), were presented by Paz-Ares et al at the 2018 ASCO Annual Meeting (Abstract 105).
Major Findings
In this study, the pembrolizumab-plus-chemotherapy combination significantly improved overall survival, reducing the risk of death by 36% compared to chemotherapy alone (hazard ratio [HR] = 0.64, 95% confidence interval [CI] = 0.49–0.85; P = .0008). This is the first time that a combination of an anti–programmed cell death protein 1 (PD-1) therapy and chemotherapy has significantly extended overall survival in the first-line treatment of patients with squamous NSCLC.
Findings from prespecified exploratory analyses showed an overall survival benefit regardless of programmed cell death ligand 1 (PD-L1) expression, as follows: patients whose tumors did not express PD-L1 (HR = 0.61, 95% CI = 0.38–0.98); patients whose tumors had PD-L1 tumor proportion scores (TPS) of 1% to 49% (HR = 0.57, 95% CI = 0.36–0.90); and patients who had a TPS ≥ 50% (HR = 0.64, 95% CI = 0.37–1.10).
The addition of pembrolizumab to carboplatin plus paclitaxel or nab-paclitaxel chemotherapy also significantly improved progression-free survival, with a reduction in the risk of progression or death of nearly half for patients in the pembrolizumab combination group, compared with chemotherapy alone (HR = 0.56, 95% CI = 0.45–0.70; P < .0001). A progression-free survival improvement in the pembrolizumab combination group was observed in patients whose tumors did not express PD-L1 (HR = 0.68, 95% CI = 0.47–0.98); patients with a TPS of 1% to 49% (HR = 0.56, 95% CI = 0.39–0.80); and patients with a TPS ≥ 50% (HR = 0.37, 95% CI = 0.24–0.58).
“Metastatic squamous NSCLC is a difficult-to-treat type of lung cancer,” said Luis Paz-Ares, MD, PhD, study investigator and Professor of Medicine at the Hospital Universitario 12 de Octubre, Madrid. “In KEYNOTE-407, first-line treatment with pembrolizumab in combination with traditional chemotherapy significantly improved both overall survival and progression-free survival in these patients, regardless of PD-L1 expression.”
Data from KEYNOTE-407 have been submitted to the U.S. Food and Drug Administration for review.
Study Details
KEYNOTE-407 is investigating pembrolizumab in combination with carboplatin/paclitaxel or carboplatin/nab-paclitaxel, compared with carboplatin/paclitaxel or carboplatin/nab-paclitaxel alone, in 559 patients with metastatic squamous NSCLC. Patients had not previously received systemic therapy for advanced disease. The dual primary endpoints are overall and progression-free survival, and secondary endpoints include objective response rate and duration of response.
In this study, the median overall survival was 15.9 months in the pembrolizumab combination group (95% CI = 13.2–not estimable) and 11.3 months in the chemotherapy-alone group (95% CI, 9.5–14.8). Of the 42.8% of patients (n = 89) randomly assigned to the chemotherapy-alone group who discontinued chemotherapy went on to receive subsequent anti–PD-1 or anti–PD-L1 therapy, 75 patients received pembrolizumab monotherapy as part of in-study crossover.
In addition to subgroups based on PD-L1 expression levels, improvements in overall survival were observed in all other patient subgroups evaluated, including age, sex, EGOG performance status score, region of enrollment, and type of taxane prescribed (ie, paclitaxel or nab-paclitaxel). The median progression-free survival was 6.4 months for the pembrolizumab combination (95% CI = 6.2–8.3) compared with 4.8 months for chemotherapy alone (95% CI = 4.3–5.7).
As previously announced, at the first interim analysis, pembrolizumab plus carboplatin and paclitaxel or nab-paclitaxel showed an overall response rate of 58.4% (95% CI = 48.2%–68.1%) compared to 35.0% (95% CI = 25.8%–45.0%) for chemotherapy alone (P = .0004). At the time of the second interim analysis, which also included the survival results announced at the 2018 ASCO Annual Meeting, the overall response rate data were similar to the first, alpha-controlled response rate analysis, as follows: 57.9% (95% CI = 51.9%–63.8%) for the pembrolizumab combination group compared to 38.4% (95% CI = 32.7%–44.4%) for the chemotherapy group. Among patients in the pembrolizumab combination group, the median duration of response was 7.7 months (range = 1.1+ to 14.7+ months) compared with 4.8 months in the chemotherapy alone group (range = 1.3+ to 15.8+ months).
Safety and Adverse Events
The safety of pembrolizumab in combination with chemotherapy was consistent with the safety profiles of pembrolizumab and chemotherapy in previous trials among patients with metastatic NSCLC, with no new safety signals identified. Grade 3 to 5 adverse events from any cause occurred in 69.8% of patients in the pembrolizumab plus carboplatin and paclitaxel or nab-paclitaxel group and 68.2% in the chemotherapy-alone group.
Adverse events of any grade and from any cause with an incidence of 20% or more in the pembrolizumab combination group were anemia (53.2%), alopecia (46.0%), neutropenia (37.8%), nausea (35.6%), thrombocytopenia (30.6%), diarrhea (29.9%), decreased appetite (24.5%), constipation (23.0%), fatigue (22.7%), asthenia (21.6%), arthralgia (20.5%), and peripheral neuropathy (20.5%). The most common immune-mediated adverse events of any grade in patients in the pembrolizumab combination group were hypothyroidism (7.9%), hyperthyroidism (7.2%), pneumonitis (6.5%), colitis (2.5%), hepatitis (1.8%), severe skin reactions (1.8%), hypophysitis (1.1%), thyroiditis (1.1%), and nephritis (0.7%). There were 10 treatment-related deaths in the pembrolizumab combination group and 6 in the chemotherapy-alone group, including 1 case of pneumonitis in each group.
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