On September 17, the U.S. Food and Drug Administration (FDA) approved pembrolizumab (Keytruda) with pemetrexed and platinum chemotherapy as first-line treatment of unresectable advanced or metastatic malignant pleural mesothelioma.
Efficacy and Safety
Efficacy was investigated in KEYNOTE-483 (ClinicalTrials.gov identifier NCT02784171), a randomized, open-label trial in patients with unresectable advanced or metastatic malignant pleural mesothelioma and no prior systemic therapy for advanced or metastatic disease. Patients were randomly assigned (1:1) to receive either pembrolizumab for up to 2 years in combination with pemetrexed and platinum-based chemotherapy for up to six cycles (n = 222) or pemetrexed and platinum-based chemotherapy for up to six cycles (n = 218).
The main efficacy outcome measure was overall survival. Additional efficacy outcome measures were progression-free survival, objective response rate, and duration of response, as assessed by blinded independent central review, according to modified Response Evaluation Criteria in Solid Tumors version 1.1 for mesothelioma.
The trial demonstrated a statistically significant improvement in overall survival for patients treated with pembrolizumab with chemotherapy compared with those who received chemotherapy alone. Median overall survival was 17.3 months (95% confidence interval [CI] = 14.4–21.3 months) vs 16.1 months (95% CI = 13.1–18.2 months; hazard ratio [HR] = 0.79; 95% CI = 0.64–0.98; P = .0162).
Median progression-free survival was 7.1 months (95% CI = 6.9–8.1 months) vs 7.1 months (95% CI = 6.8–7.7 months) with pembrolizumab plus chemotherapy and chemotherapy alone, respectively (HR = 0.80; 95% CI = 0.65–0.99; P = .0194). The confirmed objective response rate was 52% (95% CI = 45.5%–59.0%) in the pembrolizumab-plus-chemotherapy arm and 29% (95% CI = 23.0%–35.4%) in the chemotherapy-alone arm. Median duration of response was 6.9 months (95% CI = 5.8–8.3 months) and 6.8 months (95% CI = 5.5–8.5 months), respectively.
Adverse reactions occurring in patients with malignant pleural mesothelioma were similar to those in other patients receiving pembrolizumab with pemetrexed and platinum chemotherapy. See the prescribing information for complete details.
Dosage and Regulatory Information
The recommended pembrolizumab dose is 200 mg every 3 weeks or 400 mg every 6 weeks until disease progression or unacceptable toxicity for up to 2 years.
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence, and the FDA collaborated with the Australian Therapeutic Goods Administration and Health Canada. The application reviews are ongoing at the other regulatory agencies.
This review used the Assessment Aid, a voluntary submission from the applicant, to facilitate the FDA’s assessment. The application was also granted Priority Review.
