Pembrolizumab Plus Lenvatinib as Second- and Third-Line Treatments of Pleural Mesothelioma

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In a Dutch single-institution phase II trial (PEMMELA) reported in The Lancet Oncology, Douma et al found that the combination of pembrolizumab and lenvatinib showed activity as second- and third-line treatments of patients with pleural mesothelioma.

Study Details

A total of 38 evaluable patients with disease progression after platinum/pemetrexed chemotherapy who had received no prior immunotherapy were enrolled in the study at the Netherlands Cancer Institute between March 2021 and January 2022. Patients received pembrolizumab at 200 mg every 3 weeks plus lenvatinib at 20 mg once daily for up to 2 years or until disease progression or unacceptable toxicity. The primary outcome measure was investigator-assessed objective response rate, with a targeted minimal rate of 40%.   

Key Responses

At data cutoff (end of January 2023), median follow-up was 17.7 months (interquartile range = 13.8–19.4 months). On investigator assessment, objective responses (all partial) were observed in 22 of 38 patients (58%, 95% confidence interval [CI] = 41%–74%). An additional 13 patients (34%) had stable disease. Median response duration was 6.2 months (95% CI = 2.9–10.2 months). Disease control rates at 3 and 6 months were 84% and 47%, respectively. Objective responses were observed in 4 of 17 patients (24%) who had PD-L1–negative disease and in 11 of 18 (61%) who had PD-L1–positive disease (P = .040). Median progression-free survival was 5.6 months (95% CI = 4.5–8.5 months).

On independent review, objective responses were observed in 17 patients (45%, 95% CI = 29%–62%), including a complete response in 1. An additional 20 patients (53%) had stable disease. Disease control rates at 3 and 6 months were 79% and 47%, respectively. Median response duration was 7.6 months (95% CI = 5.6 months to not reached). Median progression-free survival was 5.7 months (95% CI = 4.2–9.0 months).

Adverse Events

The most common treatment-related adverse events of any grade were hoarseness (66%), fatigue (63%), anorexia (50%), and diarrhea (47%). The most common treatment-related grade ≥ 3 adverse events were hypertension (21%), anorexia (11%), and lymphopenia (11%). Serious treatment-related adverse events occurred in 26% of patients. At least one dose reduction or discontinuation of lenvatinib was required in 76% of patients, with treatment discontinuation because of thromboembolic events occurring in five patients (13%).

The investigators concluded: “Pembrolizumab plus lenvatinib showed promising antitumor activity in patients with pleural mesothelioma with considerable toxicity, similar to that in previous studies. Available evidence from the literature suggests a high starting dose of lenvatinib for optimal antitumor activity. This, however, demands a high standard of supportive care. The combination therapy of pembrolizumab and lenvatinib warrants further investigation in pleural mesothelioma.”

Jacobus A. Burgers, MD, PhD, of the Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, is the corresponding author of The Lancet Oncology article.

Disclosure: The study was funded by Merck Sharp & Dohme. For full disclosures of the study authors, visit

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