Background: Pembrolizumab (anti-PD-1 antibody) plus lenvatinib (multityrosine kinase inhibitor) showed high clinical activity in PEMMELA cohort 1 in patients with pleural mesothelioma pre-treated with platinum-based chemotherapy. This study (cohort 2) aimed to investigate the clinical activity of this combination in patients with pleural mesothelioma who progressed after first-line nivolumab plus ipilimumab.
Methods: PEMMELA is a prospective, single-centre, single-arm, open-label, investigator-initiated phase 2 trial, done at the Netherlands Cancer Institute, Amsterdam, the Netherlands. Cohort 2 included patients aged 18 years and older with histologically confirmed pleural mesothelioma, an Eastern Cooperative Oncology Group performance status 0–1, and measurable disease according to the modified Response Evaluation Criteria in Solid Tumors for mesothelioma version 1.1, who progressed after treatment with nivolumab plus ipilimumab. Pembrolizumab (200 mg every 3 weeks intravenously) plus lenvatinib (20 mg orally daily) was administered for up to 2 years, or until disease progression, or unacceptable toxicity. The primary endpoint was objective response rate assessed by the local investigator. All patients who had received at least one cycle of pembrolizumab plus lenvatinib and had their disease evaluated were considered evaluable for the primary endpoint. All patients who received at least one cycle of the study treatment were included in the safety analysis set. Patients were not involved in study design. This study is registered with ClinicalTrials.gov (NCT04287829), and is complete.
Findings: Between Dec 14, 2022, and March 5, 2023, 24 patients were screened, of whom 20 were enrolled and received at least one cycle of pembrolizumab plus lenvatinib. Of these 20 patients, 17 patients (85%) were male and three (15%) were female. At data cutoff (Sept 1, 2024), with a median follow-up of 11·9 months (IQR 10·8–15·8), 12 (60%, 95% CI 36–81%) of 20 patients had an objective response. 14 (70%) of 20 patients developed grade 3 or 4 treatment-related adverse events, of which most common grade 3 events were hypertension (five patients [25%]) and fatigue including malaise (four patients [20%]). Ten treatment-related serious adverse events were observed in seven patients. Nine (45%) of 20 patients required at least one dose reduction and two (10%) discontinued treatment due to toxicity. There were no treatment related deaths.
Interpretation: This study met its primary endpoint, showing high clinical activity of pembrolizumab plus lenvatinib, but with substantial toxicity, in patients with pleural mesothelioma who had progressed after first-line nivolumab plus ipilimumab. This drug combination is promising for future studies in pleural mesothelioma.
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