Highlights
– Pembrolizumab combined with lenvatinib achieved an objective response rate (ORR) of 60% (12 of 20; 95% CI 36–81%) in patients with pleural mesothelioma who progressed after first‑line nivolumab plus ipilimumab.
– Median follow‑up was 11.9 months (IQR 10.8–15.8). Grade 3–4 treatment‑related adverse events (TRAEs) occurred in 70% of patients; common grade 3 events included hypertension (25%) and fatigue/malaise (20%).
– The combination met its primary endpoint in this small, single‑centre phase 2 cohort but is associated with substantial toxicity, highlighting the need for randomized confirmation and optimization of dosing and sequencing.
Background: disease burden and unmet need
Malignant pleural mesothelioma is an aggressive malignancy linked to asbestos exposure, with limited effective systemic therapies and a historically poor prognosis. Immune checkpoint blockade has changed the first‑line landscape: combination PD‑1 and CTLA‑4 blockade is active in frontline disease, but many patients eventually progress and face few proven second‑line options. The optimal strategy after progression on PD‑1/CTLA‑4 therapy is undefined. Combining immune checkpoint inhibitors (ICIs) with antiangiogenic or multikinase inhibitors (MKIs) has shown synergistic activity in several tumour types due to vascular normalization and favourable modulation of the tumour immune microenvironment, prompting investigation of pembrolizumab (anti‑PD‑1) plus lenvatinib (a multi‑tyrosine kinase inhibitor with antiangiogenic properties) for mesothelioma.
Study design and patient population
PEMMELA is a prospective, single‑centre, single‑arm, open‑label, investigator‑initiated phase 2 trial conducted at the Netherlands Cancer Institute. Cohort 2 enrolled adults (≥18 years) with histologically confirmed pleural mesothelioma, ECOG performance status 0–1, and measurable disease by modified RECIST for mesothelioma (v1.1), specifically after progression on first‑line nivolumab plus ipilimumab. Patients received pembrolizumab 200 mg IV every 3 weeks and lenvatinib 20 mg orally daily for up to 2 years, until progression or unacceptable toxicity. The primary endpoint was objective response rate assessed locally; all patients receiving at least one cycle and with disease assessment were evaluable for response. Safety analysis included all who received at least one cycle. The trial is registered at ClinicalTrials.gov (NCT04287829).
Key results
Between Dec 14, 2022 and Mar 5, 2023, 24 patients were screened and 20 were enrolled and treated. Baseline characteristics included 85% male (17/20) and 15% female (3/20). At data cutoff (Sept 1, 2024), median follow‑up was 11.9 months (IQR 10.8–15.8).
Primary efficacy
The investigator‑assessed ORR was 60% (12 of 20 patients; 95% CI 36–81%). This is notable given prior exposure to dual ICI (nivolumab plus ipilimumab), a setting in which response rates to subsequent therapies are generally modest. The study met its predefined primary endpoint of demonstrating clinical activity in this population.
Secondary and safety outcomes
Toxicity was substantial. Fourteen of 20 patients (70%) developed grade 3 or 4 treatment‑related adverse events. The most common grade 3 events were hypertension (5 patients, 25%) and fatigue/malaise (4 patients, 20%). Ten treatment‑related serious adverse events occurred in seven patients. Dose reductions due to toxicity were required in nine patients (45%), and two patients (10%) discontinued treatment because of toxicity. There were no treatment‑related deaths reported.
Follow‑up and durability
Median follow‑up was just under 12 months, which provides initial signals about response durability but is insufficient to draw robust conclusions about long‑term progression‑free survival (PFS) or overall survival (OS). Longer follow‑up and larger cohorts are required to characterize durability and survival impact.
Interpretation and clinical implications
The reported ORR of 60% in this small cohort is encouraging in a heavily pretreated population previously exposed to dual checkpoint blockade. The result supports biological plausibility: lenvatinib’s inhibition of VEGF receptors and other kinases can reduce immunosuppressive myeloid populations and normalize tumour vasculature, potentially improving T‑cell infiltration and enhancing PD‑1 blockade efficacy. The combination of pembrolizumab with lenvatinib has proven efficacy in other tumour types, providing translational rationale for mesothelioma.
However, the substantial frequency of grade 3–4 toxicities (70%)—including hypertension and debilitating fatigue—underscores a precarious risk–benefit balance. Lenvatinib‑associated toxicities are well known and may be amplified in combination with immune checkpoint blockade. High rates of dose modifications (45%) and treatment discontinuation (10%) indicate that tolerability will be a key barrier to broader clinical use unless dosing strategies or patient selection are optimized.
Expert commentary: strengths, limitations, and next steps
Strengths of this report include prospective design, a clearly defined post‑ICI population (progression after nivolumab plus ipilimumab), and clinically meaningful response rates that suggest the combination can re‑induce tumour regression after prior dual ICI exposure.
Important limitations temper enthusiasm: the cohort was small (n=20), single‑arm, and single‑centre, which raises risks of selection bias and limited generalizability. The absence of a control arm prevents comparison with alternative second‑line options (chemotherapy, single‑agent ICI rechallenge, or best supportive care). Key biomarker analyses (for example, PD‑L1 expression, tumor mutational burden, BAP1 status, or microenvironmental signatures) were not reported here but will be crucial to identify patients most likely to derive benefit while minimizing harm.
Operationally, future research priorities should include randomized studies comparing pembrolizumab plus lenvatinib versus standard second‑line therapies in this setting, prospective biomarker‑driven selection, exploration of alternate dosing regimens (for example, lower starting doses of lenvatinib or adaptive dose‑escalation strategies), and dedicated quality‑of‑life assessments. Mechanistic correlative studies evaluating immune infiltration, angiogenic markers, and resistance pathways after prior CTLA‑4/PD‑1 blockade will help interpret and refine combinatorial strategies.
How this fits into current practice
For clinicians treating pleural mesothelioma, this study provides proof‑of‑concept that pembrolizumab plus lenvatinib can induce responses after progression on first‑line dual ICI. However, given the small size and toxicity profile, the combination should not yet replace existing second‑line standards outside of a clinical trial. Patients with rapidly progressive disease, limited performance status, or significant cardiovascular comorbidity may be poor candidates for an MKI‑containing regimen. Enrollment in controlled trials that can define comparative efficacy and safety remains the preferred route when available.
Conclusion and research gaps
PEMMELA cohort 2 demonstrates promising antitumour activity of pembrolizumab plus lenvatinib in pleural mesothelioma that has progressed after frontline nivolumab plus ipilimumab, achieving a 60% objective response rate. The regimen, however, is associated with high rates of grade 3–4 adverse events and frequent dose modifications. Larger randomized studies with embedded biomarker programs are required to validate the efficacy signal, optimize dosing and sequencing, and define the patient subsets most likely to benefit with acceptable toxicity.
Funding and trial registration
Funding: Merck Sharp and Dohme. ClinicalTrials.gov identifier: NCT04287829.
References
1. Douma LH, van der Noort V, Lalezari F, de Vries JF, Monkhorst K, Smesseim I, Baas P, Schilder B, Vermeulen M, Burgers JA, de Gooijer CJ. Pembrolizumab plus lenvatinib as second-line treatment in patients with pleural mesothelioma (PEMMELA): cohort 2 of a single-arm, phase 2 study. Lancet Oncol. 2025 Dec;26(12):1676-1684. doi: 10.1016/S1470-2045(25)00514-5. PMID: 41308680.
2. ClinicalTrials.gov. NCT04287829. PEMMELA: Pembrolizumab With Lenvatinib in Pleural Mesothelioma. Available at: https://clinicaltrials.gov/ct2/show/NCT04287829 (accessed 2025).
Author note
This article synthesizes and interprets cohort 2 results from the PEMMELA study to inform clinicians and investigators about the potential role, risks, and research priorities associated with pembrolizumab plus lenvatinib after progression on nivolumab plus ipilimumab in pleural mesothelioma.
