Volrustomig, a novel bispecific PD-1/CTLA-4 monoclonal antibody, as single-agent first-line therapy for unresectable pleural mesothelioma: Substudy 5 of the eVOLVE-02 phase 2 study.

TPS8126 Background: Standard first-line treatment for unresectable pleural mesothelioma has evolved recently to include anti-PD-1 ± anti-CTLA-4 immunotherapy-based options. Nivolumab + ipilimumab and pembrolizumab + pemetrexed + platinum chemotherapy showed improved survival vs chemotherapy alone, with greater benefit in non-epithelioid compared to epithelioid pleural mesothelioma. However, there is still significant unmet need given the ongoing poor prognosis; further study is needed to optimize dual checkpoint approaches across histologic subtypes and refine regimen selection. Volrustomig is a monovalent, bispecific, humanized IgG1 monoclonal antibody engineered to specifically inhibit PD-1 and CTLA-4, with increased CTLA-4 blockade on PD-1-positive activated T cells compared to PD-1-negative resting peripheral T cells. Volrustomig + chemotherapy is being evaluated as first-line treatment in unresectable pleural mesothelioma in the phase 3 eVOLVE-Meso trial. Volrustomig monotherapy has shown encouraging results in a Phase 1 study of patients with solid tumors; this new eVOLVE-02 (NCT06535607) substudy will evaluate its efficacy and safety as monotherapy in unresectable pleural mesothelioma. Methods: ~75 patients with unresectable pleural mesothelioma (epithelioid or non-epithelioid histology) will receive intravenous volrustomig until disease progression, unacceptable toxicity, consent withdrawal, or maximum treatment duration is reached. Eligibility criteria include age ≥18 years, Eastern Cooperative Oncology Group performance status 0/1, histologically confirmed pleural mesothelioma with known histology, advanced unresectable disease, measurable disease per mRECIST (modified Response Evaluation Criteria in Solid Tumors) v1.1 (pleural lesions) and/or RECIST v1.1 (metastatic non-pleural lesions), no prior systemic therapy for pleural mesothelioma, and no prior exposure to immune-mediated therapy. The primary endpoint is objective response rate. Secondary endpoints include disease control rate, time to response, duration of response, progression-free survival, and overall survival. eVOLVE-02 is recruiting patients; 3 substudies are ongoing in cervical cancer and head and neck squamous cell carcinoma. Substudy 5 enrollment is planned at sites in 8 countries/regions: Australia, Canada, China, Germany, Italy, Taiwan, UK, and USA. Clinical trial information: NCT06535607 .