Safety and Preliminary Antitumor Activity of Ivonescimab Plus Pemetrexed and Platinum-Based Chemotherapy in Advanced Malignant Pleural Mesothelioma

Ivonescimab is administered at 3, 10, or 20 mg/kg every 3 weeks in combination with pemetrexed 500 mg/m² and cisplatin 75 mg/m² or carboplatin AUC 5 for 4 to 6 cycles. Dose escalation follows a conventional 3+3 design, with dose-limiting toxicities assessed during the first 28 days. Safety, tolerability, and preliminary antitumor activity are evaluated to support dose selection for subsequent dose expansion. Peripheral blood, pleural effusion, and pleural tissue samples will be collected for exploratory analyses.

• Ivonescimab Combined With Chemotherapy (Drug): Ivonescimab is administered intravenously at sequential dose levels of 3, 10, and 20 mg/kg every 3 weeks (Q3W), in combination with pemetrexed 500 mg/m² and cisplatin 75 mg/m² or carboplatin AUC 5 for 4 to 6 cycles. Maintenance treatment with ivonescimab at the assigned dose with or without pemetrexed may be continued Q3W.

Primary outcomes

• Dose-Limiting Toxicities [From the first dose through Day 28]: Incidence of protocol-defined dose-limiting toxicities.

Secondary outcomes

• Treatment-Emergent Adverse Events [From the first dose through the last available safety assessment, up to 24 months.]: Incidence and severity of treatment-emergent adverse events according to CTCAE v5.0.
• Objective Response Rate [From the first dose through the last available tumor response assessment, up to 24 months.]: Proportion of participants with a best overall response of complete response or partial response according to modified RECIST for malignant pleural mesothelioma.
• Disease Control Rate [From the first dose through the last available tumor response assessment, up to 24 months.]: Proportion of participants with a best overall response of complete response, partial response, or stable disease according to modified RECIST for malignant pleural mesothelioma.
• Progression-Free Survival [From the first dose until disease progression or death from any cause, assessed up to 24 months.]: Time from the first dose to the first documented disease progression or death from any cause, whichever occurs first.
• Overall Survival [From the first dose until death from any cause, assessed up to 24 months.]: Time from the first dose to death from any cause.

Sex: All, ages: 18 Years to 75 Years

Inclusion Criteria:

1. Age 18 to 75 years.
2. Histologically confirmed advanced or metastatic malignant pleural mesothelioma not amenable to surgery.
3. No prior systemic anticancer therapy for advanced disease.
4. ECOG PS 0-1.
5. At least one measurable lesion according to modified RECIST (mRECIST).
6. Adequate organ function for study treatment.
7. Patients with asymptomatic or stable brain metastases are eligible.
8. Able to understand the study, provide written informed consent, and comply with study procedures.

Exclusion Criteria:

1. Active autoimmune disease requiring systemic treatment or other contraindications to immunotherapy.
2. Uncontrolled hypertension, significant bleeding risk, or other contraindications to antiangiogenic therapy.
3. Active interstitial lung disease or noninfectious pneumonitis.
4. Active infection requiring systemic treatment.
5. Other active malignancies requiring anticancer treatment.
6. Severe uncontrolled medical conditions that may interfere with study treatment.
7. Pregnant or breastfeeding women.