Sintilimab plus anlotinib and chemotherapy as first-line treatment for advanced malignant pleural mesothelioma (SACH-MPM): A prospective, single-arm, phase II trial.

Abstract

8050 Background: Standard first-line treatments for advanced malignant pleural mesothelioma (MPM) include platinum-pemetrexed with bevacizumab or nivolumab plus ipilimumab. While the addition of atezolizumab to chemotherapy and bevacizumab improved PFS in the BEAT-meso trial (9.2 vs. 7.6 m, HR 0.72), it failed to show an OS benefit. Anlotinib is a multi-target TKI targeting VEGFR, FGFR, and PDGFR. We investigated the efficacy and safety of sintilimab (anti-PD-1) combined with anlotinib and chemotherapy as first-line treatment for advanced MPM. Methods: This open-label, dual-center, single-arm Phase II study (NCT05188859) enrolled systemic treatment-naive pts with unresectable locally advanced or metastatic MPM. Pts received sintilimab (200 mg D1) and anlotinib (12 mg D1-14) plus chemotherapy (pemetrexed 500 mg/m² with cisplatin 75 mg/m² or carboplatin AUC 5, D1) Q3W for 4-6 cycles, followed by maintenance sintilimab, anlotinib, and pemetrexed until disease progression, intolerable toxicity, or up to 24 months. Primary endpoint was ORR per modified RECIST (mRECIST) 1.1 for mesothelioma. A Simon’s two-stage design (H0 = 41.3%, H1 = 60%, α = 0.1) planned for 23 evaluable pts, requiring ≥12 responses. Results: From Sep 2024 to Jan 2026, 30 pts were enrolled (median age 58.5 y; 76.7% epithelioid, 80% stage IIIB). At data cutoff, 29 pts were evaluable. Median follow-up was 7.4 months (m). The primary endpoint was met, with a confirmed ORR of 65.5% (95% CI: 45.7-82.1). DCR was 100%. Median time to response was 1.4 m; median DoR was not reached (0.7+-8.4+ m). PFS and OS were not mature. The 6- and 12-m PFS rates were 100% and 67.5%, respectively. OS rate was 100% at cutoff. Grade ≥3 TRAEs (36.7%) included neutrophil count decreased (13.3%), platelet count decreased (10.0%), pulmonary embolism (6.7%), diarrhea (6.7%), and hypertension (3.3%; any grade 10.0%). Bleeding events were Grade 1-2 (epistaxis 13.3%). TRAEs led to anlotinib dose reduction or discontinuation in 20.0%. No Grade 5 events occurred. Conclusions: Sintilimab plus anlotinib and chemotherapy demonstrated superior ORR compared to historical controls with a manageable safety profile. The study met its primary endpoint, and the high 12-month PFS rate suggests a potential survival benefit. These findings support integrating a multi-target TKI with PD-1 blockade and chemotherapy as a potent first-line strategy for advanced MPM. Clinical trial information: NCT05188859 .