Multinational phase 1 study of sofetabart mipitecan for high-grade ovarian cancer

Folate receptor alfa (FRα) is overexpressed in most high-grade ovarian cancers (HGOC), but the use of the FRα-targeting drug mirvetuximab soravtansine-gynx (MIRV) is limited by expression-level restrictions and toxicity. Sofetabart mipitecan (Sofe-M) is a novel FRα-targeting antibody-drug conjugate designed to overcome these barriers. A multinational, first-in-human phase 1 study evaluated Sofe-M in patients with HGOC, regardless of FRα expression level. Prior MIRV treatment was permitted. A total of 105 HGOC patients (majority platinum resistant) received Sofe-M at doses of 2 to 6 mg/kg every 21 days. Median age was 63.0 years, median number or prior treatments was 5 (range 1-11), 18.1% had received prior MIRV, and 51.4% had tumor FRα expression <75% at ≥2+ intensity. Overall response rate was 50.5% (95% CI 40.5-60.4) among all patients, 58.8% (32.9-81.6) at 3 mg/kg, 44% (30.9-58.6) for FRα < 75%, 56.5% (41.1-71.1) for FRα ≥ 75%, and 57.9% (33.5-79.7) for patients with prior MIRV exposure. Median progression-free survival was 8.1 months (95% CI 6.4-8.5). Most common treatment-emergent adverse events were nausea (64.8% of patients), fatigue (56.2%), and anemia (47.6%). No keratopathies or grade ≥ 3 neuropathy were observed. At 3 and 4 mg/kg, the rate of grade ≥ 3 treatment-related adverse events was 35.3% and 56.4%, respectively. Treatment discontinuation due to adverse events occurred in 10.5% of patients. The authors conclude that Sofe-M demonstrated a favorable tolerability profile and durable clinical activity in heavily pretreated HGOC patients regardless of FRα expression or prior MIRV. The recommended phase 3 dose for the FRAmework-01 trial is 3 mg/kg.