Multicenter phase 1-2 trial of first-line avelumab plus methotrexate for low-risk gestational trophoblastic tumors

Low-risk gestational trophoblastic tumors (GTT; FIGO score ≤ 6) are typically treated with single-agent chemotherapy, achieving cure rates of approximately 70%. Avelumab (anti-PD-L1) has demonstrated activity in chemotherapy-resistant GTT. The multicenter phase 1-2 TROPHAMET trial in France evaluated the combination of avelumab and methotrexate as first-line treatment for low-risk GTT. Patients received avelumab (800 mg intravenously on day 1) and methotrexate (1 mg/kg intramuscularly on days 1, 3, and 7 alternating with oral folinic acid) in 2-week cylces until normalization of human chorionic gonadotropin (hCG) level ; and followed by 3 consolidation cycles. Phase 1 primary endpoint was dose-limiting toxic effects (DLTs); phase 2 primary endpoint was the rate of serum hCG normalization permitting treatment discontinuation. Of 27 female patients treated (median age 35 years; range 20-50), 26 were evaluable for efficacy. Eight patients (31%) had FIGO scores 1-2; eight patients (31%) had FIGO scores 3-4, and ten patients (38%) had FIGO scores 5-6. The treatment regimen demonstrated acceptable safety, with 1 DLT (grade 3 sepsis on central venous catheter) and no grade 4 or 5 events. The rate of successful hCG normalization was 96.2% (90% CI 85.9-97.9). After median follow-up of 41 months (IQR 37-45) no relapses were observed. Among patients with pregnancy intention, 13 of 14 (93%) achieved pregnancy. The authors conclude that avelumab plus methotrexate demonstrated a manageable safety profile and high efficacy as first-line treatment for low-risk GTT, with durable responses and preserved fertility in a high percentage of patients.