Avelumab Plus Methotrexate for Gestational Trophoblastic Tumors: The TROPHAMET Phase 1/2 Nonrandomized Clinical Trial.
In a multicenter, nonrandomized phase 1/2 trial, first-line avelumab plus methotrexate produced serum hCG normalization in 96.2% of 26 assessable patients with low-risk gestational trophoblastic tumors, with manageable reported toxicity, no relapses at a median 41-month follow-up, and pregnancies in 13 of 14 patients who intended pregnancy.
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In a multicenter, nonrandomized phase 1/2 trial, first-line avelumab plus methotrexate produced serum hCG normalization in 96.2% of 26 assessable patients with low-risk gestational trophoblastic tumors, with manageable reported toxicity, no relapses at a median 41-month follow-up, and pregnancies in 13 of 14 patients who intended pregnancy.
Research significance
The trial provides preliminary human evidence that adding PD-L1 blockade to methotrexate can achieve durable hCG normalization while preserving fertility in low-risk GTT; it is an inference, not yet comparative evidence, that this combination improves cure rates or is especially beneficial for patients at higher risk of methotrexate resistance.
Source abstract
IMPORTANCE: Low-risk gestational trophoblastic tumors (GTT; International Federation of Gynecology and Obstetrics [FIGO] score ≤6) are typically treated with single-agent chemotherapy, achieving cure rates of approximately 70%. Avelumab (anti-programmed cell death 1 ligand 1 monoclonal antibody) has demonstrated activity in chemotherapy-resistant GTT, supporting investigation in earlier treatment settings. OBJECTIVE: To evaluate the safety and efficacy of avelumab combined with methotrexate as first-line therapy in patients with low-risk GTT. DESIGN, SETTING, AND PARTICIPANTS: TROPHAMET (Avelumab and Methotrexate in Low-Risk Gestational Trophoblastic Neoplasias as First-Line Treatment) was a multicenter, phase 1/2 nonrandomized clinical trial of patients with low-risk GTT (FIGO score ≤6) treated at academic referral centers. The study period was from April 14, 2020, to December 5, 2023, with a follow-up of 41 months. Data were analyzed from December 20, 2024, to July 3, 2025. INTERVENTIONS: Avelumab, 800 mg, intravenously on day 1 plus methotrexate, 1 mg/kg, intramuscularly on days 1, 3, 5, and 7 alternating with oral folinic acid in 2-week cycles until normalization of human chorionic gonadotropin (hCG) level; and followed by 3 consolidation cycles. MAIN OUTCOMES AND MEASURES: Phase 1 primary end point was dose-limiting toxic effects (DLTs); phase 2 primary end point was the rate of serum hCG normalization permitting treatment discontinuation. RESULTS: Of 27 female patients treated (median [range] age, 35 [20-50] years), 26 were assessable for efficacy. Eight patients (31%) had FIGO scores of 1 to 2; 8 patients (31%) had scores of 3 to 4; and 10 patients (38%) had scores of 5 to 6. The treatment regimen demonstrated acceptable safety: 1 DLT occurred (grade 3 sepsis on central venous catheter); immune- and treatment-related adverse events of grade 2 or higher occurred in 6 patients (22%), all of which fully resolved except for 1 case of grade 2 dysthyroidism; and there were no grade 4 or higher events. The rate of successful hCG normalization was 96.2% (90% CI, 85.9%-97.9%). After a median (IQR) follow-up of 41 (37-45) months, no relapses were observed. Among patients with childbearing potential and pregnancy intention, 13 of 14 achieved pregnancy (93%). CONCLUSIONS AND RELEVANCE: In this nonrandomized clinical trial, avelumab combined with methotrexate demonstrated a manageable safety profile and high efficacy in low-risk GTT in more than 95% of patients, with durable responses and preserved fertility. This combination may represent a promising first-line strategy warranting evaluation in comparative studies, particularly for patients at higher risk of chemoresistance. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04396223.