Avelumab Plus Methotrexate in Low-Risk Gestational Trophoblastic Neoplasia

Key Takeaways

• hCG normalization was observed in 25 of 26 assessable patients, with a median 3.4 months to normalization.
• One dose-limiting event occurred, 6 patients had grade 2 or higher immune-related treatment-related adverse events, no grade 4 or higher events occurred, and hypothyroidism persisted in 1 patient.
• No relapses were reported after a median 41-month follow-up, and 13 of 14 patients with pregnancy intention became pregnant.

In the TROPHAMET study, hCG normalization was achieved in 25 of 26 efficacy-assessable patients receiving first-line avelumab plus methotrexate for low-risk gestational trophoblastic neoplasia. Longer follow-up showed durable remission, with no reported relapses among patients whose hCG levels normalized.

The TROPHAMET trial was an investigator-initiated, open-label, multicenter phase 1/2 study conducted across 9 centers in the French Gestational Trophoblastic Center network. Eligible participants were adult women with low-risk gestational trophoblastic tumors or neoplasia, defined by a FIGO score of 6 or lower, and were treated at academic referral centers. Treatment consisted of avelumab 800 mg intravenously on day 1 plus methotrexate 1 mg/kg intramuscularly on days 1, 3, 5, and 7 of 2-week cycles. Oral folinic acid alternated with methotrexate, and 3 consolidation cycles followed hCG normalization. Phase 1 focused on dose-limiting toxic effects, and phase 2 evaluated serum hCG normalization permitting treatment discontinuation.

Among 27 treated patients, 26 were assessable for efficacy, and hCG normalization occurred in 25, yielding a 96.2% rate with a 90% CI of 85.9% to 97.9%. The median time to hCG normalization was 3.4 months. Enrollment ran from April 14, 2020, to December 5, 2023, and after a median follow-up of 41 months, no relapses were observed.

One dose-limiting toxicity occurred during the safety run-in: grade 3 sepsis related to a central venous catheter infection. Grade 2 or higher immune-related treatment-related adverse events were reported in 6 patients, or 22%, and no grade 4 or higher events occurred. Treatment discontinuation or dose modification of methotrexate, avelumab, or both occurred in 5 patients, or 19%. Two patients developed grade 2 immune-related colitis, prompting a protocol amendment that excluded patients with a first-degree family history of autoimmune disorders. Steroids were used in 4 patients, and all immune-related events resolved except grade 2 hypothyroidism in 1 patient.

Among patients with childbearing potential and pregnancy intention, 13 of 14 became pregnant, or 93%, after pregnancy outcomes were assessed at a median 33 months. The phase 2 portion was single-arm and open-label, the sample was small, and hCG measurements were not centralized, features that may have affected the precision of hCG kinetics.