At the 2024 ESMO annual meeting, Benoit You from the Lyon Sud Hospital Center, France, presented the results of the phase I/II TROPHAMET trial (abstract number 711O) in the preferred oral report session and was interviewed by Oncology Frontier.

Oncology Frontier：TROPHAMET is a phase I/II trial evaluating Avelumab + methotrexate for first-line treatment of low-risk gestational trophoblastic tumors. Can you talk about the research background and main findings of TROPHAMET?

Dr. You: Gestational trophoblastic tumors (GTT) are rare tumors developed from the placenta in the context of pregnancy. Standard first-line treatment relies on methotrexate which is known to be associated with hCG normalization at the rate of about 70%. In the literature, there is plenty of evidence suggesting that immunotherapy is active in these cases, so we decided to conduct a trial to show that the combination of the PD-L1 monoclonal antibody, avelumab, combined with methotrexate could increase the hCG normalization rate to >90%. To achieve that aim, we designed a French multicenter trial and enrolled 26 patients. Out of 26 assessable patients, 25 patient experienced hCG normalization. With more than two years follow-up, none of the patients have relapsed, meaning that these patients are likely to be cured. In other words, the GTT cure rate is close to 96%, which is far above our expectations.

Oncology Frontier：Could you talk about the adverse events that occurred in the TROPHAMET study and how to manage the side effects of Avelumab and methotrexate?

Dr. You: The tolerability of methotrexate plus avelumab was excellent. Most side effects were grade 1 or grade 2. No grade 4 or 5 were observed. A few patients had grade 3 adverse events including two patients with stomatitis (well known with methotrexate), two patients had immune-related hepatitis, and one patient had a catheter infection. There were, of course, immune-related adverse events, but all of them resolved, except for one patient who had dysthyroidism.

Oncology Frontier：PD-1/PD-L1 inhibitors have been proven to be an effective treatment method for gestational trophoblastic tumors. Can the combination of PD-1/PD-L1 inhibitors and chemotherapy play a greater role in high-risk and low-risk gestational trophoblastic tumors?

Dr. You: Immunotherapy with anti-PD-1/anti-PD-L1 monoclonal antibodies has activity in both high-risk and low-risk disease. Based on the result of the TROPHAMET trial and the previously published TROPHIMMUN trial, we know that avelumab is active in patients with low-risk gestational trophoblastic tumors. Regarding high-risk disease, there are several case reports showing the efficacy of pembrolizumab. Moreover, there is a Chinese phase II trial with camrelizumab plus apatinib showing a complete response rate of 50% in patients with chemotherapy resistant disease.

Oncology Frontier：Many important trial results in gynecologic oncology were announced at ESMO 2024. Can you talk about the data that impressed you?

Dr. You: I was very impressed with the outcome of KEYNOTE-A18 that assessed the efficacy of pembrolizumab combined with chemoradiation in patients with localized or locally advanced cervical cancer at high risk of recurrence. Standard treatment relies on chemoradiation, and in the trial, the investigators compared chemoradiation with or without pembrolizumab, followed by pembrolizumab for two years. We already knew the addition of pembrolizumab to chemoradiation would increase disease control by increasing progression-free survival by 10-11% at two years, but we now have the results for overall survival, and we could see that there was an improvement in overall survival by about 8% at three years. This is a great improvement, because we can contribute to increasing the rate of cure of cervical cancer.

Reference

1.You B, et al. Avelumab + methotrexate to eradicate low-risk gestational trophoblastic tumors in first-line setting: TROPHAMET phase I/II trial. ESMO Congress 2024, Abstract 711O.