"It is a proof of concept of the efficacy of an immunotherapy in [patients with] gestational trophoblastic tumors , confirming the rationale we had."
Frontline avelumab (Bavencio) has potential to treat patients with gestational trophoblastic tumors (GTTs) that resist chemotherapy. According to finding from a cohort of the ongoing phase 2 TROPIMMUN trial, avelumab is the first immunotherapy to demonstrate efficacy in this patient population.
“We demonstrate the feasibility of a trial with an innovative treatment in such a rare tumor, thanks to the organization of the network of French gestational trophoblastic center,” Benoit You, MD, PhD, told Targeted Oncology. “It is a proof of concept of the efficacy of an immunotherapy in [patients with] GTT, confirming the rationale we had.”
In a presentation of the study findings in a press program ahead of the 2020 American Society of Oncology (ASCO) Virtual Scientific Program, You, an academic staff physician in the Medical Oncology Department of Lyon University Hospital in France, first explained the rarity of GTTs. These tumors develop in the placenta during pregnancy and occur predominantly in young patients. Active GTT is characterized by its ability to form high levels of the hCG hormone in the blood.
Chemotherapy is included among standard treatment options for this disease, but with the high cure rate of chemotherapy comes substantial toxicity. The toxicity constitutes the need for new therapies. Avelumab’s mechanism of action of activating the immune system against tumor cells, provides strong rationale for the treatment of GTT.
Cohort A of the TROPIMMUN trial included patients with resistance to single-agent chemotherapy. The other cohort of the study included patients with resistance to combination chemotherapy. Avelumab 10 mg/kg was administered to these participants every 2 weeks with the primary goal of evaluating the efficacy of the drug, which was defined by normalization of hCG levels in the blood.
Of the 17 patients enrolled in the trial over a 2-year period, 15 patients were treated with avelumab and were included in the efficacy analysis. The results showed that avelumab successfully normalized hCG levels in 53% of patients (n = 8), allowing those subjects to discontinue treatment. Following the discontinuation of avelumab, no subsequent relapse was observed, which signaled to the investigators that avelumab potentially led to cure among the cohort A responders.
The remaining 47% of patients (n = 7) developed resistance to avelumab, which was managed with chemotherapy with or without surgery. As of the data cutoff date, there have been no patient deaths.
Among the 8 avelumab responders, there was 1 patient who had a normal pregnancy and delivered a healthy baby 1 year after discontinuing treatment with avelumab. This event marks the first report of a patient having a normal pregnancy after treatment with an immunotherapeutic agent. You noted that this case provided encouraging proof of concept of the idea that immunotherapy preserves fertility.
Regarding safety, avelumab demonstrated very satisfactory tolerability with only mild to moderate adverse events (AEs) reported. Some AEs observed with patients were fatigue, nausea/vomiting, infusion-related reaction, dry eye, and diarrhea. There were no serious AEs reported, but 3 patients did experience immunological effects in terms of thyroid disorders. There were also no dose reductions or delays needed due to toxicity.
Data from TROPIMMUN show that with 27 months of follow-up, roughly 50% of patients had hCG normalization without relapse following treatment with avelumab, making avelumab a new therapeutic option for treatment of patients with GTT who are resistant to single-agent chemotherapy. The TROPIMMUN study is ongoing with plans to enroll 29 patients with GTT.
The key secondary end points being explored in the study include resistance-free survival, progression-free survival, overall survival, and overall response rate.
When asked about future research with avelumab as treatment of GTT, You mentioned a similar study that is currently ongoing: “No randomized phase 2 or phase 3 trial is planned. Indeed, a recent phase 3 trial [GOG174] was stopped prematurely due to insufficient recruitment in first-line setting and there is no possibility for a randomized trial in second-line setting. However, we are conducting another phase 1/2 trial called TROPHAMET [NCT04396223] meant to assess the safety and efficacy of the combination methotrexate plus avelumab in first-line setting before the occurrence of resistance. We would like to cure 95% of patients.”
You B, Bolze PA, Lotz JP, et al. Avelumab in patients with gestational trophoblastic tumors resistant to monochemotherapy: Final outcomes of TROPHIMMUN phase II trial, cohort A. J Clin Oncol. 2020;38(suppl; abstr LBA6008). doi:10.1200/JCO.2020.38.15_suppl.LBA6008