Avelumab Demonstrates Favorable Activity in Gestational Trophoblastic Tumors

Benoit You, MD, PhD

Avelumab (Bavencio) could represent a new standard of care as the first immunotherapy to be tested in patients with single-agent chemotherapy-resistant gestational trophoblastic tumors, according to results from the phase 2 TROPHIMMUN study, which demonstrated favorable human chorionic gonadotrophin (hCG) normalization and safety in this patient population.

In the trial, patients with resistance to methotrexate and/or actinomycin-D chemotherapy were enrolled in cohort A, and those with resistance to multiagent chemotherapy regimens were enrolled in cohort B.

Successful hCG normalization served as the primary end point of the trial, and secondary end points included safety, resistance-free survival (RFS), and overall survival (OS).

Eligible patients received 10 mg/kg of intravenous avelumab every 2 weeks until hCG normalization, followed by an additional 3 cycles of treatment.

At a median follow-up of 25 months, 8 patients (53.3%) experienced hCG normalization following a median of 9 cycles of therapy. The majority of patients (87.5%; n = 7) experienced hCG normalization during treatment, and 12.5% (n = 1) experienced hCG normalization after treatment discontinuation. Following normalization, and at 29 months of follow-up, no patients had relapsed.

Regarding the secondary end points of the trial, the median RFS was not reached. However, the 4-month RFS rate was 73.3% (95% CI, 43.6%-89.0%) and the OS rate was 100%.

Adverse effects (AEs), the most common of which included fatigue (33.3%), nausea/vomiting (33.3%), and infusion-related reactions (26.7%), were reported in 14 patients (93.3%) and were mainly grade 1/2. No grade 3 or greater AEs were reported. Notably, no dose reduction or treatment delay was required for toxicity.

Moreover, 1 patient who was cured with avelumab was able to carry out a normal pregnancy, representing the first report of a normal pregnancy after successful treatment with immunotherapy, according lead study author, Benoit You, MD, PhD.

“The next step is to see if we can [further demonstrate the utility of this agent] for patients, especially for those who are resistant to single-agent chemotherapy and who should be treated with polychemotherapy,” said You. “Perhaps we can prevent these patients from experiencing the toxicity of chemotherapy [by using] avelumab.”

In an interview with OncLive, You, an academic staff physician in the Medical Oncology Department of Lyon University Hospital, discussed the need for novel and well-tolerated agents in chemotherapy-resistant gestational trophoblastic tumors and ongoing research efforts designed to bring avelumab to the forefront of the treatment paradigm.

OncLive: Could you discuss the current prognosis of patients with gestational trophoblastic tumors that are resistant to chemotherapy?

You: Gestational trophoblastic tumors are rare tumors that are essentially treated with chemotherapy. We treat patients who develop resistance to single-agent chemotherapy with another single-agent chemotherapy. In Europe, usually the first-line chemotherapy is methotrexate, and the second-line chemotherapy is actinomycin-D; the efficacy is about 70%. Approximately 70% of patients have hCG normalization.

For patients who develop resistance to methotrexate and who have high hCG or who are resistant to both single-agent chemotherapies, the standard treatment is polychemotherapy, and the main regimen is a macroregimen, which is very toxic. It’s probably 1 of the most toxic regimens, so there’s really a need for an innovative approach to treat these patients while avoiding toxic polychemotherapy.

What is the basis for evaluating avelumab in this setting?

There is a strong rationale for immunotherapy [in this setting]. We know that the immune system [plays an] important [role] in the immune [microenvironment] of gestational trophoblastic tumors. We have seen cases of spontaneous regression. We also know that all these tumors overexpress PD-L1, and there was a case report of efficacy with pembrolizumab (Keytruda).

Avelumab is very interesting [in this setting] because gestational trophoblastic tumors are

infiltrated by natural killer (NK) cells; that means that there is an additional immunological effect with avelumab that induces antibody-dependent cell cytotoxicity, which we know is related to NK cells. This is why we believe avelumab is a very good immunotherapy for patients with gestational trophoblastic tumors.

Could you discuss the TROPHIMMUN trial? How was it designed?

TROPHIMMUN is a phase 2 trial that was conducted in partnership with the French Gestational Trophoblastic Tumor center. There is a big network of centers in France, and this is an academic phase 2 trial that was sponsored by Lyon University Hospital.

In the trial, we [set out to assess] the efficacy of avelumab, so we enrolled patients with resistance to single-agent chemotherapy. Patients received avelumab at 10 mg/kg every 2 weeks. We evaluated hCG normalization and this was the primary efficacy end point. Patients were treated with avelumab until normalization of serum hCG and for 3 additional cycles, after which avelumab was stopped. We evaluated how many patients did not relapse after stopping avelumab.

What were the results that were reported from cohort A?

We enrolled 15 patients, 8 of which experienced hCG normalization. Once we stopped avelumab, no patients relapsed with 25 months of follow-up. Patients who had successful treatment [were relapsed free] up to 29 months [after stopping avelumab]. One patient who was successfully treated with avelumab developed a normal pregnancy 1 year after discontinuing avelumab and [achievement of] normal hCG. This woman had a normal pregnancy and delivered a normal baby. This was the first report of a normal pregnancy after successful treatment with immunotherapy. The 7 remaining patients who were resistant to avelumab were successfully treated with chemotherapy with or without surgery.

How was the agent tolerated?

[The safety profile] was excellent. Most patients experienced AEs, but the vast majority were grade 1, sometimes grade 2. No grade 3/4 AEs were reported, and the toxicity [profile] was much better than what we see with chemotherapy.

What are the next steps for this research?

One question is, can we avoid the recurrence of resistance in first-line treatment? We are now conducting a phase 1/2 trial called TROPHAMET, where patients are treated with methotrexate plus avelumab in the first-line setting, before the development of resistance. We feel that we can cure 95% of patients with this combination, so we can avoid resistance and the need for toxic polychemotherapy.

Is there anything else that you want to emphasize?

We are used to saying it’s impossible to conduct trials with innovative agents for rare tumors. However, we showed the feasibility of [running] a trial in such a rare tumor. We showed that with a well-organized, national gestational trophoblastic center, we can could enroll 15 patients in 2 years.

Reference

You B, Bolze PA, Lotz JP, et al. Avelumab in patients with gestational trophoblastic tumors resistant to monotherapy: final outcomes of TROPHIMMUN phase II trial, cohort A. J Clin Oncol. 2020;38(suppl 18):LBA6008. doi:10.1200/JCO.2020.38.18_suppl.LBA6008