1. Fuerst, Mark L.

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Immunotherapy with avelumab may be a new therapeutic option for patients with a rare uterine cancer, gestational trophoblastic tumors (GTT), who are resistant to single-agent chemotherapy. This small phase II trial, the first to explore the use of immunotherapy in GTT patients, found avelumab therapy potentially cured 8 out of 15 women with the cancer who were resistant to single-agent chemotherapy.

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GTT are rare tumors that develop in the placenta during pregnancy and mainly involve young patients. They are characterized by high levels of human chorionic gonadotropin (hCG) as long as the disease is active. The hormone hCG is used as biomarker for the disease.


"Standard treatments rely on chemotherapy, either as single-agent in low-risk disease or polychemotherapy in high-risk disease. Chemotherapy is associated with a high cure rate, but it is also associated with significant toxicity," said lead author Benoit You, MD, PhD, who is a medical oncologist at Centre Hospitalier Lyon-Sud and Lyon Investigational Center for Treatments in Oncology and Hematology in France, at a press briefing before the 2020 ASCO Annual Meeting. "There is a need for innovative treatments in GTT patients."


A strong rationale exists for assessing avelumab, a checkpoint inhibitor that blocks the programmed death-ligand 1 (PD-L1) protein on cancer cells that helps them hide from the body's immune system. GTT overexpresses PD-L1, making avelumab a reasonable alternative for these tumors.


Study Results

This multi-site study included 15 patients, median age 34 years, with GTT that was resistant to mono-chemotherapy; 47 percent were stage III with metastases (Abstract LBA 6008). All patients had progressed on treatment with methotrexate; one patient had also progressed on actinomycin D. The patients received avelumab until hCG levels returned to normal, followed by three additional cycles.


You and his colleagues found that 8 of 15 patients (53%) with GTT had no sign of disease relapse at 29 months follow-up. If disease has not relapsed after 12 months and monitoring of hCG has concluded, researchers consider the patient cured. He noted that the majority of trophoblastic tumors relapse within 6 months, if not within the 12 months after treatment discontinuation.


Seven patients achieved normal levels of hCG during treatment with avelumab, and one had normalization after discontinuation of avelumab. Among those who did not relapse, normal levels of hCG have been maintained. Avelumab resistance was observed in the remaining seven patients (47%), requiring chemotherapy with actinomycin D or polychemotherapy with or without surgery. No patient has died so far.


"We had one happy event," said You. One patient who normalized blood hCG delivered a healthy baby 1 year after discontinuing avelumab. "This is the first report of a normal pregnancy in a patient cured from her tumor with an immunotherapy. This provides reassuring data for the impact of immunotherapy on fertility," he noted.


The adverse events were generally mild or moderate, with 93 percent of patients having grade 1 or 2 drug-related adverse events. Fatigue was the most common (33% of patients), followed by nausea and vomiting (33%), and infusion-related reactions (27%).


"Drug tolerance was much better with avelumab than with chemotherapy," said You. There were no dose reductions or dose delays due to toxicity, and no severe adverse events. Three patients had immunologic effects consisting of thyroid disorders.


"This proof-of-concept study shows that treatment with the immunotherapy avelumab works against these tumors when resistance to single-agent chemotherapy develops," You explained. "Although more evidence is needed before changing clinical practice, these are highly promising results, suggesting that avelumab could prevent patients with chemo-resistant disease from the severe toxicity of chemotherapy combinations."


In conclusion, You said: "We provide data about efficacy of avelumab in GTT patients resistant to single-agent chemotherapy. About 50 percent of patients had hCG normalization without any relapse despite treatment discontinuation with 29 months of follow-up, meaning these patients are likely cured. Tolerability was excellent. Avelumab is a new therapeutic option for GTT patients who are resistant to single-agent chemotherapy."


The researchers are now conducting a similar trial in the first-line setting. The ongoing TROPHAMET trial is assessing the efficacy of methotrexate plus avelumab. "The idea is to avoid the resistance to chemotherapy, and the objective is to cure 95 percent of patients. With methotrexate alone, we estimate we cure about 70 percent," he said.


ASCO President Howard A. Burris III, MD, President and Chief Medical Officer of Sarah Cannon Research Institute, commented: "Given the number of patients with disease who did not relapse, and reduced toxicity compared with standard single-agent chemotherapy, avelumab merits additional investigation."


ASCO Chief Medical Officer, Richard Schilsky, MD, was less sanguine about the use of first-line immunotherapy for these patients. "This study suggests that at least half of them may be cured by giving immunotherapy subsequently to methotrexate. To expose all the patients to an expensive immunotherapy upfront to benefit the very small proportion who won't be cured otherwise is a big leap in the wrong direction."


He pointed out that methotrexate is "highly effective," with a cure rate of about 70 percent of GTT patients, and costs "practically nothing."


Mark L. Fuerst is a contributing writer.