Immunotherapy Potentially Curative in Rare Placenta Cancer

A majority of women with gestational trophoblastic tumors (GTTs) who had failed on single-agent chemotherapy showed no evidence of disease after treatment with avelumab (Bavencio), a small phase II study found.

Eight of 15 women (53%) with the rare gynecologic cancer had normalization of their human chorionic gonadotropin (hCG) levels following treatment with the PD-L1-directed immune checkpoint inhibitor, and none relapsed at a median follow-up of 29 months, reported Benoit You, MD, PhD, of Lyon University Hospital in France.

"These patients are likely to be cured," he said during an American Society of Clinical Oncology (ASCO) annual meeting press briefing.

GTTs are rare tumors that develop in the placenta during pregnancy (roughly one in every 10,000), he explained, and the disease is characterized by high levels of hCG in the blood. Standard treatment consists of single-agent chemotherapy for low-risk disease and multi-agent chemotherapy for high-risk tumors. Patients are typically considered cured if their hCG levels normalize and they don't relapse within a year.

But while chemotherapy is associated with high cure rates, it is also associated with significant toxicity. Expression of PD-L1, often used as a biomarker for response to PD-1/L1 immune checkpoint inhibitors, is highly expressed in GTTs, which provided the rationale for the trial, said You.

One of the eight women who was successfully treated with avelumab went on to have a normal pregnancy and delivered a healthy baby.

"This provides reassuring data regarding the impact of immunotherapy on fertility," said You.

While an ongoing phase I/II trial is now underway to test chemotherapy plus avelumab as initial treatment for women with newly diagnosed GTTs, ASCO's chief medical officer, Richard Schilsky, MD, sounded a word of caution against such an approach.

"Of the women who are not cured with methotrexate, this study suggests that at least half of them may be cured by giving immunotherapy subsequently to the methotrexate," he said. "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 -- I think -- in the wrong direction."

Schilsky pointed out that methotrexate, which is associated with cure rates in the range of 70%, costs "practically nothing."

From 2016 to 2019, the 15 women in cohort A of the TROPHIMMUN trial received intravenous avelumab (10 mg/kg every 2 weeks), with the therapy administered until hCG normalization, followed by three cycles of consolidation (median eight cycles in all). Patients enrolled had either stage I (53%) or stage III disease (47%), and had all progressed on single-agent methotrexate or actinomycin-D (one patient).

Seven of the responding patients had hCG normalization during avelumab treatment and one after discontinuation. Patients who were resistant to avelumab went on to have normalized hCG with subsequent chemotherapy -- 42% received actinomycin-D and 57% received multi-agent chemotherapy plus surgery.

Tolerability with avelumab was excellent, said You, with no dose reductions or treatment delays for toxicity. In all, 93% of patients experienced a drug-related grade 1/2 adverse event, including fatigue in 33%, nausea or vomiting in 33%, infusion-related reactions in 27%, and thyroid disorder, dry eyes, and diarrhea in 20% each. One grade 3 event was reported (bleeding of the uterus), but was deemed unrelated to therapy.

Cohort B of the multicenter trial is examining avelumab in GTT patients with resistance to multi-agent chemotherapy.

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