Avelumab Offers Post-Chemo Hope to Women With Rare Tumor

Liam Davenport

May 29, 2020

Some women with gestational trophoblastic tumors (GTT), a rare type of cancer that develops in the placenta during pregnancy, respond to immunotherapy when they are resistant to single chemotherapy, French researchers report.  

The finding comes from the TROPHIMMUN phase 2 trial with the anti-programmed death ligand 1 (PD-L1) drug avelumab (Bavencio, Merck/Pfizer).

The study will be presented at the plenary session of the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting, held virtually because of the pandemic.

A glimpse of the results was given at a pre-meeting presscast by lead author Benoit You, MD, PhD, Lyon Investigational Center for Treatments in Oncology and Hematology, France.

The trial, conducted in collaboration with the French Gestational Trophoblastic Disease Center, involved 15 women with GTT who were given the immunotherapy after progression on single-agent chemotherapy.

Eight of the 15 women (53%) achieved normalization of human chorionic gonadotropin (hCG) levels, which is used as a biomarker of activity in GTT.

Moreover, one of these women went on to have a normal pregnancy 1 year after stopping avelumab and delivered a healthy baby.

This is the first report of a normal pregnancy after having a tumor cured with immunotherapy, which is "reassuring" in terms of the impact of the treatment on fertility, You commented.

"This proof-of-concept study shows that treatment with the immunotherapy avelumab works against these tumors when resistance to single-agent chemotherapy develops," You said.

He added that "drug tolerance was much better with avelumab than with chemotherapy."

Although You cautioned that "more evidence is needed before changing clinical practice," he said the results are "highly promising" and suggest the drug could prevent patients with chemoresistant disease experiencing the "severe toxicity of chemotherapy combinations."

Indeed, during the press conference he estimated that, in their study, one third of patients could "escape from toxic polychemotherapy because they were successfully treated with avelumab."

Howard A. Burris III, MD, ASCO president, commented that, "given these promising results, as well as the reduced toxicity compared with chemotherapy, avelumab merits additional investigation as a potential treatment for these patients."

Approached for comment, Konstantin Zakashansky, MD, director of gynecologic oncology at Mount Sinai West, New York City, said it was "not surprising" that avelumab was effective as there have been a number of studies involving the PD-1 inhibitor pembrolizumab (Keytruda, Merck).

He would alsolike to see "detailed information on which primary therapy" these patients received, as "only about 10%" of patients eligible for single-agent chemotherapy will need polychemotherapy to achieve remission.

Also, as the response rates with polychemotherapy are "close to 100%...the 53% remission rates seen in this nonrandomized study of low-risk patients does not seem acceptable."

He said "more information is needed" to evaluate the approach and determine whether "there may be some promising way" to include avelumab into the GTT management scheme, "given its demonstrable monotherapeutic efficacy and favorable side effect profile."

Zakashansky added that the current analysis "provides an important contribution, proving the concept of PD-L1 targeting" in patients with GTT.

Study Details

GTTs are characterized by high blood levels of hCG during disease activity, You explained.

In low-risk disease, the preferred approach is single-agent chemotherapy, and polychemotherapy is used in high-risk disease. Although polychemotherapy is associated with "a high cure, it is also associated with significant toxicity," You emphasized.

Moreover, the majority of tumors relapse within 6 months of treatment discontinuation.

It is also known, however, that PD-L1 is overexpressed in GTT, offering "a strong rationale" for assessing avelumab immunotherapy in these patients.

You explained that such overexpression may be necessary in pregnancy to provide "a kind of immune tolerance" for the baby, which is half-derived from the father's genes. Conversely, this may also allow GTT to be tolerated.

For the study, the team recruited patients with GTT resistant to single-agent chemotherapy. They gave participants intravenous avelumab every 2 weeks until normalization of hCG levels, followed by three additional cycles.

Of 17 patients enrolled over 2 years, 15 were treated and could be assessed. The median age was 34 years, and 47% had metastatic stage 3 disease.

All patients had progressed on methotrexate, with one having also received actinomycin-D.

At 29 months of follow-up, eight (53%) of the women had achieved normalization of hCG levels, allowing the drug to be discontinued.

As they did not subsequently relapse, despite no longer receiving avelumab, they could be considered "potentially cured," You commented.

The remaining seven (47%) patients were resistant to avelumab and were managed with chemotherapy, with or without surgery.

You reported that the tolerability of the drug was "very satisfactory," with no dose reductions or delays due to toxicity.

Adverse events, including fatigue (33%), nausea/vomiting (33%), and infusion-related reactions (27%), were mild or moderate, with 93% of patients having grade 1/2 events. There were no severe adverse events, and no patient has died.

However, he noted that three patients developed thyroid disorders following treatment.

During the press conference, You said the investigators will conduct translational research to better understand why some patients responded well and others did not.

They are also currently conducting a phase 1/2 trial, TROPHAMET, to assess the efficacy of methotrexate and avelumab in the first-line setting, before resistance can occur.

"With methotrexate, we estimate that we can cure 70% of patients," You said. "What we expect is that, with the combination with avelumab, we will be able to cure 95% of patients."

The study was funded by Merck Serono/Pfizer. You has reported holding a consulting or advisory role for Amgen, AstraZeneca, Bayer, Clovis Oncology, ECS progastrin, GSK, LEK, Novartis, Roche/Genentech, Tesaro; receiving research funding from Merck Serono, Roche/Genentech; and receiving reimbursement for travel, accommodations, and expenses from AstraZeneca, Bayer, BMS, MSD Oncology, and Roche/Genentech. Burris III has reported employment by HCA Healthcare/Sarah Cannon; holding a consulting or advisory role for AstraZeneca, Forma Therapeutics, Celgene, Incyte; and receiving research funding from Roche/Genentech, Bristol-Myers Squibb, Incyte, AstraZeneca, MedImmune, MacroGenics, Novartis, Boehringer Ingelheim, Lilly, Seattle Genetics, Merck, Agios, Jounce Therapeutics, Moderna Therapeutics, CytomX Therapeutics, GSK, Verastem, Tesaro, Millennium, BioMed Valley Discoveries, TG Therapeutics, Vertex, eFFECTOR Therapeutics, Janssen, Gilead Sciences, BioAtla, CicloMed, Harpoon Therapeutics, Arch, Arvinas, Revolution Medicines, Array BioPharma, Bayer, BIND, Kymab, miRNA Therapeutics, Pfizer Expert Testimony, and Novartis.

ASCO 2020. Abstract LBA6008.

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