Avelumab safe, effective for treatment of gestational trophoblastic tumors
Avelumab appeared effective and safe for women with gestational trophoblastic tumors resistant to monochemotherapy, according to results of a single-arm phase 2 study presented during the ASCO20 Virtual Scientific Program.
“This study shows that the immunotherapy avelumab [Bavencio; EMD Serono, Pfizer] works against these tumors in patients when they are resistant to single-agent chemotherapy,” Benoit You, MD, PhD, medical oncologist at Centre Hospitalier Lyon-Sud and Lyon Investigational Center for Treatments in Oncology and Hematology in France, said during a presentation. “Although more evidence is needed before changing clinical practice, these are highly promising results, suggesting that avelumab could prevent patients with chemoresistant disease from the severe toxicity of chemotherapy combinations.”
Gestational trophoblastic tumors (GTT) are rare tumors that develop in the placenta during pregnancy. Standard treatment consists of single-agent chemotherapy. Those resistant to monochemotherapy receive historic chemotherapy regimens that are effective but very toxic.
Previous studies have shown constitutive expression of PD-L1 in all GTT subtypes and involvement of HLA-G and natural killer cells in immune-surveillance.
The multicenter trial by You and colleagues included 15 women (median age, 34 years) with GTT who were resistant to monochemotherapy.
The women received avelumab — an anti-PD-L1 monoclonal antibody that triggers cytotoxicity through natural killer cells — dosed at 10 mg/kg twice per week until human chorionic gonadotropin (hCG) normalization, followed by three consolidation cycles.
Over half (53%) of the women had stage I disease, whereas 47% had stage III disease. All had progressed with previous methotrexate or actinomycin-D.
Women received a median eight (range, 2-11) avelumab cycles.
The rate of women with hCG normalization served as the study’s primary endpoint.
Median follow-up was 30 months.
Results showed eight women (53%) had successful hCG normalization after a median nine avelumab cycles. Seven had normalization during the course of treatment and one had normalization after discontinuing avelumab.
No women who responded relapsed, and one woman subsequently had a healthy pregnancy.
Seven women had resistance to avelumab that required a switch to chemotherapy. They all achieved hCG normalization with actinomycin-D or with surgery and polychemotherapy.
Researchers observed no relationship between FIGO score or disease stage and likelihood of success with avelumab.
Tolerability appeared favorable, with 93% of women developing drug-related grade 1 to grade 2 toxicities. The most common toxicities included fatigue (33%), nausea and vomiting (33%), infusion-related reactions (27%), thyroid disorder (20%), dry eyes (20%) and diarrhea (20%). One woman experienced grade 3 uterus bleeding.
“Avelumab is a new therapeutic option in GTT resistant to monochemotherapy,” You said. “An ongoing phase 1/phase 2 trial is now looking at this in the first-line setting.” – by John DeRosier
Reference:
You B, et al. Abstract LBA6008. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
Disclosures: You reports consultant/advisory roles with and travel accommodations from AstraZeneca, Bayer and Roche/Genentech; consultant/advisory roles with Amgen, Clovis Oncology, ECS Progastrin, GlaxoSmithKline, LEK Consulting, Novartis and Tesaro; and research funding to his institution from Merck Serono and Roche/Genentech. Please see the abstract for all other researchers’ relevant financial disclosures.
Perspective
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This study by You and colleagues is a very exciting report on the use of immunotherapy for the treatment of gestational trophoblastic neoplasia. In preclinical studies, GTN has shown high expression of PD-L1 which often is a biomarker for response to checkpoint inhibitor therapy. For that reason, there has been a lot of excitement that these tumors might be good targets for immunotherapies.
The preliminary results of TROPHIMMUN showed that, among patients who failed initial therapy, more than half were cured with avelumab, a PD-L1 inhibitor. The agent was well-tolerated overall, with mostly manageable grade 1 or grade 2 toxicity.
Caution should be taken, though, before widely adopting immunotherapy for GTN. These are highly curable malignancies with current chemotherapy regimens. Even patients with stage IV disease have a greater than 80% chance of cure. Additionally, checkpoint inhibitor therapies can have severe, long-lasting pulmonary, gastrointestinal and endocrinologic side effects that may have not been seen in this study because of the small number of patients (n = 15). Because of this, larger phase 2 or phase 3 studies are needed before checkpoint inhibitors can be considered as upfront treatment of a potentially curable disease.
Additionally, it would be important to identify possible biomarkers to help identify those patients who would respond to checkpoint inhibition. PD-L1 positivity is so prevalent in GTN, yet only 50% of these patients responded to avelumab. At this time, it is probably best to use checkpoint inhibitors for GTN on clinical trials. Hopefully, as the data from TROPHIMMUN is fully analyzed and other studies have more data, exactly when and where to use checkpoint inhibition in GTN can be better understood.
Perspective
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In preclinical models, loss of PD-L1 signaling results in fetal rejection. At the same time, multiple previous studies showed gestational trophoblastic neoplasias (GTN) strongly express PD-L1, suggesting the ligand is involved in tumor-immune evasion. Thus, targeting the interaction of PD-1/PD-L1 could be an effective therapeutic strategy for women with chemoresistant GTN.
A number of published reports have proved the effectiveness of this approach using the PD-1 inhibitor pembrolizumab (Keytruda, Merck). Therefore, it is not surprising that avelumab — a monoclonal antibody that targets the PD-1 ligand — would work similarly. This phase 2 study provides an important contribution proving the concept of PD-L1 targeting for women with GTN.
At the same time, this is a very small study. GTN is a highly curable disease, with primary remission rates after single-agent therapy ranging from 49% to 93% depending on the regimen used. Therefore, interpreting these new data requires detailed information on which primary therapy women in this cohort received.
Only about 10% of women with GTN who are eligible for treatment with a single-agent chemotherapeutic agent will require multiagent chemotherapy to achieve remission. Cure rates for women who receive multiagent chemotherapy are close to 100%. In that context, the 53% remission rate seen in this nonrandomized study of women with low risk does not seem acceptable. More information is needed to properly evaluate this approach and determine whether there may be some promising way to incorporate avelumab into the GTN management scheme, given its demonstrable monotherapeutic efficacy and favorable adverse-event profile.
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You B, et al. Abstract LBA6008. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.