Aaron Shafer, MD

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.

Konstantin Zakashansky, MD, FACOG

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.