Gestational trophoblastic disease (GTD) is a heterogeneous group of rare pregnancy-related tumors that arise from placental trophoblasts, and are typically diagnosed in women under 20 years and over 40 years old. While the majority of GTD are benign, malignant forms can develop including invasive moles, choriocarcinoma, placental-site trophoblastic tumors and epithelioid trophoblastic tumors. Around 95% of malignant forms of GTD are low-risk gestational trophoblastic tumors (GTT). These are usually treated with single-agent chemotherapy, an 8-day methotrexate (MTX) protocol is commonly used. However, around 25-69% of patients experience MTX resistance, and are subsequently treated with actinomycin D (approximately 70% cure rate) or EMA-CO regimens (etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine), which have a 100% cure rate but with significant risk of long-term toxicities. There is an unmet need for alternative and less toxic therapies for these young women. The rationale for investigating anti-programmed death ligand (PD-L1) therapy in patients with low-risk GTT is based on evidence that PD-L1 is constitutively expressed in all GTD premalignant and malignant trophoblast subtypes, independent of Federation of Gynecology and Obstetrics (FIGO) scores, chemoresistance or fatal outcomes. This suggests that PD-L1 may have a key role in immune tolerance in GTD and inhibition of the PD-L1 pathway could potentially reverse trophoblast tolerance. 

The open-label, multi-cohort, ongoing phase II TROPHIMMUN trial is investigating the efficacy and tolerability of the anti-PD-L1 monoclonal antibody, avelumab, as monotherapy in patients with chemotherapy-resistant GTT. A recent publication reported data from Cohort A of the study that included 15 patients (median age, 34 years) who were resistant to single-agent chemotherapy. The primary endpoint of the study was the proportion of patients with normalization of human chorionic gonadotropin (hCG); secondary endpoints were resistance-free survival (RFS), overall survival (OS), and safety. Patients received avelumab intravenously at 10mg/kg every 2 weeks. In total, 8 patients (53.3%) achieved hCG normalization after a median of 9 cycles of avelumab. After median follow up of 29 months, none of these patients relapsed, which is consistent with disease cure. Furthermore, one patient had a successful pregnancy thereafter. The probability of hCG normalization was not associated with disease stage, FIGO score or baseline hCG. Median RFS and OS were not reached, the 4-month RFS and OS rate was 73.3% and 100%, respectively. Of interest, the seven patients (46.7%) whose hCG levels were not normalized with avelumab were subsequently cured with either actinomycin D or combination chemotherapy, and one patient underwent a hysterectomy. Avelumab was well tolerated and no patient discontinued avelumab due to toxicity. In total, 14 patients (93%) experienced a grade 1/2 treatment-related adverse events (TRAE); immune related AEs of any grade occurred in 3 patients (20%), 2 experienced hyperthyroidsm and 1 hypothyroidism.

The authors highlighted the importance of a network of specialized centers treating GTT that enabled a study of such a rare cancer to be conducted in a short timeframe. They concluded that based on the efficacy results (approximately 50% of patients cured) and favorable safety profile, avelumab could be a new treatment option for patients with single-agent chemotherapy resistant GTT, who would otherwise receive more toxic combination chemotherapy regimens.

Reference

You B, et al. J Clin Oncol. 2020 July 27. [Epub ahead of print]