Avelumab in Patients With Gestational Trophoblastic Tumors With Resistance to Single-Agent Chemotherapy: Cohort A of the TROPHIMMUN Phase II Trial

PURPOSE Women with gestational trophoblastic tumors (GTT) resistant to single-agent chemotherapy receive alternative chemotherapy regimens, which, although effective, cause considerable toxicity. All GTT subtypes express programmed death-ligand 1 (PD-L1), and natural killer (NK) cells are involved in trophoblast immunosurveillance. Avelumab (anti–PD-L1) induces NK cell–mediated cytotoxicity. The TROPHIMMUN trial assessed avelumab in women with chemotherapy-resistant GTT. METHODS In this phase II multicenter trial (ClinicalTrials.gov identifier: NCT03135769 ), women with GTT who experienced disease progression after single-agent chemotherapy received avelumab 10 mg/kg intravenously every 2 weeks until human chorionic gonadotropin (hCG) normalization, followed by 3 consolidation cycles. Rate of hCG normalization was the primary endpoint (2-step Simon design). RESULTS Between December 2016 and September 2018, 15 patients were treated. Median age was 34 years; disease stage was I or III in 53.3% and 46.7% of women, respectively; and International Federation of Gynecology and Obstetrics (FIGO) score was 0-4 in 33.3%, 5-6 in 46.7%, and ≥ 7 in 20% of patients. Prior treatment included methotrexate (100%) and actinomycin D (7%). Median follow-up was 25 months, and median number of avelumab cycles was 8 (range, 2-11). Grade 1-2 treatment-related adverse events occurred in 93% of patients, most commonly (≥ 25%) fatigue (33.3%), nausea/vomiting (33.3%), and infusion-related reaction (26.7%). One patient had grade 3 uterine bleeding (treatment unrelated). Eight patients (53.3%) had hCG normalization after a median of 9 avelumab cycles; none subsequently relapsed. Probability of normalization was not associated with disease stage, FIGO score, or baseline hCG. One patient subsequently had a healthy pregnancy. In avelumab-resistant patients (46.7%), hCG was normalized with actinomycin D (42.3%) or combination chemotherapy/surgery (57.1%). CONCLUSION In patients with single-agent chemotherapy-resistant GTT, avelumab had a favorable safety profile and cured approximately 50% of patients. Avelumab could be a new therapeutic option, particularly in patients who would otherwise receive combination chemotherapy.

Avelumab in patients with gestational trophoblastic tumors resistant to monochemotherapy: Final outcomes of TROPHIMMUN phase II trial, cohort A.

LBA6008 Background: Patients with gestational trophoblastic tumors (GTT) resistant to monochemotherapy are treated with historic chemotherapy regimens known to be effective, but toxic. PD-L1 is constitutively expressed in all GTT subtypes (Bolze et al. Int J Gynecol Cancer 2017). HLA-G and natural killer (NK) cells are involved in GTT immune-surveillance. The anti-PD-L1 monoclonal antibody avelumab (Pfizer & Merck KGaA) triggers cytotoxicity through NK cells. The objective of TROPHIMMUN trial was to assess the efficacy of avelumab in patients with chemoresistant GTT. Methods: In the cohort A of this academic multicenter trial (NCT03135769), avelumab was given at 10 mg/kg Q2W in patients with GTT resistant to monochemotherapy. Avelumab was prescribed until hCG normalization, and then for 3 consolidation cycles. The primary objective was the rate of patients with hCG normalization, with a 2 step Simon design. Results: 15 patients (median 34 y old) followed by the French Gestational Trophoblastic Center were treated from Dec 2016 to Sept 2019 (stage I/III: 53%/47%; FIGO score 0-4: 33%; score 5-6: 47%; score >6: 20%). They all had progressed with previous methotrexate, and 1 patient with actinomycin-D. They received median 8 avelumab cycles (range: 2-11). The tolerability was favorable. 93 % of patients developed drug-related grade 1-2 toxicities (86% grade 1), mainly including fatigue (33% patients); nausea-vomiting (33%); infusion-related reactions (27%); thyroid disorder (20%); dry eyes (20%) & diarrhea (20%). A grade 3 uterus bleeding (treatment unrelated) was observed in 1 patient. Median follow-up was 30 months. Successful hCG normalizations were obtained in 8 patients (53%, median 9 avelumab cycles), either during avelumab treatment in 7 patients, or after avelumab discontinuation in 1 patient. None presented relapse afterwards, and 1 patient had a subsequent healthy pregnancy. Avelumab resistances requiring switch to chemotherapy were observed in 7 patients (47%), who normalized hCG with subsequent actinomycin-D (42%), or surgery/polychemotherapy (57%). The likelihood of success with avelumab was not related to the FIGO score, or disease stages. Conclusions: TROPHIMMUN is the first trial of immunotherapy in GTT patients. The anti-PD-L1 monoclonal antibody avelumab was effective, with a favorable safety profile compared to chemotherapy, in patients with resistance to mono-chemotherapy. About 50 % patients could be cured of their chemoresistant diseases. Avelumab may be a new therapeutic option. Clinical trial information: NCT03135769 .

Gestational Trophoblastic Neoplasia: A Tunisian Multicenter Study

Gestational trophoblastic disease (GTD) develops from abnormal cellular proliferation of trophoblasts following fertilization. It includes benign trophoblastic disease (hydatidiform moles (HM) and the malignant trophoblastic diseases or gestational trophoblastic neoplasia (GTN). The frequency of the GTD in Tunisia is one per 918 deliveries. The aim of this study is to analyze the clinical characteristics, treatment and outcomes of GTD at Salah Azaiez Institute (ISA). Medical records of women diagnosed with GTD at ISA from January 1, 1981 to December 31, 2012 were retrospectively reviewed. FIGO (International Federation of Gynecology and Obstetrics) score was determined retrospectively for patients treated before 2002 One hundred and nine patients with GTN were included. Patients presented with metastases at 43% of cases. The most common metastatic sites was lung (30%) and vagina (13%). 56 (51%) patients had low-risk and 21 (19%) cases had high-risk, the FIGO score was not assessed in 32 cases. After a median follow-up of 46 months, 21 patients were lost to follow-up, 12 patients died, 19 progressed and 8 relapsed. At 10 years, the OS rate was 85% and the PFS rate 79%. OS was significantly influenced by the presence of metastases at presentation (M0 100 % vs. Metastatic 62 %; p < 0.0001), FIGO stage (I-II 100% VS 61% and 65% for stage III and IV; p < 0.001), FIGO score (low-risk 99 % vs. high-risk 78 %; p < 0.001). GTN is a significant source of maternal morbidity with increased risk of mortality from complications if not detected early and treated promptly.

Efficacy and safety of the APE (actinomycin D, cisplatin, etoposide) regimen for the management of high-risk gestational trophoblastic neoplasia.

5028 Background: Patients (pts) with high risk gestational trophoblastic neoplasia (GTN) or who fail low risk single agent chemotherapy (CT) require multi agent CT to be cured. The most common regimen is etoposide (E), methotrexate and actinomycin D (A) alternating weekly with cyclophophamide and vincristine (EMA/CO). Cisplatin (P) is a very active drug but its role is controversial and usually restricted to second line. We report results of a platinum based therapy: APE. Methods: We evaluated the efficacy and safety on 103 pts treated at Institut Gustave Roussy (IGR) (n=80) or other French centers (n=23) between 1983 and 2010 with APE for high risk GTN (defined by IGR criteria [Azab, Cancer, 1988] and/or FIGO score >6). Pts with brain metastasis were excluded. Results: Efficacy was evaluated on 59 pts treated for high risk GTN in first line, and on 39 pts in >2nd line including 13 pts after multi agent CT. We excluded pts with placental site trophoblastic tumors (n=2), or with FIGO score <7 and without IGR criteria (n=3). Complete remission (CR) rate was 95%. Seven pts (7 %) relapsed and a second CR was obtained for all with surgery and/or CT. Only one patient died due to GTN, after successive CRs obtained with 3 regimens. Five year overall survival (median follow-up 6.6 years) was 98%. Toxicity was evaluated on 95 pts. No toxic death occurred. Given good efficacy and to avoid acute hematotoxicity and long-term G>1 neuro and ototoxicity APE regimen was modified as detailed in the Table (below). Long-term neuro (5 pts, G1), oto (2 pts, G1 and 2 pts, G2) and renal toxicities (1 pt, G1 ) were recorded. No long-term G2 toxicities were observed with APE3. One pt developed an AML 4 after 4cy APE and 6 cy EMA/CO. 37 pts of 40 who wished to be pregnant succeeded and all of them had at least one live birth. Conclusions: With a 98% long-term overall survival rate, an excellent reproductive outcome, and no detectable long-term toxicity, APE-3 should be regarded as an alternative standard option to EMA/CO for high-risk GTN. [Table: see text]