Maveropepimut-S, Pembrolizumab and Low-dose Cyclophosphamide in Patients with Metastatic Ovarian Cancer: Final Results from Phase 1/2 PESCO trial

Background : Epithelial ovarian cancer (EOC) is characterized by a pattern of relapse and progression through successive recurrences, with increasing chemotherapy resistance. This highlights an urgent need for novel treatment strategies. Survivin, a tumor-associated antigen, is highly expressed in ovarian cancer, making it a promising target for immunotherapy. Designed to target survivin-expressing tumor cells, Maveropepimut-S (MVP-S) is a DPX-based vaccine immunotherapy that induces a cytotoxic T-cell response. PESCO trial is an investigator-initiated, open-label, non-randomized phase 1/2 trial to evaluate the safety and efficacy of combination of MVP-S with pembrolizumab and cyclophosphamide in patients with recurrent EOC. Methods : MVP-S was administered subcutaneously at two dose levels during the phase 1 dose-escalation portion: 0.25 mL or 0.5 mL every 6 weeks. This was combined with pembrolizumab (200 mg intravenously every 3 weeks) and oral intermittent low-dose cyclophosphamide (50 mg BID for 7 days, every other week). Patient enrollment occurred between February 2018 and May 2023, with a median follow-up period of 14 months (range, 1.3-39.1). Primary objectives were safety, recommended phase 2 dose (RP2D), and clinical efficacy based on disease control rate (DCR) and overall response rate (ORR). Secondary objectives included efficacy in patients with platinum sensitive (Cohort A) and platinum resistant disease (Cohort B), progression free survival (PFS) and overall survival (OS). Blood samples and biopsies were collected at baseline and during treatment for correlative studies. Survivin-specific immune responses were assessed by measuring IFNγ production following survivin peptide re-stimulation. Results : A total of 47 patients were enrolled, with a median age of 60 years (range, 36-78) and a median of 2 prior therapy lines (range, 1-7). Thirty-one patients (66%) had high grade serous carcinoma (HGSC), 11 (23%) had clear cell carcinoma (CCC), 2 (4%) had low grade serous carcinoma (LGSC), 1 (2%) had mixed histology, and 1 (2%) had mucinous carcinoma. Forty-four patients were evaluable for safety and efficacy. The most frequent treatment related adverse events (TRAEs) were injection site reactions (ISRs) in 33 (75%) patients (14 grade 1; 13 grade 2; 6 grade 3), along with anemia (44%), fatigue (46%), and nausea (37%). Grade 1 and 2 events accounted for 90% of all TRAEs. MVP-S dose level 1 of 0.25mL was established as RP2D in phase 1 dose escalation due to occurrence of dose-limiting toxicities (DLTs), grade 3 proteinuria and grade 3 ISR at dose level 2. Among evaluable patients from phase 1 dose escalation (n=14), and phase 2 cohorts A (n=10) and B (n=10), the ORR was 23% (8/34) with median duration of response of 5.5 months. DCR was 67% (23/34). In phase 2, ORR was 40% for cohort A and 10% for cohort B. PFS differed significantly between cohorts A and B (P=0.016), with a median of 6.3 months (95% CI: 0.9-10.8) for cohort A and 1.2 months (95% CI: 1.0-4.1) for cohort B. MVP-S induced survivin-specific immune responses in 15/24 (62%) tested patients and were correlated with disease control in 14/15 patients (93%). The longest detected immune response lasted 195 weeks and this patient remains in complete response for 3 years. Conclusions : The combination of MVP-S, pembrolizumab and low dose cyclophosphamide in EOC is tolerable and demonstrated promising and sustained clinical activity. These findings reinforce survivin as a viable target for immunotherapy in EOC.