Depletion of T-regulatory cells by denileukin diftitox-cxdl (E7777) in combination with pembrolizumab in relapsed/refractory (r/r) gynecologic malignancies: Phase 1 study results.

2564 Background: Denileukin diftitox-cxdl (E7777) is an FDA-approved direct cytotoxic agent that depletes T-regulatory cells by targeting the IL-2 receptor. Pre-clinical studies have demonstrated synergistic activity between the immunomodulator E7777 and PD-1 immune checkpoint inhibitor (ICI). Here, we report positive results from a phase I study of E7777 + pembrolizumab (P) in r/r gynecological (GYN) malignancies. Methods: Phase I dose-escalation trial of E7777 given at 4 IV dose levels (DL): 3, 6, 9, and 12 mg/kg on days 1-3, combined with P (IV 200 mg, day 1) in a 21-day cycle x8, followed by maintenance P until progression. Dose-limiting toxicities (DLTs) were assessed during cycle 1 according to CTCAE v5 criteria. Responses were measured using the RECIST 1.1 criteria. Blood samples were collected for translational studies. Results: Pt demographics included: median age 64y (43, 88); race, 88% white; histology 40% endometrial, 36% ovarian. Of the 24/25 pts evaluable for DLTs, only 1 case of reversible capillary leak syndrome (CLS) was seen at DL4. Anemia, fatigue, chills, and hypoalbuminemia were the most common AEs. A comprehensive overview of AEs, SAEs, and immune-related adverse events (irAEs) will be presented at the annual meeting. Table 1 describes the 4 DLs and their responses in the 21 pts evaluable for efficacy. An ORR of 24% (5 PRs) was reported in this heavily pretreated patient population with a mDOR of 21.1m (4.2-35.0). E7777 + P responses were seen in patients who progressed on prior ICI therapy, and across different GYN histologies. The median Progression-free survival (mPFS) was 5.8 m (1.1 – 37), with 5 pts having a PFS of ≥20 months. The clinical benefit rate (CR; PR; SD ≥ 6 m) was demonstrated in 48% of pts (n=10), who achieved a mPFS = 17.4m (6.2 – 37); patients with documented PD had a mPFS = 2.1 m (1.1 – 4.7). Conclusions: The results from this Phase I study of two immunomodulatory agents in combination, E7777 + P, in patients with r/r GYN tumors was well tolerated and demonstrated promising efficacy. A max tolerated dose wasn't established. No new significant safety signals or irAEs were reported. ORR of 24 % was demonstrated. Responders achieved a mDOR of 21.1m (4.2 - 35.0) and a mPFS = 23 m (10.4 – 37.0). Thus, E7777 + P showed prolonged responses and clinical benefit in pts with r/r GYN malignancies and limited options. These results will inform a Phase II study. Clinical trial information: NCT05200559 . Response- evaluable patients (RECIST v1.1) DL1 (N=3) DL2 (N=2) DL3 (N=6) DL4 (N=10) Total (N=21) Best response CR 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) PR 1 (33.3%) 0 (0%) 1 (16.7%) 3 (30.0%) 5 (23.8%) SD 1 (33.3%) 1 (50.0%) 2 (33.3%) 2 (20.0%) 6 (28.6%) PD 1 (33.3%) 1 (50.0%) 3 (50.0%) 5 (50.0%) 10 (47.6%) CBR w/ Durable SD (CR/PR/SD≥ 6m) 2 (66.7%) 1 (50.0%) 2 (33.3%) 5 (50.0%) 10 (47.6%) PD 1 (33.3%) 1 (50.0%) 4 (66.7%) 5 (50.0%) 11 (52.4%)