Evorpacept plus enfortumab vedotin in patients (Pts) with locally advanced or metastatic urothelial carcinoma (la/mUC): Phase 1a dose escalation results.

4575 Background: Maximizing antibody dependent cellular phagocytosis (ADCP) in the tumor microenvironment requires both the inhibition of the myeloid CD47/SIRPα checkpoint and activation of the macrophage’s FcyR by an anti-cancer specific antibody (Lakhani et al. Lancet Oncol 2021). Evorpacept (EVO) is a CD47 inhibitor with an inactivated Fc effector domain that blocks the CD47-SIRPα interaction. Enfortumab vedotin (EV) is a nectin-4-directed antibody drug conjugate (ADC) which engages the FcyR on the macrophage. We evaluated whether EVO plus EV would be safe, tolerable and active in pts with la/mUC. Methods: 20 pts with la/mUC who had received prior platinum-based chemotherapy and progressed during or after treatment with a PD-1/L1 inhibitor were administered study drug in this phase 1 study (NCT05524545). Dose escalation (DE) cohorts were administered intravenous (IV) EVO 20 mg/kg or 30 mg/kg Q2W plus standard EV 1.25 mg/kg IV on days 1, 8 and 15 of a 28-day cycle. The primary endpoint was first cycle dose limiting toxicity (DLT) using a Bayesian Optimal Interval design. Additional pts were enrolled in both dose levels as backfill cohorts to further characterize safety, PK, PD, and preliminary antitumor activity. Investigator response was based on RECIST v1.1, and data cut off was 18Jan(safety)/24Jan(efficacy) 2024. Results: Fourteen pts were administered EVO 20 mg/kg Q2W (DE n= 3; backfill n=11) and 6 pts EVO 30 mg/kg Q2W (DE n=6) plus standard EV. No DLTs were observed, and the maximum tolerated dose (MTD) of the combination was not reached. The maximum administered dose (MAD) of EVO was 30 mg/kg Q2W combined with EV. There were no treatment-related deaths on study. Treatment emergent adverse events (TEAEs) occurring in > 25% of subjects included fatigue, diarrhea, abnormal loss of weight, dysgeusia, decrease appetite, hyperglycemia, constipation, hypomagnesemia, lacrimation increased, nausea, peripheral sensory neuropathy, rash maculo-papular and urinary tract infection (UTI). There were 3 serious adverse events that were related to EVO plus EV (G3 UTI 1 pt; G4 neutrophil count decreased and G3 UTI 1 pt). Sixteen patients were response evaluable. The overall response rate (ORR) was 63% (1CR, 9PR). Accrual is ongoing and updated data will be provided at the time of presentation. Conclusions: This is the first study, to our knowledge, reporting data on the combination of a CD47 blocking agent in combination with an ADC in la/mUC. EVO plus EV is well tolerated at doses evaluated with no MTD reached and a MAD of 30 mg/kg Q2W. The combination shows early promising clinical activity compared to an ORR of 41% with EV alone in pts with la/mUC who had previously received platinum-based chemotherapy and a PD-1/L1 inhibitor (Powles et al. N Engl J Med 2021). Further investigation in this refractory population, including patients with prior EV exposure, is warranted. Clinical trial information: NCT05524545 .