First-in-human (FIH) phase 1 study of CUSP06, a cadherin-6 (CDH6)-directed antibody-drug conjugate (ADC), in patients with platinum-refractory/resistant ovarian cancer and other advanced solid tumors.

3042 Background: CDH6 is a transmembrane glycoprotein involved in cancer metastasis expressed in various tumors including ovarian cancer (OC), renal cell carcinoma (RCC), cholangiocarcinoma (CCA), and uterine cancer. CUSP06 is an ADC composed of a humanized IgG1 mAb against CDH6 conjugated with a cleavable linker to exatecan, a topoisomerase I inhibitor. In preclinical studies, CUSP06 showed CDH6-dependent cell growth inhibition in OC cell lines and tumor regression in CDH6-expressing OC, RCC, and other tumor models including those with low CDH6 expression supporting its use across various indications and CDH6 expression levels. We report here the initial results from a FIH study of CUSP06. Methods: CUSP06-1001 is a Phase 1a/1b, open-label, multi-center dose escalation and expansion study to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, recommended Phase 2 dose, and preliminary efficacy of CUSP06 in patients (pts) with platinum-refractory/resistant ovarian cancer (PRROC), advanced RCC and other advanced CDH6-positive solid tumors. Prescreening for CDH6 expression was required for those pts with solid tumors other than OC or RCC. CUSP06 was administered IV every 21 days. Phase 1a followed a standard 3+3 dose escalation design and included dose enrichment cohorts at doses that had demonstrated safety. Phase 1b consists of dose expansion cohorts for pts with OC, RCC, and other CDH6-positive solid tumors to assess the safety, tolerability and efficacy at the RDE. Results: As of 03JAN25, 26 pts were dosed with data available for 22 pts in Phase 1a (18 OC, 2 RCC, and 2 CCA) at doses from 1.6 mg/kg to 5.6 mg/kg. The median age was 60.5 yrs and the median prior therapies was 3. Of the 18 pts with OC, all pts received prior platinum and taxane, 67% received bevacizumab, and 22% received mirvetuximab (MIRV). All patients with RCC received an immune checkpoint inhibitor and a TKI. Related TEAEs occurred in 20 pts (91%). The most common related TEAEs ( > 20%) were anemia (50%), neutropenia (46%), thrombocytopenia (46%), fatigue (46%), nausea (36%), diarrhea (23%), and vomiting (23%). The most common related Grade ≥3 TEAEs were neutropenia, thrombocytopenia, and anemia. AEs led to discontinuation in 3 (14%) pts. Five of 14 GCIG-evaluable OC pts (36%) had a CA-125 response. Among the 20 RECIST-evaluable pts, 5 partial responses (4 confirmed, & 1 unconfirmed) including MIRV-pretreated pts, and 11 stable disease were observed. All PRs were in pts with platinum-resistant high grade serous OC, with an ORR of 36% (5/14). 18 pts were ongoing at the cutoff date. Conclusions: The preliminary data from the Phase 1a dose escalation portion of this study showed acceptable tolerability and encouraging efficacy in pts with OC, which support further evaluation of CUSP06 in the Phase 1b expansion cohorts. Clinical trial information: NCT06234423 .