Initial results from a first-in-human phase 1 study of LY4170156, an ADC targeting folate receptor alpha (FRα), in advanced ovarian cancer and other solid tumors.

3023 Background: Folate receptor alpha (FRα) is overexpressed in several solid tumors. LY4170156 is an Fc-silent, FRα specific humanized IgG1 ADC linked to exatecan, a topo-I inhibitor, via a novel cleavable polysarcosine linker at a homogenous DAR of 8. LY4170156 demonstrated in vivo preclinical efficacy in tumor models, across all FRα expression levels. Methods: This is a multicenter, open-label, first-in-human phase 1a/b study of LY4170156 in patients (pts) with advanced FRα-expressing ovarian, endometrial, cervical, and other solid tumors. Pts with prior ADCs targeting FRα with payloads other than topo-I (including mirvetuximab soravtansine-gynx [mirv]) were allowed. Dose escalation followed the mTPI-2 method. LY4170156 was administered Q3W IV (dose range of 2-6 mg/kg); dose limiting toxicity (DLT) evaluation period was 21 days. Dose escalation included a randomized dose optimization cohort in PROC. Key endpoints were safety, PK, and antitumor activity per RECIST v1.1. Efficacy evaluable pts were those who had a post baseline response assessment or discontinued treatment prior to the response assessment. Results: As of 27 Nov 2024, 45 pts were treated with LY4170156. Median age was 63 yrs (range, 24-85), 100% had ECOG PS 0-1, and 32 (71%) had high-grade serous ovarian cancer (HGSOC). Among the HGSOC pts (32), median lines of prior therapy was 5 (range, 1-10), 19% had received prior mirv, and 44% had FRα expression < 75% by local or central testing. PK of LY4170156, total antibody, and exatecan were linear and dose-proportional within the tested dose range. Unconjugated payload release from ADC at C max was < 4% at 4 mg/kg; median half-life of LY4170156 was 5.7-7.0 days and exatecan was 7.2-8.6 days. Main toxicities were myelosuppression and GI-related, as expected from an exatecan payload. Across all doses, the most common treatment-emergent adverse events (TEAEs; ≥15%) were nausea (58%, 2% gr 3), fatigue (44%, 0% gr 3-4), anemia (33%, 24% gr 3), vomiting (27%, no gr 3-4), diarrhea (22%, 4% gr 3), and neutropenia (20%, 11% gr 3-4). Febrile neutropenia (FN) was observed in 3 pts (7%). To date, no pulmonary or ocular toxicity were noted. Two DLTs were observed (1 gr 3 FN [6 mg/kg]; 1 gr 3 anemia [2 mg/kg]); no MTD has been established to date. Among 13 efficacy evaluable HGSOC pts (6 FRα ≥75%; 6 < 75%; 1 pending data), 9 showed reduction in target lesions; preliminary ORR was 38% (n = 5) with 1 CR, 4 PR, and 4 SD across all dose levels. Combined ORR for 4 and 6 mg/kg dose levels was 55%. All responses were unconfirmed and ongoing at the time of data cutoff. Three of 5 responders had FRa expression < 75% and two ≥75% including 1 who was mirv refractory. Conclusions: LY4170156 was well-tolerated with encouraging clinical activity among HGSOC pts, including those with FRα expression < 75% and those with prior mirv. Randomized dose optimization is ongoing and updated data will be presented. Clinical trial information: NCT06400472 .