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.
Year: 2025
Type: conference-abstract
Abstract: 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 .
Source: Journal of Clinical Oncology
Authors: Isabelle Laure Ray-Coquard, David M. O'Malley, Bhavana Pothuri, Ana Oaknin, Nehal J. Lakhani, Takafumi Koyama, Shigehisa Kitano, William Bennion McKean, Ainhoa Madariaga, Meena Okera, Myong Cheol Lim, Jose Alejandro Perez-Fidalgo, Giuseppe Curigliano, Domenica Lorusso, Ramez Nassef Eskander, Shannon Neville Westin, Umut Ozbek, Marine Manvelyan, Emin Avsar, Claire Frances Friedman
Institutions: Centre Léon Bérard, The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, NYU Langone’s Laura and Isaac Perlmutter Cancer Center, New York University, Vall d'Hebron Institute of Oncology, National Cancer Center Hospital, The Cancer Institute Hospital, Japanese Foundation For Cancer Research, Hospital Universitario 12 De Octubre, National Cancer Center, National Cancer Center Hospital, Hospital Clínico Universitario de Valencia, University of Milan, European Institute of Oncology, Humanitas University, University of California San Diego, Moores Cancer Center, The University of Texas MD Anderson Cancer Center, Eli Lilly (United States), Memorial Sloan Kettering Cancer Center
Language: English
Subfield: Reproductive Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funder: Eli Lilly and Company
OpenAlex ID: W4410814385