Eli Lilly and Company announced promising Phase 1 results for its investigational folate receptor alpha (FRα) antibody-drug conjugate LY4170156, demonstrating significant anti-tumor activity in women with heavily pre-treated platinum-resistant ovarian cancer. The data, presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, showed a preliminary overall objective response rate (ORR) of 55% at the potential recommended Phase 2 dose of 4 mg/kg.
The study represents a potential breakthrough for ovarian cancer patients who have exhausted multiple treatment options, including those previously treated with mirvetuximab soravtansine, the currently approved FRα-targeting ADC.
Novel ADC Design Shows Broad Activity
LY4170156 is composed of an Fc-silent, FRα-specific humanized monoclonal antibody linked to exatecan, a topoisomerase I inhibitor, via a proprietary cleavable polysarcosine linker (PSARlink™). This unique design enables the cytotoxic molecules to remain in the body longer, potentially broadening the therapeutic index of ADCs.
"These initial data show activity across all doses and levels of FRα expression, including in patients previously treated with a FRα targeting treatment," said Isabelle Ray-Coquard, M.D., Ph.D., president of the ENGOT group and principal investigator for the trial. "Taken together with the emerging safety and tolerability profile, these data demonstrate early potential to meaningfully improve outcomes for women living with advanced ovarian cancer."
Phase 1 Study Results
As of the March 9, 2025 data cutoff, the study enrolled 95 participants with high-grade serous ovarian cancer across four dose levels (2-6 mg/kg). The patient population was heavily pre-treated, having received a median of five prior systemic regimens (range 1-10), with 15% previously treated with mirvetuximab soravtansine.
Among the 95 patients, 51% had tumors with FRα expression less than 75%, 34% had FRα expression of 75% or higher, and 16% had expression results pending. Key endpoints included safety, pharmacokinetics, and anti-tumor activity per RECIST v1.1.
In the 58 efficacy-evaluable patients, the ORR was 45% (26/58 patients), and the disease control rate was 74% (43/58). Notably, responses were observed at all dose levels and across all FRα expression levels, including in patients who had progressed on prior mirvetuximab soravtansine.
Encouraging Safety Profile
The most common treatment-emergent adverse events across all dose levels included nausea (64%), anemia (40%), fatigue (32%), vomiting (32%), diarrhea (28%), and neutropenia (27%). Importantly, treatment-emergent neuropathy and ocular toxicity, which are common concerns with ADCs, have not been observed to date. No maximum tolerated dose has been established.
"We are excited to share these first clinical data for our FRα targeting ADC, demonstrating a promising tolerability and efficacy profile across all FRα expression levels," said David Hyman, M.D., Chief Medical Officer at Lilly. "Based on these results, we believe there is the potential to significantly expand the number of ovarian cancer patients who could benefit from a FRα ADC."
Targeting Folate Receptor Alpha
FRα is a cell-surface glycoprotein encoded by the gene FOLR1 that binds to folic acid and reduced folates, facilitating cell division and growth. The receptor is overexpressed in many solid tumors, including ovarian, non-small cell lung, and colorectal cancers, making it an attractive therapeutic target.
LY4170156 was specifically designed to target FRα across expression levels with an improved therapeutic index, potentially addressing limitations of current FRα-targeting therapies that may be restricted to patients with high receptor expression.
Path Forward
Lilly announced plans to rapidly advance LY4170156 into registrational Phase 3 clinical trials based on these encouraging Phase 1 results. The compound is currently being studied in patients with ovarian cancer as well as other FRα-expressing solid tumors under clinical trial NCT06400472.
The development represents a significant step forward in addressing the substantial unmet need for effective treatments in platinum-resistant ovarian cancer, where patients have limited therapeutic options and poor prognosis.
