FDA Grants Breakthrough Therapy Designation to Sofetabart Mipitecan in PROC

The FDA has granted breakthrough therapy designation to sofetabart mipitecan (LY4170156), a novel folate receptor alpha (FRα) antibody-drug conjugate, for the treatment of patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer (PROC), who received prior bevacizumab (Avastin) and mirvetuximab soravtansine-gynx (Elahere), according to a news release from the developer, Eli Lilly.¹

Sofetabart mipitecan targets FRα across all expression levels with improved therapeutic index. An Fc-silent FRα specific humanized monoclonal antibody linked to the topoisomerase I inhibitor exatecan can be found in sofetabart mipitecan.

Supporting results for the FDA’s decision come from a first-in-human phase 1 trial (NCT06400472), which evaluated the safety, tolerability, and preliminary efficacy of sofetabart mipitecan in patients with advanced solid tumors. Initial results were shared at the 2025 American Society of Clinical Oncology Annual Meeting, then more complete results from all dose levels were shared at the European Society of Medical Oncology 2025 Congress.^2,3

“[PROC] remains one of the most challenging settings in gynecologic oncology, with limited treatment options and poor outcomes for patients,” Bhavana Pothuri, MD, professor of Obstetrics/Gynecology and Medicine at NYU Grossman School of Medicine of NYU Langone Health and director of Clinical Trials Office at the Perlmutter Cancer Center, stated in the release.¹ “The breakthrough therapy designation and preliminary clinical data for sofetabart mipitecan across all levels of FRα expression are encouraging and point to its potential as a meaningful treatment option for patients.”

ASCO Results

With a data cutoff date of March 9, 2025, among all 58 efficacy evaluable patients included in the data set, the overall response rate (ORR) was 45%, with 3% unconfirmed complete responses (CRs) and 41% confirmed and unconfirmed partial responses (PRs); the overall disease control rate (DCR) was 74%.

Patients were treated with varying doses of intravenous sofetabart mipitecan, escalating from 2 mg/kg to 6 mg/kg every 3 weeks. Among those treated at 2 mg/kg (n = 16), the ORR was 31%, consisting of all confirmed and unconfirmed PRs, and the DCR was 75%. Among those treated at 3 mg/kg (n = 10), the ORR was 40%, consisting of all PRs, and the DCR was 80%. At 4 mg/kg (n = 20), the ORR was 55%, with 5% CRs and 50% PRs, and the DCR was 75%. At 6 mg/kg (n = 12), the ORR was 50%, consisting of 8% CRs and 42% PRs, and the DCR was 67%.

Notably, a potential recommended phase 2 dose (RP2D) of 4 mg/kg was identified.

Sofetabart mipitecan’s concentration in plasma was stable, showing minimal accumulation prior to subsequent doses. The overall pharmacokinetic profile supported dosing once every 3 weeks.

Among the 95 patients included in the safety and tolerability data set, the most common any grade treatment-emergent adverse events (TEAEs) were nausea (64%), anemia (40%), fatigue (32%), and vomiting (32%). The most common grade 3 or higher TEAEs were anemia (20%) and neutropenia (18%). Dose reductions due to AEs occurred in 20% of all patients. At 4 mg/kg, the most common any-grade TEAEs were nausea (74%), diarrhea (41%), anemia (38%), and fatigue (35%); the most common grade 3 or higher TEAEs were anemia (21%) and neutropenia (21%). Furthermore, dose reductions due to AEs were noted in 24% of those treated at 4 mg/kg.

ESMO Results

With a data cutoff date of July 30, 2025, among 104 efficacy evaluable patients included in this dataset, the ORR was 50%, with 4 CRs and 48 PRs, and the DCR was 78%. The patients were also categorized by FRα expression. Those with FRα expression from 0% to 24% had an ORR of 40%, with 10 PRs, and a DCR of 68%. For those with FRα expression from 25%-49%, the ORR was 50%, with 6 PRs, and a DCR of 83%. With FRα expression from 50% to 74%, the ORR was 50%, with 1 CR and 7 PRs, and a DCR of 81%. In those with FRα expression of 75% or greater, the ORR was 54%, with 3 CRs and 22 PRs, and a DCR of 83%.

Regarding safety, with 105 patients in the data set, TEAEs of any grade included nausea (64%), fatigue (53%), anemia (39%), and vomiting (36%). The most common grade 3 or higher TEAEs were anemia (25%) and neutropenia (24%), and 26% of patients experienced a dose reduction due to a TEAE. Notably, 8% of patients experienced grade 4 neutropenia, with 2% having febrile neutropenia. No related grade 3 or higher ocular toxicities or peripheral neuropathy were observed.

Trial Breakdown

Eligible patients in the trial were 18 years or older with a diagnosis of recurrent PROC and other select metastatic and advanced solid tumors, as well as an ECOG performance status of 0 or 1. Those who progressed on mirvetuximab soravtansine (Elahere) were also eligible to participate in the trial.

The primary end points of the trial included determining the RP2D and dose-limiting toxicities in phase 1a and ORR in phase 1b of the trial.⁴ Secondary end points included pharmacokinetics, duration of response, DCR, and progression-free survival.

References

1. Lilly's sofetabart mipitecan receives U.S. FDA's breakthrough therapy designation for the treatment of certain patients with platinum-resistant ovarian cancer. News release. Eli Lilly and Company. January 20, 2026. Accessed January 20, 2026. https://tinyurl.com/yeewxma2
2. Ray-Coquard I, O’Malley DM, Pothur B, et al. 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. Presented at the 2025 ASCO Annual Meeting; May 31 – June 3, 2025; Chicago, IL. Abstract 3023.
3. Ray-Coquard I, Kyi C, Pothuri B, et al. Results from the first-in-human phase 1 study of LY4170156, an antibody drug conjugate (ADC) targeting folate receptor alpha (FRα) in recurrent platinum resistant high-grade serous ovarian cancer (HGSOC). Presented at the ESMO 2025 Congress; October 17-21, 2025; Berlin, Germany. Abstract 1067P.
4. A study of LY4170156 in participants with selected advanced solid tumors. ClinicalTrials.gov. Updated January 14, 2026. Accessed January 20, 2026. https://tinyurl.com/725s5ejj