Sofetabart Mipitecan Elicits Responses Across FRα Levels in Ovarian Cancer

The investigational folate receptor alpha (FRα)–targeted antibody-drug conjugate (ADC) sofetabart mipitecan (LY4170156) demonstrated responses in about half of patients with heavily pretreated high-grade ovarian cancer (HGOC), regardless of tumor FRα expression level or prior mirvetuximab soravtansine-gynx (Elahere) exposure, according to results of a first-in-human phase 1 study published in Annals of Oncology.¹

Across the study's dose-finding portion (NCT06400472), which included 105 patients with HGOC, the confirmed objective response rate (ORR) was 50.5% (95% CI, 40.5%-60.4%), including 5 complete responses (4.8%) and 48 partial responses (45.7%). At 3 mg/kg, the dose selected for phase 3 testing, the ORR was 58.8% (95% CI, 32.9%-81.6%). Median progression-free survival (PFS) was 8.1 months (95% CI, 6.4-8.5) at a median follow-up of 12.9 months.

Results from the study were previously presented at the 2026 Society of Gynecologic Oncology (SGO) Annual Meeting, where presenting author Bhavana Pothuri, MD, of the Laura & Isaac Perlmutter Cancer Center at NYU Langone Health in New York, New York, noted that the ADC “showed promising clinical activity in heavily pretreated patients across all FRα expression levels.”²

Rationale and Study Design

FRα is overexpressed in up to 90% of ovarian cancers. Mirvetuximab soravtansine, the approved FRα-targeted ADC, is restricted to patients with platinum-resistant disease whose tumors show FRα expression in at least 75% of cells at 2+ or greater staining intensity, a group that represents roughly one-third of patients with platinum-resistant ovarian cancer (PROC), the authors noted.¹

Sofetabart mipitecan pairs an Fc-silent, FRα-specific humanized IgG1 antibody with exatecan, a topoisomerase I inhibitor payload, through a cleavable hydrophilic polysarcosine linker at a drug-to-antibody ratio of 8. The investigators reported that less than 3% of payload was released from the ADC at peak concentration, consistent with linker stability in circulation.

The open-label, multicenter study enrolled patients regardless of FRα expression level and allowed prior mirvetuximab soravtansine. Patients received the ADC intravenously every 21 days at 2, 3, 4, or 6 mg/kg. Patients received escalating doses of 2, 4, and 6 mg/kg; a subsequent optimization cohort randomly assigned patients equally among those levels, and investigators then added 3 mg/kg as a backfill cohort. The data cutoff was March 5, 2026.

The median patient age was 63.0 years (range, 40-89), and patients had received a median of 5 prior lines of systemic therapy (range, 1-11). Nearly all (98.1%) had platinum-resistant disease, 87.6% had received bevacizumab (Avastin), 67.6% had received a PARP inhibitor, and 18.1% had received mirvetuximab soravtansine. About half (51.4%) had tumors with FRα expression below 75%.

Efficacy by Dose and Biomarker

The individual ORRs were 37.1% at 2 mg/kg, 58.8% at 3 mg/kg, 59.0% at 4 mg/kg, and 50.0% at 6 mg/kg. The ORR was 44.4% (95% CI, 30.9%-58.6%) in patients with FRα expression below 75% and 56.5% (95% CI, 41.1%-71.1%) in those with expression of 75% or higher. Among the 19 patients previously treated with mirvetuximab soravtansine, the ORR was 57.9% (95% CI, 33.5%-79.7%), and median PFS was 7.8 months. Responses also occurred in 2 patients with no detectable FRα staining at 2+ or higher intensity. The authors cautioned that these subgroup analyses were exploratory and small.

The disease control rate (DCR) was 80.0%, and there was a median time to response of 2.1 months. The median duration of response (DOR) was 9.1 months (95% CI, 6.4-11.4), which the investigators described as immature at this time with a short median follow-up of 10.6 months (95% CI, 8.5-13.6). The 6-month PFS rate was 71.8% (95% CI, 61.6%-79.8%), and 19 of 53 responders remained on therapy at data cutoff.

Safety Findings

Nausea (64.8%), fatigue (56.2%), and anemia (47.6%) were the most common treatment-emergent adverse events (TEAEs), and 40% of patients received prophylaxis with 2 or more antiemetics. Grade 3 or higher treatment-related adverse events occurred in 42.9% of patients, mainly grade 3 anemia (21.9%) and grade 3 or 4 neutropenia. Febrile neutropenia occurred in 3.8%.

No keratopathy was reported, and all ocular events such as blurred vision (8.6%) and dry eye (6.7%) were grade 1 or 2, as was peripheral neuropathy (7.6%). Alopecia occurred in 9.5% of patients. Pneumonitis or interstitial lung disease occurred in 11.4%, including 2 grade 3 events and no grade 4 or 5 events. Of 3 grade 5 TEAEs, 1 (Pneumocystis jirovecii pneumonia) was considered treatment related. TEAEs led to dose reductions in 27.6% of patients, most commonly because of anemia, and to discontinuation in 10.5%, most commonly attributed to pneumonitis.

Patient-reported outcome assessments were collected from 59 of 60 patients in the dose-optimization cohort, with over 90% reporting no interference with daily activities from blurry vision, decreased appetite, fatigue, and numbness/tingling, and no patients reported severe or very severe interference from adverse events for any assessed symptom.

Dose Selection and Next Steps

Investigators selected 3 mg/kg as the recommended phase 3 dose. Response rates were similar at 3 and 4 mg/kg, but grade 3 or higher treatment-related adverse events (35.3% vs 56.4%) and dose reductions (23.5% vs 41.0%) were less frequent at the lower dose. The 6 mg/kg dose was not pursued because of high rates of grade 3 or higher anemia and thrombocytopenia. The authors noted that the study was open label, uncontrolled, and small, with limited follow-up.

In January 2026, the FDA granted breakthrough therapy designation to sofetabart mipitecan for patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received bevacizumab and, if eligible, mirvetuximab.³

The worldwide randomized phase 3 FRAmework-01 trial (NCT07213804) is evaluating the ADC as monotherapy in PROC in comparison with investigator’s choice of chemotherapy or mirvetuximab soravtansine, and in combination with bevacizumab compared with platinum doublet plus bevacizumab in platinum-sensitive disease. The trial has an estimated enrollment of 1630 patients. The primary end point is PFS for up to 70 months, with secondary end points including OS, ORR, DOR, and DCR.⁴

REFERENCES

1. Ray-Coquard I, O'Malley DM, Oaknin A, et al. Sofetabart mipitecan, an antibody drug conjugate targeting folate receptor alpha, in high grade ovarian cancer: results from the first-in-human phase 1 study. Ann Oncol. Published online October 8, 2026. doi:10.1016/j.annonc.2026.10.001

2. Pothuri B, Ray-Coquard I, Kyi C, et al. Updated 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: 2026 SGO Annual Meeting; April 10-13, 2025; San Juan, Puerto Rico.

3. Lilly’s sofetabart mipitecan receives US FDA’s breakthrough therapy designation for the treatment of certain patients with platinum-resistant ovarian cancer. News release. Lilly. January 20, 2026. Accessed October 22, 2026. https://tinyurl.com/2vuepavh

4. A three-part phase 3 study of sofetabart mipitecan in participants with platinum-resistant (part A) and platinum-sensitive (parts B and C) ovarian cancer (FRAmework-01). ClinicalTrials.gov. Updated October 8, 2026. Accessed October 22, 2026. https://www.clinicaltrials.gov/study/NCT07213804