FDA Breakthrough Therapy Granted for Novel ADC in Endometrial Cancer

The US FDA has granted breakthrough therapy designation to rinatabart sesutecan (Rina-S; GEN1184), an investigational folate receptor alpha (FRα)-directed antibody-drug conjugate (ADC), for the treatment of adult patients with recurrent or progressive endometrial cancer.¹ This designation applies to patients whose disease has progressed on or following prior treatment with a platinum-containing regimen and a PD-(L)1 therapy.

The regulatory decision is supported by preliminary clinical evidence from the phase 1/2 RAINFOL-01 trial (NCT05579366), which demonstrated encouraging responses in this heavily pretreated patient population.

“This breakthrough therapy designation underscores the future potential of Rina-S as a treatment option for women diagnosed with advanced endometrial cancer, who face a poor prognosis after progressing on standard of care treatment,” said Judith Klimovsky, MD, executive vice president and chief development officer of Genmab, in a press release. “Rina-S reinforces Genmab’s determination to advance wholly owned antibody medicines in areas long overdue for innovation and our commitment to driving a strong clinical development program to help redefine what’s possible to treat gynecologic cancers.”

The breakthrough therapy designation is intended to expedite the development and review of new therapies for serious or life-threatening diseases when early clinical data suggest a substantial improvement over existing treatment options. For patients with advanced or recurrent endometrial cancer, a population with a poor prognosis and limited therapeutic avenues after progressing on standard-of-care treatments, this designation represents a potential step forward in addressing a significant unmet clinical need.

Supporting Clinical Data

The designation was based on results from the endometrial cancer monotherapy dose expansion B2 cohort of the multicenter, open-label phase 1/2 RAINFOL-01 trial presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting. The study showed that with a median follow-up of 7.7 months, treatment with Rina-S 100 mg/m² every 3 weeks demonstrated a 50.0% confirmed objective response rate (ORR), including 2 complete responses (CR), in the intent-to-treat population, with a median duration of response (DOR) that was not reached.²

About RAINFOL-01

The phase 1/2 RAINFOL-01 study consists of 6 parts:

• Part A: monotherapy cohorts
• Part B: tumor-specific monotherapy dose-expansion cohorts
• Part C: platinum-resistant ovarian cancer cohort
• Part D: combination therapy cohorts with carboplatin, bevacizumab (Avastin), and pembrolizumab (Keytruda)
• Part F: a monotherapy endometrial cancer cohort
• Part K: a monotherapy-corrected QTc substudy cohort in high-grade ovarian cancer for US patients only

The study is recruiting patients across 38 sites in the US and China.³ The primary end points are incidence of treatment-emergent adverse events for parts A, B, and D; dose-limiting toxicities for parts A and D; ORR for parts C and D; and clinically significant changes in ECG findings in part K. Secondary end points include best overall response, disease control rate, progression-free survival, overall survival, DOR, and pharmacokinetics.

To be eligible for study participation, patients with endometrial cancer in part B must have previously received therapies known to confer clinical benefit and have measurable disease per RECIST v1.1. Those with a history of noninfectious interstitial lung disease or pneumonitis requiring steroids within the past 2 years or who received a prior therapy with a topoisomerase I (TOPO1) inhibitor-based ADC are not eligible for enrollment.

Mechanism of Action

Rina-S is an innovative ADC composed of a human monoclonal antibody targeting FRα, a novel hydrophilic protease-cleavable linker, and exatecan, a TOPO1 inhibitor payload.¹ This unique design enables the drug to specifically target and deliver a cytotoxic agent to cancer cells expressing FRα. The overexpression of FRα is observed in multiple tumor types, including a significant proportion of endometrial cancers, making it a promising therapeutic target. The anti-tumor activity of Rina-S was observed across a broad range of FRα expression levels in the trial cohort.

By leveraging this targeted mechanism, Rina-S seeks to deliver a potent cytotoxic payload directly to malignant cells while minimizing systemic toxicity, a common challenge with traditional chemotherapies. The use of a TOPO1 inhibitor payload further distinguishes the agent, as this class of drugs is known to interfere with DNA replication and repair, leading to apoptosis in cancer cells. The positive early signals in a group of patients with a particularly difficult-to-treat disease subset highlight the potential of this ADC approach.

Rina-S is also being investigated in other tumor types, including ovarian cancer, with a phase 3 trial (RAINFOL-02, NCT06619236) already underway. In January 2024, the FDA granted fast track designation to Rina-S in FRα-expressing ovarian cancer.⁴

This article was generated with assistance from Google Gemini. It was edited and reviewed by Targeted Oncology staff. If you have any questions about the use of AI, please contact us.

REFERENCES:

1. Genmab Receives FDA Breakthrough Therapy Designation for Rinatabart Sesutecan (Rina-S®) in Advanced Endometrial Cancer (EC). News release. Genmab. August 26, 2025. Accessed August 26, 2025. https://tinyurl.com/2vaxks8d

2. Genmab Announces Investigational Rinatabart Sesutecan (Rina-S®) Demonstrates Encouraging Anti-Tumor Activity in Heavily Pretreated Patients with Advanced Endometrial Cancer in Phase 1/2 RAINFOL™-01 Trial. News release. Genmab. June 2, 2025. Accessed August 26, 2025. https://tinyurl.com/3z9y33p5

3. Rinatabart Sesutecan (Rina-S, PRO1184, GEN1184) for Advanced Solid Tumors (GCT1184-01/​ PRO1184-001) (RAINFOL-01). ClinicalTrials.gov. Updated August 20, 2025. Accessed August 26, 2025. https://clinicaltrials.gov/study/NCT05579366

4. ProfoundBio announces rinatabart sesutecan FDA fast track designation for patients with advanced ovarian cancer. News release. ProfoundBio. January 5, 2024. Accessed August 26, 2025. http://tinyurl.com/mv2m48wd