Genmab Reports Positive Phase 3 RAINFOL-02 Results for Rina-S in Platinum-Resistant Ovarian Cancer
Genmab A/S has announced positive topline results from the global Phase 3 RAINFOL™-02 clinical trial evaluating rinatabart sesutecan (Rina-S®), an investigational folate receptor alpha (FRα)-targeted antibody-drug conjugate (ADC), in patients with platinum-resistant ovarian cancer (PROC). The findings showed statistically significant and clinically meaningful improvements in progression-free survival (PFS) and overall survival (OS) compared with investigator’s choice chemotherapy, regardless of FRα expression level or prior treatment with mirvetuximab.
The RAINFOL-02 trial met its primary endpoint of progression-free survival in both the intent-to-treat (ITT) population and the primary analysis set (PAS) population. The study also achieved its key secondary endpoint of overall survival, with statistically significant improvements reported in both groups.
These findings represent an important milestone for Genmab’s Rina-S development program and may support the development of a new treatment option for patients with platinum-resistant ovarian cancer, a setting associated with poor outcomes and limited effective treatment choices. The company plans to engage with regulatory authorities worldwide to discuss potential next steps, while the data will be submitted for presentation at a future medical meeting.
Rina-S is an investigational therapy, and the reported results do not mean that it has been approved for the treatment of ovarian cancer. Further regulatory review will be required to determine whether the clinical findings support its potential use in this patient population.
Phase 3 trial meets primary progression-free survival endpoint
The global Phase 3 RAINFOL-02 study evaluated Rina-S against investigator’s choice chemotherapy in patients with platinum-resistant ovarian cancer. The trial assessed treatment outcomes in two populations designed to evaluate the therapy’s performance across a broad patient group and a more specifically defined analysis population.
The intent-to-treat population included 584 randomized patients with platinum-resistant ovarian cancer, regardless of FRα expression level. This broad population allowed investigators to assess the treatment’s efficacy across patients with different levels of the target protein.
The primary analysis set included 492 patients. Under the study’s definition, patients with FRα expression of at least 75% at the PS2+ level were required to have previously received mirvetuximab. This population was designed to assess outcomes within the trial’s specified analysis criteria, including patients whose prior treatment history was relevant to the evaluation of Rina-S.
In the ITT population, Rina-S reduced the risk of disease progression or death by 71% compared with investigator’s choice chemotherapy. The hazard ratio was 0.29, with a 95% confidence interval (CI) of 0.23 to 0.37 and a p-value of less than 0.0001.
The result indicates a substantial reduction in the relative hazard of progression or death among patients receiving Rina-S compared with those receiving the chemotherapy control. The statistical significance also supports the conclusion that the observed difference was unlikely to be attributable to chance under the study’s statistical model.
In the PAS population, Rina-S reduced the risk of disease progression or death by 67%, with a hazard ratio of 0.33, a 95% CI of 0.26 to 0.42 and a p-value of less than 0.0001.
The consistent PFS findings across both populations are notable. The ITT results demonstrate activity in the overall randomized population, irrespective of FRα expression, while the PAS results support the treatment’s performance in the population defined by the study’s specific eligibility and analysis criteria.
Progression-free survival measures the time patients remain alive without their disease worsening. In platinum-resistant ovarian cancer, delaying progression can be clinically important because patients may have already received platinum-based chemotherapy and other treatments, leaving fewer effective options available.
Although the topline announcement did not provide median PFS values, the reported hazard ratios indicate a substantial relative reduction in the risk of progression or death with Rina-S compared with investigator’s choice chemotherapy. Additional data, including absolute PFS estimates, will help clinicians and researchers better understand the magnitude and duration of the treatment benefit.
Overall survival results show significant improvement
In addition to meeting its primary endpoint, RAINFOL-02 met its key secondary endpoint of overall survival. Genmab reported statistically significant and clinically meaningful improvements in OS in both the ITT and PAS populations.
In the ITT population, Rina-S was associated with a hazard ratio for death of 0.43, with a 95% CI of 0.31 to 0.59 and a p-value of less than 0.0001. The company described this result as a 57% reduction in the risk of death compared with investigator’s choice chemotherapy.
In the PAS population, the OS hazard ratio was 0.44, with a 95% CI of 0.31 to 0.63 and a p-value of less than 0.0001. This corresponds to a 56% reduction in the relative hazard of death.
The consistency between the two populations strengthens the overall findings. The ITT result reflects the randomized study population regardless of FRα expression, while the PAS result provides a similar survival signal in the defined primary analysis group.
Overall survival is an important endpoint in cancer clinical trials because it measures how long patients live after entering a study, regardless of whether their disease progresses or they receive subsequent therapies. A statistically significant improvement in OS can provide clinically meaningful evidence beyond disease-control outcomes alone.
The reported results are particularly relevant in platinum-resistant ovarian cancer, where disease progression after platinum-based treatment can be associated with a challenging prognosis. A treatment that improves both progression-free and overall survival could offer an important advance for patients who need additional therapeutic options.
However, the topline announcement did not provide median overall survival values, absolute survival rates or detailed subgroup results. These data will be important for understanding the timing and durability of the survival benefit, as well as the consistency of the treatment effect across different patient characteristics.
Rina-S targets folate receptor alpha through an antibody-drug conjugate approach
Rina-S is an investigational antibody-drug conjugate designed to target folate receptor alpha, a protein expressed at varying levels in ovarian cancer and other solid tumors. The therapy combines an antibody directed against FRα with a topoisomerase I (TOPO1) inhibitor payload.
Antibody-drug conjugates are designed to combine the targeting capabilities of an antibody with the cell-killing activity of a linked therapeutic payload. In principle, the antibody component helps direct the drug toward cells expressing the target, while the attached payload is intended to disrupt cellular processes needed for tumor growth and survival.
FRα is a target of interest in ovarian cancer because its expression varies across patients and tumors. Evaluating Rina-S in patients regardless of FRα expression is therefore important for understanding whether the therapy could potentially serve a broader population than treatments that require a high level of target expression.
The RAINFOL-02 results showed significant improvements in PFS and OS in the ITT population, which included patients irrespective of FRα expression level. These findings support further investigation of Rina-S across a broad patient population.
Nevertheless, the topline announcement does not provide detailed efficacy estimates for individual FRα expression subgroups. It therefore remains important to review the full dataset to determine how outcomes vary by target expression and whether particular groups experience different levels of benefit.
Results may address an important unmet need in ovarian cancer
Platinum-resistant ovarian cancer develops when the disease progresses during or shortly after platinum-based chemotherapy, or otherwise meets criteria for resistance to this treatment. The condition presents a substantial challenge for clinicians because patients may have limited responses to further platinum-based treatment and may require alternative therapeutic approaches.
Treatment decisions in this setting depend on factors such as previous therapies, tumor characteristics, the patient’s overall health and available treatment options. While chemotherapy remains an important part of care, outcomes can be poor for patients whose disease is resistant to platinum-based regimens.
The RAINFOL-02 findings suggest that Rina-S could become an important investigational option if the results are confirmed and the therapy receives regulatory approval. The magnitude of the reported relative reductions in progression or death and in the risk of death may be particularly relevant in a population with significant unmet medical needs.
The trial also examined outcomes in a population whose analysis criteria incorporated prior mirvetuximab treatment for patients with high FRα expression. This provides relevant context for assessing Rina-S in patients whose treatment history may include another FRα-directed therapy.
However, additional information will be needed to establish how prior mirvetuximab exposure affects treatment response, how outcomes differ according to FRα expression and whether the efficacy findings are consistent across other clinically relevant subgroups.
Genmab highlights the significance of the first Phase 3 readout
Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab, described the positive topline results as a significant milestone for the company and its Rina-S development program.
“As the first Phase 3 readout from our Rina-S program, the positive topline results from RAINFOL-02 mark a significant milestone for Genmab and strengthen our confidence in Rina-S’s potential for patients with platinum-resistant ovarian cancer,” van de Winkel said.
He added that the results advance the company’s ambition to become a leader in gynecologic oncology and reflect its commitment to improving outcomes for patients with high unmet medical needs.
Van de Winkel also said Genmab looks forward to discussing the results and potential next steps with regulatory authorities worldwide. He expressed appreciation for the patients, caregivers and investigators who contributed to the study.
The announcement marks a key development for Genmab as it continues to expand the clinical evaluation of Rina-S across gynecologic cancers and other solid tumors. Positive Phase 3 findings may provide a foundation for regulatory discussions, although the next steps will depend on the full clinical dataset and the requirements of relevant authorities.
Study investigator emphasizes potential clinical impact
Angeles Alvarez Secord, MD, MHSc, the study’s lead investigator for the Gynecologic Oncology Group (GOG) and Professor of Obstetrics and Gynecology at the Duke Cancer Institute, highlighted the continuing challenges faced by patients with platinum-resistant ovarian cancer.
“Platinum-resistant ovarian cancer remains one of the greatest challenges in gynecologic oncology, with patients often facing a poor prognosis and limited effective treatment options,” Secord said.
She described the RAINFOL-02 findings as an important development in addressing this unmet need, noting that the study demonstrated substantial reductions in the risk of disease progression and death.
Secord said the 71% reduction in the risk of progression or death and the 57% reduction in the risk of death reported in the ITT population underscore Rina-S’s potential to change clinical practice if approved.
The possibility of a treatment option for a broader patient population, regardless of FRα expression, could be clinically important. However, whether Rina-S will ultimately be available for this population will depend on regulatory review, the full evidence package and the approved indication, if authorization is granted.
Broad clinical development program continues
Beyond RAINFOL-02, Genmab is evaluating Rina-S in a wider clinical development program spanning several gynecologic cancers and other solid tumors. The company said the program includes five Phase 3 trials in different treatment settings.
These include:
- RAINFOL-02: Phase 3 evaluation in platinum-resistant ovarian cancer (PROC), registered as NCT06619236.
- RAINFOL-03: Phase 3 study in recurrent or progressive endometrial cancer, registered as NCT07166094.
- RAINFOL-04: Phase 3 evaluation of Rina-S as maintenance therapy for platinum-sensitive ovarian cancer (PSOC), registered as NCT07225270.
- RAINFOL-07: Phase 3 study in second-line platinum-sensitive ovarian cancer, registered as NCT07564141.
- RAINFOL-10: Phase 3 study evaluating Rina-S as maintenance therapy in first-line ovarian cancer, registered as NCT07859215.
The development program also includes the Phase 1/2 RAINFOL-01 trial (NCT05579366) and Phase 2 studies in non-small cell lung cancer through RAINFOL-05 (NCT07288177) and advanced gastrointestinal cancers through RAINFOL-09 (NCT07539311).
This broad clinical program reflects Genmab’s effort to investigate whether the FRα-targeted ADC approach can provide benefit in additional tumor types and across different stages of treatment. The studies span treatment settings ranging from recurrent disease to maintenance therapy, where the objectives and clinical endpoints may differ.
Results from these trials will be needed to determine the potential role of Rina-S in each indication. Positive findings in platinum-resistant ovarian cancer do not automatically establish efficacy in other cancers, where target expression, disease biology, prior treatment and clinical outcomes may differ.
Regulatory discussions and future data presentation planned
Following the RAINFOL-02 topline results, Genmab plans to engage with regulatory authorities worldwide to discuss potential next steps. The company also intends to submit the data for presentation at a future medical meeting.
Further details from the trial will be important for assessing the full clinical profile of Rina-S, including the duration of treatment benefit, absolute survival outcomes, safety results and effects across relevant patient subgroups. The topline announcement stated that the observed safety profile was consistent with the known profile of Rina-S, with no new safety signals or unexpected safety concerns identified.
Genmab also announced that it will host an investor update on Wednesday, October 28, at 5:00 p.m. Central European Time (CET) / 12:00 p.m. Eastern Daylight Time (EDT). Registration information is available through the company’s events and presentations page.
Overall, the RAINFOL-02 results represent a significant clinical milestone for Genmab’s Rina-S program. The investigational ADC met its primary PFS endpoint and key secondary OS endpoint in both the ITT and PAS populations, demonstrating substantial relative reductions in the risks of disease progression or death and death compared with investigator’s choice chemotherapy.
The findings support continued development of Rina-S as a potential treatment for platinum-resistant ovarian cancer, including a broad population regardless of FRα expression. Regulatory review and further disclosure of the full clinical data will determine the next steps in development and whether the therapy can become a new treatment option for patients facing this difficult-to-treat disease.
About the RAINFOL-02 Trial
RAINFOL-02 (NCT06619236) is a randomized, open-label, multicenter Phase 3 study evaluating the efficacy and safety of Rina-S versus investigator’s choice chemotherapy in 582 patients with PROC regardless of FRα expression level. Patients are randomized 1:1 to receive either Rina-S 120 mg/m² on Day 1 of each three-week treatment cycle or one of four standard-of-care chemotherapy agents: paclitaxel, topotecan, PLD, or gemcitabine. The primary endpoint is investigator-assessed PFS. Key secondary endpoints are OS and objective response rate (ORR).
Other secondary endpoints include PFS by blinded independent central review, duration of response, incidence of adverse events and laboratory abnormalities, time from randomization to second disease progression or death, and change from baseline in global health status/quality of life. Efficacy is evaluated in two populations. The ITT population (N = 584) includes all randomized patients, regardless of FRα expression level. The PAS (N=492), a subset of the ITT population, includes only patients with FRα expression <75% PS2+ and patients previously treated with mirvetuximab if eligible based on FRα expression ≥75% PS2+ and available in the region.
About Ovarian Cancer
Ovarian cancer (OC) is a major global health issue, more than 320,000 new cases diagnosed annually worldwide.i It ranks as the eighth most common cancer and the eighth leading cause of cancer-related deaths among women globally.ii The disease is often diagnosed at an advanced stage because its symptoms, including abdominal bloating, pelvic pain and difficulty eating, can be subtle and nonspecific.iii Approximately 70-90% of women with advanced-stage OC worldwide experience a recurrence after initial treatment.iv OC has a low five-year survival rate, which varies significantly by region, but generally hovers around 30-50%.v,vi
About Rinatabart Sesutecan (Rina-S; GEN1184)
Rina-S (GEN1184) is an investigational ADC. It is composed of a novel human monoclonal antibody directed at FRα, a hydrophilic protease-cleavable linker, and exatecan, a TOPO1 inhibitor payload. The clinical trial program for Rina-S continues to expand, including ovarian, endometrial, and other cancers with unmet need.
The safety and efficacy of Rina-S have not been established. Please visit https://clinicaltrials.gov/ for more information.
About Genmab
Genmab is an international biotechnology company dedicated to improving the lives of people with cancer and other serious diseases through innovative antibody medicines. For over 25 years, its passionate, innovative and collaborative team has advanced a broad range of antibody-based therapeutic formats, including bispecific antibodies, ADCs, immune-modulating antibodies and other next-generation modalities. Genmab’s science powers eight approved antibody medicines, and the company is advancing a strong late-stage clinical pipeline, including wholly owned programs, with the goal of delivering transformative medicines to patients.