Genmab A/S announced promising new data from its Phase 1/2 study of rinatabart sesutecan (Rina-S), an investigational folate receptor-alpha (FRα)-targeted, Topo1 antibody-drug conjugate (ADC), at the European Society of Medical Oncology (ESMO) Congress 2024 in Barcelona, Spain. The study demonstrated encouraging anti-tumor activity as a single agent in heavily pretreated patients with ovarian and endometrial cancers.
Promising Objective Response in Ovarian Cancer
The data revealed a confirmed objective response rate (ORR) of 50.0% (95% CI) in ovarian cancer patients treated with Rina-S at a dose of 120 mg/m2 once every three weeks (Q3W), irrespective of FRα expression levels. This data was derived from the dose expansion part of a multi-part study assessing the safety and efficacy of single-agent Rina-S in ovarian cancer (OC) and endometrial cancer (EC).
In Part B of the study, 42 previously-treated patients with histologically or cytologically confirmed advanced OC (epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer) were randomized to receive either Rina-S 100 mg/m2 (n=22) or Rina-S 120 mg/m2 (n=20). Notably, 95% of patients in the 120 mg/m2 group and 90.9% in the 100 mg/m2 group were identified as having platinum-resistant ovarian cancer (PROC).
The results indicated a confirmed ORR of 18.2% in patients receiving Rina-S 100 mg/m2, compared to the significantly higher 50.0% in those receiving 120 mg/m2. In the 120 mg/m2 arm, one patient (5.6%) achieved a complete response, and eight patients (44.4%) experienced a partial response. The disease control rate (DCR) was 86.4% and 88.9% (95% CI: 65.3-98.6) for the 100 mg/m2 and 120 mg/m2 doses, respectively. With a median follow-up of 24 weeks, all confirmed responses in the 120 mg/m2 dose group were ongoing at the time of data cutoff. Based on these findings, the Rina-S 120 mg/m2 dose has been selected for further evaluation in a Phase 3 trial for patients with advanced ovarian cancer, expected to commence in 2024.
Expert Commentary
"Ovarian cancer presents a significant challenge, especially for those with advanced or recurrent cases, where treatment options and prognosis are often limited," said Elizabeth Lee, MD, a medical oncologist at Dana-Farber. "The encouraging Phase 1/2 data for Rina-S demonstrates the potential for future treatment options for patients. We are looking forward to additional data from tumor-specific dose expansion cohorts."
Safety Profile
The most common treatment-emergent adverse events (TEAEs) observed in the Phase 1/2 study included anemia, neutropenia, nausea, thrombocytopenia, leukopenia, fatigue, vomiting, alopecia, and diarrhea. Dose reductions and treatment discontinuations were infrequent, and no signals of ocular toxicities, neuropathy, or interstitial lung disease (ILD) were reported.
Future Development
"We are encouraged by the data from this ongoing Phase 1/2 trial evaluating Rina-S in a patient population that is in need of new therapeutic options and believe the data support the potential for Rina-S to demonstrate anti-tumor activity beyond first-generation folate receptor-alpha based therapies," said Jan van de Winkel, Ph.D., President and Chief Executive Officer of Genmab. The company aims to evaluate the full potential of Rina-S in patients with ovarian, endometrial, and other solid tumor cancers.
Trial Design
The open-label, multicenter Phase 1/2 study (NCT05579366) is designed to assess the safety and efficacy of rinatabart sesutecan (Rina-S) as a single agent Q3W at various doses in solid tumors known to express FRα. The study includes dose-escalation cohorts (Part A), tumor-specific monotherapy dose-expansion cohorts (Part B), a platinum-resistant ovarian cancer (PROC) cohort (Part C), and combination therapy cohorts (Part D).
Part A involved dose escalation in patients with locally advanced and/or metastatic solid tumors, including epithelial ovarian cancer, endometrial cancer, breast cancer, non-small cell lung cancer, and mesothelioma. In patients with OC (n=32) and EC (n=11), treatment with Rina-S 100-120 mg/m2 (n=23 and n=5, respectively) showed a confirmed Objective Response Rate (ORR) of 30.8% (95% CI: 14.3-51.8).
Part B included a dose expansion study in patients with histologically or cytologically confirmed advanced OC. Patients were randomized 1:1 to 100 mg/m2 and 120 mg/m2 dose groups. Study participants had previously been treated with a median of 3 prior lines of therapy, including bevacizumab and PARP inhibitors. Responses in patients with OC were observed across FRα expression levels.
Ovarian Cancer Burden
Ovarian cancer is a significant global health concern, with over 320,000 new cases diagnosed annually worldwide. It is the eighth most common cancer and the eighth leading cause of cancer-related deaths among women globally. Due to its subtle and non-specific symptoms, the disease is often diagnosed at an advanced stage. Platinum-based chemotherapy, often combined with targeted therapies and surgery, remains the standard treatment. However, approximately 70-90% of women with advanced-stage ovarian cancer experience a recurrence after initial treatment, resulting in a low five-year survival rate.
