Avutometinib Plus Defactinib Gains FDA Approval in KRAS+ Ovarian Cancer
Avutometinib given with defactinib is now approved for the treatment of adult patients with recurrent low-grade serous, KRAS-positive ovarian cancer.
US FDA
- The FDA granted accelerated approval to the combination of avutometinib (VS-6766) plus defactinib (VS-6063; Avmapki Fakzynja co-pack) for the treatment of recurrent low-grade serous ovarian cancer.
- This approval is intended for adult patients who have received at least 1 prior systemic therapy and harbor a KRAS mutation.
- Data from the phase 2 RAMP 201 trial (NCT04625270) and phase 1 FRAME trial (NCT03875820) support this approval.
The FDA has granted accelerated approval to the combination of avutometinib plus defactinib for the treatment of adult patients with recurrent low-grade serous ovarian cancer harboring a KRAS mutation and who have undergone at least 1 prior systemic therapy.1
Findings from the primary analysis of the phase 2 RAMP 201 trial support this approval as the combination of avutometinib plus defactinib generated durable responses in this patient population. Additionally, the combination was found to be generally well tolerated.
Data from the phase 1 FRAME study, the first trial conducted with this combination in recurrent low-grade serous ovarian cancer, also supported this approval.
Ovarian cancer: © Dr_Microbe - stock.adobe.com
In the multicenter, randomized, open-label RAMP 201 trial, the safety and efficacy of avutometinib given alone and with defactinib was examined in patients with histologically confirmed low-grade serous ovarian or peritoneal cancer.2 Patients aged 18 years and older with an ECOG performance status of 0 or 1, disease progression or recurrence following 1 or more lines of systemic therapy in the metastatic setting, measurable disease per RECIST 1.1 criteria, and adequate organ function were eligible for enrollment. In addition, patients were required to be fully recovered from toxicities related to previous treatments.
Part A of the trial administered avutometinib as a monotherapy or in combination with defactinib. Here, investigators aimed to identify the optimal dose for the expansion portion of the trial. In parts B and C, patients were given avutometinib plus defactinib at the optimal dose, which was determined to be 3.2 mg of avutometinib twice weekly and 200 mg of defactinib twice daily. Finally, part D utilized a lower dose of the regimen.
Overall response rate (ORR) per RECIST 1.1 criteria served as the key primary end point of the study, and secondary end points consisted of investigator-assessed ORR, duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival.
Updated findings from the RAMP 201 trial were presented at the 2024 International Gynecologic Cancer Society Annual Meeting. At a median follow-up of approximately 12 months, the confirmed ORR was 31% (95% CI, 23%-41%) per blinded independent central review among evaluable patients with measurable disease in the overall population receiving the combination of avutometinib and defactinib. This group consisted of 109 patients.3 In this group, the median DOR was 3.1 months (95% CI, 14.8-31.1), the 6-month DCR rate was 61%, and the median PFS was 12.9 months (95% CI, 10.9-20.2).
The confirmed ORR was 44% (95% CI, 31%-58%) for those given the combination who were harboring KRAS mutations (n = 57) and 17% (95% CI, 8%-30%) for those with KRAS wild-type disease (n = 52). The median DORs in these respective groups were 31.1 months (95% CI, 14.8-31.1) and 9.2 months (95% CI, 5.5-not evaluable). The 6-month DCR rates in the KRAS-mutated and wild-type populations were 70% and 50%, respectively. Further, the median PFS was 22 months (95% CI, 11.1-36.6) vs 12.8 months (95% CI, 7.4-18.4) across these arms, respectively.
For safety, 10% of patients receiving the combination discontinued treatment due to adverse events (AEs). The most common any-grade treatment-related AEs included nausea (67.0%), diarrhea (58.3%), and increased blood creatine phosphokinase levels (60.0%). Additionally, no new safety signals were reported.
