Rolling NDA Completed for Avutometinib Combo in Ovarian Cancer Subtype

Developers initiated the rolling NDA submission for avutometinib/defactinib as a therapy for those with KRAS-mutated recurrent LGSOC in May 2024.

Developers Verastem Oncology have completed a rolling new drug application (NDA) submission to the FDA seeking accelerated approval of avutometinib in combination with defactinib for adult patients with recurrent low-grade serous ovarian cancer (LGSOC) harboring KRAS mutations who have received at least 1 prior line of systemic therapy, according to a press release from the developers.¹

The FDA has received a request for priority review from the developers based on the avutometinib combination’s potential to meet an unmet need among patients with recurrent LGSOC. A filing decision from the agency is anticipated before the end of 2024. If approved, the regimen would become the first commercially available therapy intended for adults with KRAS-mutated LGSOC.

“We believe that avutometinib in combination with defactinib has the potential to change the treatment paradigm for patients with recurrent KRAS mutant [LGSOC]. Completing our NDA submission is a significant milestone not only for Verastem as we plan for potential FDA approval in mid-2025, but also for patients as there are no FDA-approved treatments specifically for this rare ovarian cancer,” Dan Paterson, president, and chief executive officer at Verastem Oncology, said in the press release.¹

Developers initiated the rolling NDA submission for avutometinib/defactinib as a therapy for those with KRAS-mutated recurrent LGSOC in May 2024.² Supporting data for the application came from the phase 2 RAMP 201 trial (NCT04625270). Investigators presented updated findings from the RAMP 201 trial at the International Gynecologic Cancer Society (IGCS) 2024 Annual Meeting in Dublin, Ireland.³

The confirmed overall response rate (ORR) with avutometinib/defactinib was 31% (95% CI, 23%-41%) across all evaluable patients (n = 109) per blinded independent central review. In the KRAS-mutated disease subgroup (n = 57), data showed a confirmed ORR of 44% (95% CI, 31%-58%). Additionally, the ORR was 17% (95% CI, 8%-30%) for those with KRAS wild-type disease (n = 52).

Treatment with avutometinib/defactinib produced a median progression-free survival (PFS) of 12.9 months (95% CI, 10.9-20.2) across all evaluable patients. Additionally, the median PFS was 22.0 months (95% CI, 11.1-36.6) and 12.8 months (95% CI, 7.4-18.4) among patients with KRAS mutations and KRAS wild-type disease, respectively.

Data showed that 10% of patients discontinued study therapy due to adverse effects (AEs). Any-grade and grade 3 or higher treatment-related AEs, respectively, included nausea (67.0% vs 2.6%), diarrhea (58.3%, 7.8%), and blood creatine phosphokinase level elevations (60.0% vs 24.3%).

“The notable response rates and low discontinuation rate seen with the combination of avutometinib and defactinib are significant. These updated results confirm the potential of this new combination therapy to change practice and be the new standard for care for recurrent low-grade serous ovarian cancer, which previously had limited effective treatment options,” lead trial investigator Susana Banerjee, MBBS, MA, PhD, FRCP, a consultant medical oncologist at The Royal Marsden NHS Foundation Trust and Team Leader in Women’s Cancers at The Institute of Cancer Research in London, United Kingdom, stated in a press release on these findings.³

In the two-part, multicenter, open-label RAMP 201 trial, investigators are assessing the safety and efficacy of avutometinib as monotherapy and in combination with defactinib among those with recurrent LGSOC. Based on findings from part A of the trial, patients will receive a go-forward regimen consisting of avutometinib at 3.2 mg twice weekly plus defactinib at 200 mg twice daily in parts B and C. In part D of the trial, investigators will assess a low dose of avutometinib plus defactinib to help determine individualized dose reduction.

Investigators are enrolling patients with recurrent LGSOC of any KRAS mutation status as part of the international phase 3 RAMP 301 trial (NCT06072781). This investigation will serve as a confirmatory trial for the avutometinib combination in this indication and may support expanded indications for any KRAS mutation status.

References

1. Verastem Oncology completes rolling NDA submission to the FDA for avutometinib plus defactinib as a treatment for recurrent KRAS mutant low-grade serous ovarian cancer. News release. Verastem Oncology. October 31, 2024. Accessed November 1, 2024. https://tinyurl.com/2eakc933
2. Verastem Oncology announces the initiation of a rolling submission of NDA to FDA seeking accelerated approval of avutometinib and defactinib combination for the treatment of adult patients with recurrent KRAS mutant low-grade serous ovarian cancer. News release. Verastem Oncology. May 24, 2024. Accessed November 1, 2024. https://tinyurl.com/mfxmuk29
3. Verastem Oncology presents positive updated RAMP 201 data for avutometinib and defactinib combination in recurrent low-grade serous ovarian cancer at the International Gynecologic Cancer Society (IGCS) 2024 Annual Meeting. News release. Verastem Oncology. October 17, 2024. Accessed November 1, 2024. https://tinyurl.com/zuxdeuwh