FDA Receives Rolling NDA for Avutometinib Combo in KRAS+ Ovarian Cancer

Developers have reached an agreement with the FDA in which primary efficacy analysis findings from the phase 2 RAMP 201 trial (NCT04625270) may be submitted with a year of follow-up.

Developers have begun their rolling submission of a new drug application (NDA) to the FDA intended to support the accelerated approval of avutometinib plus defactinib as a treatment for adults with recurrent low-grade serous ovarian cancer (LGSOC) harboring KRAS mutations previously treated with 1 line of systemic therapy, according to a press release from Verastem Oncology.¹

As part of the rolling review process, developers can submit individually completed sections of an application before all portions are available for review. Developers have reached an agreement with the FDA in which primary efficacy analysis findings from the phase 2 RAMP 201 trial (NCT04625270) may be submitted with a year of follow-up. Moreover, developers intend to submit the clinical module portion in the second half of 2024 to complete the NDA submission.

“The initiation of our rolling NDA submission of the avutometinib and defactinib combination for accelerated approval is an important step towards addressing the significant unmet needs that patients [have] living with KRAS mutant [LGSOC],” Dan Paterson, president and chief executive officer at Verastem Oncology, said in the press release. “The data from our ongoing RAMP 201 trial continues to support our belief that the avutometinib and defactinib combination has the potential to be a new standard of care in patients with recurrent low-grade serous ovarian cancer, if approved.”

According to findings from the RAMP 201 trial presented at the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer, treatment with avutometinib/defactinib yielded an overall response rate (ORR) of 45% (n = 13; 95% CI, 26%-46%).² Additionally, the ORR was 60% among patients with KRAS mutations (n= 15) and 29% in those with KRAS wild-type disease (n = 14). Investigators reported that 86% of patients had tumor regression following study treatment.

The rate of grade 3 or higher treatment-emergent adverse effects (TEAEs) with avutometinib/defactinib was comparable among patients who received 1 to 3 prior lines of therapy and those who had at least 4 prior lines of therapy. Common toxicities of this type included nausea, diarrhea, vomiting, vision blur, fatigue, rash, and dry skin.

The RAMP 201 trial included 4 parts: the selection phase, the expansion phase, the combination expansion phase, and the lower-dose combination expansion phase. In all phases, patients were assigned to receive avutometinib at 3.2 mg twice weekly plus defactinib at 200 mg twice daily.

The trial’s primary end point across all phases was ORR per RECIST v1.1 criteria.³ Secondary end points included duration of response, disease control rate, progression-free survival, and overall survival.

Patients 18 years and older with histologically confirmed LGSOC that has progressed or recurred following 1 or more prior lines of systemic therapy in the metastatic setting were eligible for enrollment on the trial. Additional eligibility criteria included having measurable disease based on RECIST v1.1 guidelines, an ECOG performance status of 0 or 1, adequate organ function, and adequate recovery from toxicities associated with prior therapies.

Those with receipt of systemic anti-cancer therapy within 4 weeks of study entry or co-existing high-grade ovarian cancer or another histology were unable to enroll on the study. Patients were also unsuitable for study entry if they had major surgery within 4 weeks of beginning treatment, symptomatic brain metastases requiring management with steroids, a history of rhabdomyolysis, or concurrent ocular disorders.

Investigators anticipate presenting mature data from the RAMP 201 trial at a future medical conference in the second half of 2024.

References

1. 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 May 24, 2024. https://tinyurl.com/mfxmuk29
2. Banerjee SN, Nieuwenhuysen EV, Santin AD, et al. Avutometinib + defactinib in recurrent low-grade serous ovarian cancer (LGSOC): a subgroup analysis of ENGOT-ov60/GOG-3052/RAMP 201 part A. Presented at: 2024 SGO Annual Meeting on Women’s Cancer; March 16-18, 2024; San Diego, CA.
3. A study of avutometinib (VS-6766) v. avutometinib (VS-6766) + defactinib in recurrent low-grade serous ovarian cancer with and without a KRAS mutation (RAMP 201). ClinicalTrials.gov. Accessed May 24, 2024. https://tinyurl.com/4maksf86