Avutometinib With Defactinib Accepted for Review by FDA in Recurrent LGSOC

Avutometinib/defactinib was granted priority review by the FDA in the treatment of patients with recurrent, KRAS-mutant low-grade serous ovarian cancer.

A new drug application (NDA) for avutometinib, an oral RAF/MEK clamp, with defactinib, an oral FAK inhibitor, has been accepted and granted priority review by the FDA in the treatment of adult patients with recurrent low-grade serous ovarian cancer (LGSOC) who have a KRAS mutation and have received at least 1 prior systemic therapy, according to a press release from the developer, Verastem Oncology.¹

The regimen’s NDA has also been granted a Prescription Drug User Fee Act date of June 30, 2025.

Previously, in March 2024, avutometinib plus defactinib received orphan drug designation.² In November 2024, developers completed their rolling NDA for the drug combination in the specified patient population.³

Results from the randomized, open-label phase 2 RAMP 201 trial (NCT04625270) assessing the safety and efficacy of avutometinib in combination with defactinib compared with avutometinib monotherapy in patients with recurrent LGSOC supported the decision. Data were shared at the International Gynecologic Cancer Society (IGCS) 2024 Annual Meeting in Dublin, Ireland in October 2024.⁴

“The FDA filing acceptance and priority review for the combination of avutometinib and defactinib underscores the critical unmet need among patients diagnosed with this rare and insidious disease. We are excited by today’s news and to potentially bring the first ever FDA-approved treatment specifically for recurrent KRAS-mutant LGSOC to patients in the US,” Dan Paterson, president and chief executive officer of Verastem Oncology, stated in the press release.¹ “With the acceptance of this NDA, we’re taking an important step forward in addressing a condition that has long been overlooked, and we look forward to working with the FDA during its review process and preparing for a commercial launch in mid-2025.”

The primary analysis, with a cutoff date of June 30, 2024, demonstrated a confirmed overall response rate (ORR) by blinded independent central review (BICR) of 31% (n = 34/109; 95% CI, 23%-41%) in all evaluable patients who had measurable disease and approximately 12 months of follow-up.⁴ In patients with KRAS-mutated disease, the confirmed ORR was 44% (n = 25/57; 95% CI, 31%-58%). The confirmed ORR was 17% (n = 9/52; 95% CI, 8%-30%) in patients with KRAS wild-type disease. The disease control rate (DCR) at 6 or more months was 61% in all evaluable patients, 70% in the KRAS-mutant group, and 50% in KRAS wild-type group.

Median duration of response (DOR) was 31.1 months (95% CI, 14.8-31.1) in all evaluable patients, 31.1 months (95% CI, 14.8-31.1) in patients with KRAS-mutant disease, and 9.2 months (95% CI, 5.5-not estimated [NE]) in those with KRAS wild-type disease. Median progression-free survival (PFS) was 12.9 months (95% CI, 10.9-20.2) in all evaluable patients, 22.0 months (95% CI, 11.1-36.6) in the KRAS-mutant group, and 12.8 months (95 CI, 7.4-18.4) in the KRAS wild-type group.

Regarding safety, 10% of patients discontinued treatment due to adverse effects (AEs). The most common treatment-related AEs (any grade, grade 3 or higher) were nausea (67.0%, 2.6%), diarrhea (58.3%, 7.8%), and increased blood creatine phosphokinase levels (60.0%, 24.3%).

The RAMP 201 trial consisted of 4 parts: part A, to determine the optimal regimen of avutometinib/defactinib or avutometinib monotherapy based on ORR; part B, to determine the efficacy of the optimal regimen chosen in part A; part C, to evaluate additional efficacy parameters for the optimal regimen identified in part A; and part D, to evaluate additional efficacy parameters for a lower dose of avutometinib with defactinib.⁵ The expansion parts of the trial (part B and C) determined the efficacy of the combo regimen, which was 3.2 mg of avutometinib twice weekly and 200 mg of defactinib twice daily.¹

Inclusion criteria include histologically proven LGSOC, progression or recurrence of disease after at least 1 prior line of therapy, measurable disease per RECIST v1.1 criteria, an ECOG performance status of 1 or lower, and adequate organ function.⁵

Patients were excluded from participation if they had history of a prior malignancy with recurrence less than 3 years from time of enrollment, co-existing high-grade ovarian cancer or another histology, concurrent heart disease or severe obstructive pulmonary disease, and history of rhabdomyolysis, among other criteria.

Additionally, results from the phase 1 FRAME trial (NCT03875820), the first study conducted with avutometinib/defactinib in recurrent LGSOC, were included in the NDA.¹

Patients with recurrent LGSOC, regardless of KRAS mutation status, are currently being enrolled in the international phase 3 RAMP 301 trial (NCT06072781), a confirmatory study for the initial indication that holds the potential to support an expanded indication regardless of KRAS status.

References

1. Verastem Oncology announces FDA acceptance and priority review of new drug application for avutometinib in combination with defactinib for the treatment of recurrent KRAS mutant low-grade serous ovarian cancer. News release. Verastem Oncology. December 30, 2024. Accessed January 2, 2025. https://tinyurl.com/57brbv3n
2. Verastem Oncology receives orphan drug designation from FDA for avutometinib alone or in combination with defactinib in recurrent low-grade serous ovarian cancer. News release. Verastem Oncology. March 5, 2024. Accessed January 2, 2025. https://tinyurl.com/2pesac44
3. 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 January 2, 2025. https://tinyurl.com/2eakc933
4. 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 January 2, 2025. https://tinyurl.com/zuxdeuwh
5. 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. Updated March 12, 2024. Accessed January 2, 2025. https://tinyurl.com/5etkr3ve