FDA Awards Orphan Drug Designation to Avutometinib Alone or With Defactinib for Recurrent Low-Grade Serous Ovarian Cancer


Avutometinib alone or in combination with defactinib has received an orphan drug from the FDA for recurrent low-grade serous ovarian cancer.



The FDA has granted an orphan drug designation to avutometinib (VS-6766) alone or in combination with defactinib (VS-6063) for the treatment of patients with recurrent low-grade serous ovarian cancer.1

Avutometinib is a RAF/MEK clamp intended to induce inactive complexes of MEK with ARAF, BRAF, and CRAF to potentially create a more complete and durable antitumor response through increased RAS/MAPK pathway inhibition. Unlike past MEK inhibitors, avutometinib blocks both MEK kinase activity and the ability of RAF to phosphorylate MEK, allowing avutometinib to block MEK signaling without the compensatory activation of MEK, which could limit the efficacy of other MEK-only inhibitors.

Data from the phase 2 RAMP 201 trial (NCT04625270) were presented at the 2023 ASCO Annual Meeting and showed that patients with recurrent low-grade serous ovarian cancer treated with avutometinib plus defactinib (n = 29) experienced an overall response rate (ORR) of 45% (95% CI, 26%-64%). All responders achieved a partial response (PR), and the rates of stable disease (SD) and progressive disease (PD) were 45% and 10%, respectively. The disease control rate (DCR) was 90%.2

Those treated with avutometinib monotherapy (n = 30) experienced an ORR of 10% (95% CI, 2%-24%). One patient (3%) in the monotherapy arm had a complete response, and 2 patients (7%) had a PR. The SD rate, PD rate, and DCR were 83%, 10%, and 93%, respectively.

“The FDA orphan drug designation for avutometinib alone or in combination with defactinib in low-grade serous ovarian cancer is an important step in recognizing this rare cancer as a distinct disease that currently has no FDA-approved treatments,” Dan Paterson, president and chief executive officer of Verastem Oncology, stated in a news release.1 “We are rapidly advancing the development program for avutometinib and defactinib in low-grade serous ovarian cancer with our ongoing phase 3 clinical trial to deliver this new combination treatment to patients as quickly as possible. We remain on track to begin submission of a new drug application to the FDA for accelerated approval of this combination in the first half of 2024 and preparing for a potential launch in 2025.”

RAMP 201 enrolled patients with recurrent low-grade serous ovarian cancer who received prior chemotherapy and had measurable disease per RECIST v1.1 criteria. Notably, prior treatment with a MEK inhibitor was permitted.

During parts A and B of the study, patients were assigned to receive avutometinib alone or in combination with defactinib. Those in the monotherapy arm received oral avutometinib at 4 mg twice per week on a 3-weeks-on, 1-week-off schedule. In the combination arm, avutometinib was dosed at 3.2 mg twice per week in combination with 200 mg of oral defactinib once per day on a 3-weeks-on, 1-week-off schedule.

ORR per blinded independent review served as the trial’s primary end point.

Additional data showed that patients with KRAS-mutated disease treated with the combination (n = 15) achieved an ORR of 60% and a DCR of 100%. For patients with KRAS wild-type disease (n = 14), those rates were 29% and 79%, respectively.

In the monotherapy arm, patients harboring KRAS mutations (n = 15) experienced a confirmed ORR of 13% and a DCR of 93%. Those with KRAS wild-type disease had an ORR and DCR of 6% and 88%, respectively.

Regarding safety, 29% of all patients treated with avutometinib monotherapy (n = 70) and 17% of patients given the combination therapy (n = 81) required dose reductions. Additionally, 12.3% of patients in the combination group discontinued avutometinib or defactinib due to treatment-emergent adverse effects (AEs), including 4.9% who discontinued treatment due to increased creatine phosphokinase (CPK) in the blood.

In the monotherapy arm, the most common treatment-related AEs (TRAEs) reported in more than 20% of patients included nausea (any grade, 55.7%; grade ≥3, 4.3%), diarrhea (71.4%; 4.3%), increased CPK (50.0%; 22.9%), peripheral edema (48.6%; 0%), vomiting (40.0%; 5.7%), blurred vision (41.4%; 1.4%), acneiform dermatitis (38.6%; 8.6%), fatigue (38.6%; 2.9%), rash (37.1%; 1.4%), dry skin (32.9%; 0%), and anemia (27.1%; 11.4%).

For avutometinib plus defactinib, the most common TRAEs that occurred in more than 20% of patients consisted of nausea (any grade, 61.7%; grade ≥3, 0%), diarrhea (49.4%; 3.7%), increased CPK (48.1%; 18.5%), peripheral edema (42.0%; 1.2%), vomiting (37.0%; 0%), blurred vision (35.8%; 0%), acneiform dermatitis (34.6%; 2.5%), fatigue (33.3%;, 3.7%), rash (30.9%; 2.5%), dry skin (22.2%; 0%), and anemia (17.3%; 3.7%).

Enrollment in the dose-optimization, dose-expansion, and low-dose cohorts of RAMP 201 have completed enrollment, per Verastem Oncology. The confirmatory phase 3 RAMP 301 trial (NCT06072781), which is evaluating the combination of avutometinib and defactinib compared with standard chemotherapy or hormonal therapy in patients with recurrent low-grade serous ovarian cancer, is ongoing.


  1. 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 March 6, 2024. https://investor.verastem.com/news-releases/news-release-details/verastem-oncology-receives-orphan-drug-designation-fda
  2. Banerjee SN, Ring KL, Van Nieuwenhuysen E, et al. Initial efficacy and safety results from ENGOT-ov60/GOG-3052/RAMP 201: A phase 2 study of avutometinib (VS-6766) ± defactinib in recurrent low-grade serous ovarian cancer (LGSOC). J Clin Oncol. 2023;41(suppl 16):5515. doi:10.1200/JCO.2023.41.16_suppl.5515
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