Avutometinib/Defactinib Betters ORR in Recurrent Ovarian Cancer

Gynecologic Cancer Illustration: © Crystal Light - stock.adobe.com

The combination of avutometinib (VS-6766) and defactinib (VS-6063) demonstrated improvements in overall response rate (ORR) compared with prior lines of therapy in patients with recurrent low-grade serious ovarian cancer (LGSOC), according to findings from a subgroup analysis of part A of the RAMP 201 trial (NCT04625270).

Findings were presented at the Annual Global Meeting of the International Gynecologic Cancer Society in Seoul, Korea, and showed that among patients in the combination arm who had received 1-3 prior lines of treatment the ORR was 45.5% (5/11; 95% CI, 17-77), while the ORR was 44.4% (8/18; 95% CI, 22-69) in patients who had received 4 or more prior lines of therapy. The combination of avutometinib and defactinib delivered an ORR of 43.5% across this subgroup while before enrollment, only 2 of 23 patients (8.7%) responded to their last prior treatment.

Safety profiles appeared to be similar across less and more heavily pretreated populations, and the safety data were consistent with what was previously reported. Most treatment-emergent adverse events were mild to moderate.

“Patients with recurrent LGSOC currently have no medicines approved by the U.S. [United States] Food and Drug Administration and limited treatment options for their disease,” said Rachel Grisham, MD, section head, Ovarian Cancer and Director, Westchester Gynecologic Medical Oncology at Memorial Sloan Kettering Cancer Center, and the lead U.S. investigator of the study, in a press release.¹ “The results from this analysis are encouraging as the combination of avutometinib and defactinib demonstrates robust efficacy in recurrent LGSOC irrespective of the number of prior therapies, and for most of which, response to previous therapy was poor.”

Initial results from the phase 2, open-label, randomized RAMP 201 trial showed an ORR of 45% (n = 13) and tumor shrinkage in 86% (n = 25) in 29 evaluable patients treated with avutometinib and defactinib.

About RAMP 201

RAMP 201 is an open-label, multicenter, randomized, phase 2 trial evaluating avutometinib, a dual RAF/MEK inhibitor, and defactinib, an FAK inhibitor, for efficacy, safety, and tolerability in patients with recurrent LGSOC with and without a KRAS mutation. The trial has an estimated enrollment of 225 and an estimated completion date of December 2026.²

The trial’s primary endpoint is ORR per RECIST v1.1. The secondary end points are ORR assessed by investigator, duration of response, disease control rate, progression-free survival, and overall survival.

Patients were eligible for the trial if they were female, aged 18 years or older, had histologically proven LGSOC, progression or recurrence of disease after at least 1 prior line of therapy, measurable disease according to RECIST v1.1, an ECOG performance status of 1 or more, adequate organ function, and adequate recovery from toxicities from prior treatments.

Patients were not eligible to participate if they had received systemic anti-cancer therapy within 4 weeks of enrollment, co-existing high-grade ovarian cancer, received major surgery within 4 weeks of enrollment, symptomatic brain metastases requiring medical intervention, a history of rhabdomyolysis, or concurrent heart or obstructive pulmonary disease.

Next Steps

The phase 3 RAMP 301 trial is a confirmatory trial investigating avutometinib and defactinib vs standard-of-care chemotherapy or hormonal therapy in LGSOC. Avutometinib is also being investigated in combination with sotorasib (Lumakras) and adagrasib (Krazati) in KRAS G12C-mutated non­–small cell lung cancer. A phase 1b/2 trial is also evaluating avutometinib and defactinb with gemcitabine/nab-paclitaxel in patients with metastatic pancreatic cancer.¹

REFERENCES:

1. Verastem Oncology announces efficacy and safety data of avutometinib and defactinib in recurrent low-grade serious ovarian cancer (LGSOC) in heavily pretreated patient population. News release. Verastem Oncology. November 6, 2023. Accessed November 6, 2023. https://tinyurl.com/wf4kb6nr

2. A study of avutometinib (VS-6766) v. avutometinib (VS-6766) + defactinib in recurrent low-grade serious ovarian cancer with and without a KRAS mutation (RAMP 201). ClinicalTrials.gov. Updated September 15, 2023. Accessed November 6, 2023. https://www.clinicaltrials.gov/study/NCT04625270