The RAF/MEK and FAK inhibitor combination avutometinib (VS-6766) plus defactinib (VS-6063) represents a novel area of exploration that has displayed clinical activity and a manageable safety profile in patients with low-grade serous ovarian cancer, according to Bradley J. Monk, MD, FACS, FACOG.

In 2021, avutometinib plus defactinib received breakthrough therapy designation from the FDA for patients with recurrent low-grade serous ovarian cancer, based on findings from the phase 1 FRAME trial (NCT03875820). In FRAME, the combination led to an overall response rate (ORR) of 46% in this population.¹

Moreover, findings from the RAMP 201 trial (NCT04625270), presented at the 2023 ASCO Annual Meeting, showed that patients with low-grade serous ovarian cancer who received the combination achieved an ORR of 45% vs 10% in those who received avutometinib alone.²

“[This is] great news for patients that now we have a combination that is tolerable and has an ORR of 45%,” Monk said.

In an interview with OncLive®, Monk discussed the rationale for investigating avutometinib plus defactinib in patients with low-grade serous ovarian cancer, key findings from RAMP 201, and how this research may influence the ovarian cancer treatment paradigm going forward.

Monk is a professor in the Division of Gynecologic Oncology at the University of Arizona College of Medicine and Creighton University School of Medicine, both in Phoenix, as well as director and principal investigator of Community Research Development at HonorHealth Research Institute in Scottsdale, Arizona. He is also the vice president and a member of the Board of Directors of the GOG-Foundation and co-director of GOG-Partners.

OncLive: What is the role of the RAS/MAPK pathway in low-grade serous ovarian cancer, and what is the rationale for evaluating avutometinib and defactinib in this population?

Monk: The MAPK pathway, characterized by RAS, RAF, MEK, and ERK alterations, drives the biology and malignant phenotype of low-grade serous ovarian cancer. It is activated in greater than 70% of low-grade serous ovarian cancers and can be targeted with a MEK inhibitor, such as avutometinib. There [may also be] an exaggerated effect with [the addition of] FAK inhibitors such as defactinib.

Avutometinib is a RAF/MEK inhibitor that is unique compared with other MEK inhibitors. It has novel intermittent dosing, and it has a breakthrough therapy designation in low-grade serous ovarian cancer. It is potentially the best-in-class [agent] based on its activity, as well as its tolerability. The preclinical antiproliferative activity [with this agent] across multiple MAPK pathway alterations, [including] RAS, BRAF, and MEK, is transformational. Defactinib is a FAK inhibitor developed by the same sponsor, and there’s an idea that maybe together they could be synergistic.

Low-grade serous ovarian cancer is different than high-grade serous ovarian cancer [because it is] not BRCA related. It’s much less common than the high-grade serous counterpart. There are currently no approved therapies for low-grade serous ovarian cancer. Because MAPK alterations [are activated in] greater than 70% [of patients], we want to utilize this new medication, avutometinib, in combination with defactinib.

What is the design of the RAMP 201 trial?

The [GOG 3052/ov-60/RAMP 201 trial], in collaboration with ENGOT, initially asked 2 questions. [One was:] Is the combination of avutometinib and defactinib better than single-agent avutometinib? That question has been answered, and the answer is yes, the combination is better. The second question that was asked was: Is it important to restrict the [study] population to patients with MAPK alterations, particularly KRAS mutations? The answer is no. This combination is active in KRAS-mutant and KRAS wild-type [disease].

What efficacy findings have been seen with avutometinib plus defactinib?

Ultimately, what was presented at ASCO was an update, now that those 2 questions have been answered [and we know that] the combination is important and [patients] do not need the biomarker. At ASCO, presented by Susana Banerjee, MBBS, MA, PhD, FRCP, of The Royal Marsden NHS Foundation Trust in London, United Kingdom, with other investigators both from ENGOT and the GOG, was mature data with 29 patients [who received the combination].

In those 29 patients with low-grade serous ovarian cancer, the response rate was 45%. In the patients with KRAS-mutant disease, it was a little higher, at 60%, [and it was] 29% in the patients with KRAS wild-type disease. The tumor shrinkage [rate], the number of patients whose cancer stopped growing and began to shrink, was 86%. It took time [for patients] to develop a response. The median time to response was 5.5 months. Because of the tolerability [of the combination], 83% [± 20%] of the patients maintained the dose intensity.

What does that 45% objective tumor response rate mean? The GOG [led the phase 2/3] Study 281 [NCT02101788] with another MEK inhibitor, trametinib [Mekinist], and [the ORR] was 26% vs 6% with chemotherapy. Then, I reported [findings from] the [phase 3] MILO trial [NCT01849874] with another MEK inhibitor binimetinib [(Mektovi), which elicited a] 16% [ORR] vs 13% with standard-of-care [SOC] chemotherapy.

This 45% ORR [with avutometinib plus defactinib] seems better than [the ORRs with] SOC chemotherapy, 6% or 13%, and better than [the ORRs with] other MEK inhibitors, trametinib and binimetinib, 26% and 16%. If you combine [the RAMP 201 findings with those from] the FRAME study, the initial study that led to breakthrough therapy designation [for avutometinib plus defactinib], in which [patients who received the combination] had a response rate of 46%, now, we have [treated] 53 patients with [the combination, which has displayed] activity that is important and clinically meaningful.

What is the safety profile of this combination?

The adverse effects [AEs] need to be noted. The most common any-grade AE [with the combination] was nausea, but there was no grade 3/4 [nausea]. There was also a 49.4% rate [of any-grade] diarrhea, but only 3.7% [of events were] grade 3/4. The third most common AE was blood creatine phosphokinase elevations, which were asymptomatic. [Other AEs included] edema, and rash. This dermatitis actinic form rash now has a mitigation strategy, which has been effective. Rash and some of these other AEs are class effects, but this appears encouraging. There were few treatment discontinuations because of AEs, 12.3% in the combination [arm].

What are the next steps for this research?

The target enrollment for the primary analysis of 72 patients has now been reached. The data are not yet mature. The plan is to combine [the findings from] RAMP 201 and [FRAME to support] accelerated approval [of this combination]. The company will soon provide an update about these FDA interactions, and ultimately, a confirmatory trial will need to be done. Congratulations to ENGOT and the GOG.

If these data continue to be positive and [avutometinib plus defactinib] reaches clinical practice, what might the addition of this combination to the treatment paradigm mean for patients with low-grade serous ovarian cancer, who currently have no approved therapies?

If we can get this medication FDA approved, this will change the SOC. This will be the SOC in patients with prior therapy [exposure] with low-grade serous ovarian cancer. [This combination generated] tumor shrinkage in most patients and an ORR, at least preliminarily, of 45%. However, we need to get the confirmatory trial going to get accelerated approval. Once we get accelerated approval in [the United States], we’ll probably need to stop the confirmatory trial enrollment here, but that will take time. For now, look for the confirmatory trial and get it enrolled so we can get this medication approved.