RAF/MEK Inhibitor VS-6766 Plus Defactinib Under Exploration in Recurrent Low-Grade Serous Ovarian Cancer

The oral small molecule inhibitor VS-6766 (formerly CH5126766), developed by Verastem Oncology, is now under investigation alone and in combination with the FAK inhibitor defactinib in a recently initiated, registration-directed, phase 2 trial (GOG3052; NCT04625270) in patients with recurrent low-grade serous ovarian cancer (LGSOC).¹

“The majority of patients [with LGSOC] experience a significant amount of pain and impact on their lives over a long period of time as response rates with current therapies have historically been low and the toxicity profiles of these agents make it difficult to keep patients on therapy,” Rachel N. Grisham, MD, principal investigator of the trial in the United States, as well as section head of Ovarian Cancer and director of Gynecologic Medical Oncology, at Memorial Sloan Kettering Cancer Center, stated in a press release. “This trial represents an opportunity to further evaluate the potential for improved outcomes for patients with LGSOC.” 

VS-6766 was designed to inhibit the RAF/MEK signaling pathway in a way that differs from other MEK inhibitors in development. Specifically, the agent blocks the MEK kinase activity and hinders the ability of RAF to phosphorylate MEK. Moreover, the drug’s mechanism of action is unique in that it is able to block MEK signaling without compensatory activation of MEK.

In the adaptive, multicenter, parallel cohort, open-label phase 2 trial, investigators will further examine the safety and efficacy of VS-6766 as a monotherapy and in combination with defactinib in patients with recurrent LGSOC.

In the first portion of the study, investigators will identify the optimal regimen for these patients, who will be randomized to receive the monotherapy or the combination. Data regarding objective responses will inform which regimen will be explored in the expansion portion of the trial. In this portion, investigators will evaluate the safety and efficacy of the selected regimen.

Enrollment is underway at clinical sites across the United States and Europe.

The intermittent dosing of VS-6766 was previously evaluated in patients with RAS/RAF-mutated solid tumors and multiple myeloma as part of a phase 1 (NCT03875820) trial.² The trial was comprised of 2 parts: the dose-escalation portion sought to establish the recommended dose of the agent (n = 29) and the basket expansion portion sought to evaluate the safety and efficacy of the agent when delivered at the recommended dose, which was determined to be 4 mg, twice weekly (n = 29).

Early results from the basket expansion portion of the trial showed that 26.9% of the 26 patients with RAS mutations who were determined evaluable experienced objective responses with the agent. Patients with non–small cell lung cancer (NSCLC) achieved a response rate of 30% (n = 3/10), while those with gynecologic malignancies had rate of 60% (n = 3/5) and those with multiple myeloma had a rate of 16.7% (n = 1/6). The 4 patients with colorectal cancer (CRC) and the 1 patient with melanoma did not respond.

All 6 patients with solid tumors who had responded to treatment experienced a reduction in tumor size at the time of the first restaging scan following 2 cycles of treatment. In these patients, partial responses (PRs) were confirmed after 2 to 4 cycles of therapy. The majority of these responses (n = 5/6) persisted for longer than 6 months.

Additionally, preliminary data from the phase 1/2 FRAME study showed that VS-6766, when paired with defactinib, showcased promising response rates, duration of response, and a favorable safety profile specifically in patients with LGSOC.³

In the trial, VS-6766 was given using a twice-weekly dose-escalation schedule; the agent was delivered 3 out of every 4 weeks. Defactinib was given using a twice-daily dose-escalation schedule, 3 out of every 4 weeks. Dose levels were evaluated in 3 cohorts: cohort 1 received VS-6766 at 3.2 mg and defactinib at 200 mg; cohort 2 received VS-6766 at 4 mg and defactinib at 200 mg, and cohort 2b was given VS-6766 at 3.2 mg and defactinib at 400 mg.

Updated data presented during the 2nd Annual RAS-Targeted Drug Development Summit showed that among the 17 patients with LGSOC, the doublet elicited an ORR of 41% (n = 7); all of these patients experienced PRs.⁴ 

Among a subset of 9 patients with KRAS G12V–mutant LGSOC, the ORR was even higher, at 56% (n = 5). Of the 7 patients who experienced a response with VS-6766/defactinib, 5 had previously received 1 or more MEK inhibitors.

Moreover, in patients with KRAS-mutant LGSOC who had been given the recommended phase 2 dosing (RP2D) of the regimen, which was VS-6766 at 3.2 mg and defactinib at 200 mg, the ORR was 50% (n = 3/6).

At the time of the August 17, 2020 data cutoff, 53% of patients were still on the study and 3 patients had already received treatment for 2 years or longer. The most frequently reported grade 3 or higher toxicities associated with the RP2D of the regimen included rash (4%) and elevated creatinine kinase (4%). However, no patients discontinued treatment because of treatment-related toxicities.

To take a closer look at the activity of these agents in patients whose tumors harbor KRAS G12V mutations specifically, investigators conducted a combined analysis of findings from the combination and single-agent study that had utilized a twice-weekly dosing schedule; these data were presented during the 2020 AACR Virtual Annual Meeting I.⁴ Results revealed a 57% objective response rate (ORR) in patients with KRAS G12V–mutant NSCLC mutations (n = 4/7) and a 60% ORR in those with KRAS G12V–mutant gynecologic cancers.

“Based on my experience treating patients with low-grade serous ovarian cancer in the phase 1/2 FRAME trial, I have seen firsthand the potential for the combination of VS-6766 and defactinib, particularly in KRAS-mutated tumors, which may address the significant limitations we have seen with other therapeutic approaches,” lead Europen trial investigator Susana Banerjee, MD, PhD, medical oncologist and research lead for the Gynaecology Unit at The Royal Marsden and team leader at The Institute of Cancer Research, London, Global, added in the release. “This [phase 2] trial will further explore the encouraging response rates, durability, and safety profile of VS-6766 and defactinib demonstrated in early phase 3 studies and enable us to evaluate VS-6766 alone and in combination with defactinib to address the unmet needs of women with this specific type of ovarian cancer.”

References

1. Varastem Oncology initiates phase 2 registration-directed trial of VS-6766 and defactinib in recurrent low-grade serous ovarian cancer. News release. Verastem, Inc. November 30, 2020. Accessed January 6, 2021. http://bit.ly/38iqHu3.
2. Verastem Oncology announces new data published in The Lancet Oncology supports potential of VS-6766 as treatment for RAS mutant tumors. News release. Verastem, Inc. October 28, 2020. Accessed January 6, 2021. http://bit.ly/2MByE5f.
3. Verastem Oncology announces presentation of updated phase 1/2 FRAME study data at the 2nd Annual RAS-Targeted Drug Development Summit. News release. Verastem, Inc. September 16, 2020. Accessed January 6, 2021. http://bit.ly/2XgD7wj.
4. Verastem Oncology announces preliminary data from investigator-initiated study highlighting clinical activity of RAF/MEK and FAK combination in KRAS mutant tumors presented at the American Association for Cancer Research 2020 Virtual Annual Meeting I. News release. Verastem, Inc. April 27, 2020. Accessed January 6, 2021. http://bit.ly/35iTXz1.