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Clinical Activity of RAF/MEK + FAK Combo in KRAS-Mutant Tumors

Nalley, Catlin

doi: 10.1097/01.COT.0000681588.72619.4b
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KRAS-Mutant Tumors
KRAS-Mutant Tumors:
KRAS-Mutant Tumors

Results from a phase I study suggest that a novel intermittent schedule of a RAF-MEK plus FAK inhibitor has promising clinical activity among patients with KRAS-mutant, low-grade serous ovarian cancer (LGSOC), including patients previously treated with a MEK inhibitor, according to findings presented at the AACR 2020 Virtual Annual Meeting (Abstract CT143).

“KRAS-mutant tumors are highly aggressive, notoriously difficult to treat, and quite common across advanced solid tumors, including LGSOC, non-small cell lung cancer (NSCLC), and colorectal cancer (CRC), resulting in the need for novel treatments in an area of significant medical need,” noted lead investigator Udai Banerji, MBBS, MD, DNB, PhD, FRCP, Professor of Molecular Cancer Pharmacology at The Institute of Cancer Research, London, and Honorary Consultant in Medical Oncology at The Royal Marsden NHS Foundation Trust.

“I felt that early signals in preclinical research warranted a clinical trial; so that, combined with my RAS experience, made pursuing the phase I study a clear fit,” he continued. “Our aim was to explore RAF and RAS inhibitor combinations in multiple tumor types, and the only way to do that is through clinical trials.”

Study Details

The data presented at AACR describe safety and dose response findings from the dose-escalation portion and expansion cohorts from an open-label, investigator-initiated phase I study assessing the combination of VS-6766 and defactinib in patients with LGSOC and KRAS-mutant NSCLC.

The expansion cohorts are currently ongoing among patients with advanced solid tumors, including LGSOC, KRAS-mutant NSCLC, and KRAS-mutant CRC.

The researchers administered the RAF-MEK inhibitor, VS-6766, in a highly intermittent, twice-a-week schedule, according to Banerji. “The FEK inhibitor, defactinib, was given on a twice-a-day schedule,” he explained during the AACR poster presentation. “Both drugs were given on a 3-week-on, 1-week-off cycle. Once we reached our recommended phase II dose, we planned expansions in 20 patients with LGSOC, 20 patients with KRAS-mutant NSCLC, and 10 patients with KRAS-mutant CRC.

“In studies, MEK inhibitors, especially in combination, have historically experienced issues with toxicities,” Banerji told Oncology Times. “So, my colleagues and I designed the phase I study such that it allowed us to give patients enough of the drug in an intermittent schedule to be able to inhibit the target for periods of time without resulting in high toxicity in patients observed to date.”

The dose levels explored included cohort 1 (VS-6766 3.2 mg, 200 mg defactinib), cohort 2a (VS-6766 4 mg, defactinib 200 mg), and cohort 2b (VS-6766 3.2 mg, defactinib 400 mg). Researchers determined that the recommended phase II dose was cohort 1.

The investigators collected pharmacokinetic data at cycle 1, day 15 when both drugs were administered, according to the study authors. “In a subset of patients consenting to multiple biopsies, three biopsies were performed (baseline, after a single dose of VS-6766 run in, and after 8-15 days of the combination therapy),” they noted.

Safety Profile & Clinical Activity

At the time of the presentation, 42 patients have been treated on the trial. Researchers reported no dose-limiting toxicities (DLTs) in the first three patients in cohort 1, so patients were recruited to cohort 2a and 2b.

“The cohort 2b dose level was deemed intolerable because of 2/3 patients experiencing DLTs of grade 2 rash, not allowing dosing of 75 percent of the planned dose,” they explained. “No DLTs were seen in the first six patients treated on schedule 2a. However, given chronic grade 2 toxicities in patients on treatment >6 months, the recommended phase II dose was deemed to be cohort 1.”

The most common side effects were rash, CK elevation, AST elevation, hyperbilirubinemia, and nausea, most of which were grade 1-2. The researchers reported that all changes were reversible.

The researcher found that the pharmacokinetic profile was similar to what has been observed in single-agent studies. In terms of pharmacodynamics, they conducted multiple tumor biopsies in patients, one before treatment, one after a single dose of the RAF-MEK inhibitor, and one after the combination, according to Banerji.

“We have demonstrated increase in p-FAK after the RAF-MEK inhibitor was administered and this came down after the combination with the FEK inhibitor,” he said. “We've also shown reduction in FOXP3 cells with the combination.”

Early preliminary efficacy findings support the clinical activity of this combination approach. Among patients with LGSOC (n=8), the response rate was 50 percent (n=4). For those with KRAS-mutant LGSOC (n=6), it was 67 percent (n=4). Of the four patients who responded, three had been previously treated with a MEK inhibitor. Median time on treatment was 20.5 months.

A number of patients with KRAS-mutant NSCLC showed tumor regression, according to Banerji. In this cohort (n=10), one patient achieved a partial response. Additionally, one patient with KRASG12D-mutant NSCLC achieved a 22 percent tumor reduction and was still on treatment as of November 2019, he reported.

Seventy percent continued on treatment at least 12 weeks and 30 percent of patients continued on treatment at least 24 weeks. The median time on treatment for this cohort was approximately 18 weeks.

“The preliminary data reported in the study suggest that a novel intermittent dosing schedule of RAF/MEK and FAK inhibitor combination therapy has promising clinical activity in patients with KRAS-mutant LGSOC and KRASG12V-mutant NSCLC, including patients with LGSOC previously treated with a MEK inhibitor,” Banerji said. “Expansion cohorts remain ongoing in areas of high unmet clinical need in oncology.”

Clinical Implications

This data has potential implications for patients with LGSOC, a subset of ovarian cancer where more than 50 percent of cases have RAS or RAF mutation, according to Banerji.

“Currently, the standard of care for LGSOC is chemotherapy and response rates are quite low, less than about 10 percent. Other treatments are hormonal treatments which have a response rate of about 13 percent,” he said. “Overall, the combination of VS-6766 and defactinib in LGSOC was well-tolerated by the patients in the trial and shows promising clinical activity, including durable response that is associated with clinically meaningful benefit, which is encouraging to see.

“In lung cancer, we've been looking for a treatment for RAS for the last 30 years, and there's a lot of excitement for compounds that target specific KRAS mutations,” Banerji noted. “We are starting to see signals of KRAS-mutant response, which could be a game changer. The data for lung cancer are currently not as strong as in ovarian cancer, but there are positive signals that need to be explored.”

This phase I combination regimen may have also had broader implications for other disease types. “Given that the RAS gene is mutated in about 30 percent of cancers, it is encouraging to see that, for KRAS-proven cancers, this combination regimen was well-tolerated in patients observed to date and demonstrated clinical activity,” he concluded. “The research sets us up to evaluate the potential of this combination and regimen in patients with other cancer subsets.”

Catlin Nalley is a contributing writer.

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