Dual RAF/MEK Inhibitor Shows Promising Activity in Tumors with RAS/RAF Mutations

VS-6766, a unique inhibitor of the RAF/MEK-signaling pathway, has shown antitumor activity in RAS/RAF mutation–positive solid tumors and in multiple myeloma, when administered on an intermittent dosing schedule, according to recently published data (Guo C, et al. Lancet Oncol. 2020;21:1478-1488).

According to the investigators, this phase 1 study is the first to show proof-of-concept single-agent activity of a RAF/MEK inhibitor, which is administered using an intermittent twice-weekly schedule, across a wide range of RAS/RAF-driven cancers.

KRAS mutations are extremely challenging to target, with no effective targeted therapy currently available against the majority of cancers with RAS mutations.

“The positive results observed with this innovative intermittent dosing regimen of VS-6766 demonstrate its significant potential across various cancers with RAS/RAF/MEK pathway mutations,” said lead investigator Udai Banerji, MBBS, MD, DNB, PhD, FRCP, Professor of Molecular Cancer Pharmacology, Institute of Cancer Research, London, United Kingdom.

“This intermittent schedule can be used alone, or for combination therapy schedules with other anticancer agents, for a variety of difficult-to-treat cancers,” he added.

The study, which consisted of 2 parts, enrolled 58 patients, 51 with solid tumors and 7 with multiple myeloma. Part 1 was a dose-escalation phase to determine the recommended dosage (N = 29); part 2 was a basket dose-expansion phase to investigate the efficacy and safety of the recommended dosage of 4 mg twice weekly, which was determined during the dose-escalation phase (N = 29). No dose-limiting toxicities were observed at the recommended phase 2 dosage.

Study Results

In the basket dose-expansion phase, 7 (26.9%) of 26 patients evaluable for response who had RAS mutations achieved objective responses, including 6 of 20 (30%) patients with solid tumors. In all 6 responders with solid tumors, tumor shrinkage was observed at the time of the first restaging scan after 2 cycles of treatment, with partial responses confirmed after 2 to 4 cycles. Of the 6 responses, 5 lasted >6 months.

The response rate was 30% (3/10) in patients with non–small-cell lung cancer (NSCLC), with all responses lasting >6 months; 0% (3/5) in patients with gynecologic malignancies; 0% (0/4) in those with colorectal cancer; 0% (0/1) in those with melanoma; and 16.7% (1/6) in patients with multiple myeloma, who achieved a partial response with a progression-free survival of 30 weeks. One other patient with multiple myeloma had received 5 previous lines of therapy and remains on treatment after 72 weeks of disease stability. Responders in the cohort with gynecologic malignancies were all resistant to platinum-based chemotherapy, the researchers noted.

According to the investigators, these results indicate the possibility of using a RAF/MEK inhibitor as a monotherapy, as well as in combination with other targeted therapies, in cancers that are driven by the RAS/RAF/MEK pathway mutations.

Adverse Events

Among the 57 safety-evaluable patients, the most common grade 3 or 4 treatment-related adverse events were rash (19%), creatinine phosphokinase elevation (11%), hypoalbuminemia (11%), and fatigue (7%). A total of 35 patients had treatment-

related ocular adverse events, and 5 (9%) patients had treatment-related serious adverse events.

All adverse events were manageable and resolved spontaneously or were reversed with dose modification. No treatment-related deaths were reported.

Combination Therapy

Phase 2 clinical trials with VS-6766, alone and in combination with the investigational FAK and PYK2 inhibitor defactinib, in patients with low-grade serous ovarian cancer and in patients with NSCLC and KRAS mutations are expected to begin by year-end.

Defactinib is an oral small molecule that is being evaluated as a potential therapy in combination with VS-6766 for the treatment of various solid tumors. This combination has previously been found to be clinically active in patients with cancers associated with the KRAS mutation.

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