RAF-MEK Inhibitor/Defactinib Combo Is Active in KRAS-Mutant Cancers

Udai Banerji, MD

The combination of the RAF-MEK inhibitor VS-6766 (CH5126766) and the FAK inhibitor defactinib (VS-6063) elicited early signals of clinical activity in a group of patients with KRAS-mutant advanced cancers, according to preliminary results from a small, ongoing phase 1 trial (NCT03875820) that were presented during the 2020 AACR Virtual Annual Meeting I.¹

Specifically, results showed that in patients with KRAS-mutant low-grade serous ovarian cancer (LGSOC; n = 6), the overall response rate (ORR) with the combination was 67%. In all patients with LGSOC, the ORR was 50%; three of the patients who responded had previously received a MEK inhibitor. Additionally, responses were found to be durable, as a number of patients remained on treatment for 1 year or longer.

Additionally, in patients with KRAS-mutant non—small cell lung cancer (NSCLC; n = 10), 1 partial response (PR) was reported and 8 patients achieved disease control. One patient experienced a 22% tumor reduction and was still on treatment as of November 2019.

Responses were also observed in patients who had KRAS-mutant disease, but who did not harbor the G12C alteration, explained senior author Udai Banerji, MD, who is the National Institute for Health Research Professor of Molecular Cancer Pharmacology and Honorary Consultant in Medical Oncology at the Royal Marsden NHS Foundation Trust, in a virtual presentation during the meeting.

“We have a recommended phase 2 dose of the combination; we have proof-of-concept pharmacodynamic changes; and we have found that the pharmacokinetic profile is not dissimilar to [that of] the single agents,” Banerji said. “We have early promising clinical efficacy in low-grade serous ovarian cancer, and studies in other KRAS-mutant cancers are ongoing.”

Standard regimens for patients with LGSOC—such as chemotherapy (<10%), letrozole (13%), and trametinib (Mekinist; 26%)—are associated with low to modest ORRs, Banerji explained.

Preclinical experimental models have demonstrated tumor regression with the combination of FAK inhibition plus VS-6766.² Following MEK inhibition, there is a rewiring of signal transduction, and FAK inhibition leads to a reduction in T-reg populations.

The ongoing, open-label, dose-escalation, and dose-expansion phase I trial had a number of cohorts: VS-6766 administered at 3.2 mg twice weekly on a 3-weeks-on/1-week-off schedule combined with 200 mg twice daily of defactinib, also on a 3-weeks-on/1-week-off schedule (cohort 1); VS-6766 at 4 mg twice weekly plus defactinib given at 200 mg twice daily, both on a 3-weeks-on/1-week-off schedule (cohort 2a); VS-6766 given at 3.2 mg twice weekly combined with defactinib given at 400 mg twice daily, both at a 3-weeks-on/1-week-off schedule (cohort 2b); and VS-6766 given at 4 mg twice weekly plus defactinib at 400 mg twice daily, both at a 3-weeks-on/1-week-off schedule (cohort 3).

Safety was evaluated in 3 of the dose-escalation cohorts. In cohort 1 (n = 3), grade 1/2 adverse events (AEs) included rash (n = 2), CK elevation (n = 2), nausea (n = 1), hyperbilirubinemia (n = 1), diarrhea (n = 2), vomiting (n = 1), paronychia (n = 1), and conjunctivitis (n = 11); 2 grade 3/4 AEs of hyperbilirubinemia and anemia (n = 1 each) were reported.

In cohort 2a (n = 6), 28 grade 1/2 AEs included: rash (n = 6), CK elevation (n = 2), nausea (n = 3), hyperbilirubinemia (n = 1), diarrhea (n = 1), visual disturbance (n = 2), vomiting (n = 2), paronychia (n = 1), aspartate aminotransferase (AST) elevation (n = 1), fatigue (n = 2), alanine aminotransferase (ALT) elevation (n = 1), alopecia (n = 2), thrombocytopenia (n = 2), skin infection (n = 1), and mouth soreness (n = 1). There were 2 grade 3/4 AEs, which included CK elevation (n = 1) and hyperbilirubinemia (n = 1).

In cohort 2b (n = 3), the grade 1/2 AEs included rash (n = 3), CK elevation (n = 1), nausea (n = 2), hyperbilirubinemia (n = 1), diarrhea (n = 2), visual disturbance (n = 2), paronychia (n = 1), AST elevation (n = 1), ALT elevation (n = 1), anemia (n = 1), skin infection (n = 1), fever (n = 1), and face pain (n = 1). No grade 3/4 AEs were reported.

Based on these safety data, the recommended phase 2 dose was determined to be VS-6766 at 3.2 mg twice weekly plus 200 mg of defactinib twice daily, both given on a 3-weeks-on/1-week-off schedule in 28-day cycles.

The post-recommended phase 2 dose expansions were conducted in patients with LGSOC (n = 20), KRAS-mutated NSCLC (n = 20); and KRAS-mutated colorectal cancer (CRC; n = 10).

Regarding pharmacokinetics, which were assessed on day 15 of the combination treatment, the profile of the combination was similar to what has been seen in single-agent studies. For pharmacodynamics, this was assessed via multiple tumor biopsies in patients, which was conducted prior to treatment, following a single dose of VS-6766, and another biopsy following treatment with the combination.

Additional data showed that, in the LGSOC subset, the median time on treatment was 20.5 months. In the NSCLC cohort, 70% of patients continued on treatment for at least 12 weeks, and 30% of patients continued on therapy for at least 24 weeks.

“We have demonstrated an increase in phospho-FAK after the RAF-MEK inhibitors were administered, and this came down after the combination with defactinib,” said Banerji. “We also showed a reduction in FOXP3 cells with the combination.”

A combined analysis, which was not part of the presentation during the 2020 AACR Virtual Annual Meeting, looked at data from the combination study and a prior single-agent study of VS-6766 to understand the activity in patients with KRAS G12V mutations.³

The subsequent, combined analysis demonstrated a 57% ORR (n = 4/7 patients), with single-agent VS-6766 (n = 2/5 patients) and in combination with defactinib (n = 2/2 patients) in patients with KRAS G12V—mutant NSCLC. The combined analysis also showed a 60% ORR (n = 3/5 patients); as a single agent (n = 1/2 patients) and in combination with defactinib (n = 2/3 patients) in KRAS G12V—mutant gynecologic cancers.

References

1. Shinde R, Terbuch A, Little M, et al. Phase I study of the combination of a RAF-MEK inhibitor CH5126766 and FAK inhibitor defactinib in an intermittent dosing schedule with expansions in KRAS mutant cancers. Presented at: 2020 AACR Virtual Annual Meeting; April 27-28, 2020. Abstract CT143.
2. Serrels A, Lund T, Serrels B, et al. Nuclear FAK controls chemokine transcription, Tregs, and evasion of anti-tumor immunity. Cell. 2015;163(1):160-173. doi:10.1016/j.cell.2015.09.001
3. 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. bwnews.pr/35gGVRh. Accessed April 29, 2020.

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