Poster Session During the 2019 Annual Meeting of the American Association for Cancer Research. Photo Courtesy 2019 AACR.

Results from the ongoing investigator-initiated Phase I clinical study investigating VS-6766 (formerly known as CH5126766, CKI27, and RO5126766), an RAF/MEK inhibitor in combination with defactinib, an oral small-molecule inhibitor of FAK and PYK2 being developed by Verastem Oncology, shows a 67% (4/6 Patients) Overall Response Rate (ORR) in KRAS Mutant Low-Grade Serous Ovarian Cancer.

A subsequent combined analysis (VS-6766 monotherapy and defactinib combination) demonstrates 57% (4/7 Patients) overall response rate in KRASG12V Non-Small Cell Lung Cancer (NSCLC).

The data to be presented as a virtual poster during the American Association for Cancer Research (AACR) 2020 Virtual Annual Meeting I being held April 27-28, 2020.

Dose escalation and expansion
This ongoing study is an open-label, dose-escalation, and expansion study. The expansion cohorts are currently ongoing in patients with advanced solid tumors, including low-grade serous ovarian cancer (LGSOC), KRAS mutant non-small cell lung cancer (NSCLC), and KRAS mutant colorectal cancer (CRC).

In the LGSOC cohort, among the patients with KRAS mutant tumors (n=6), 4 patients responded, for an overall response rate (ORR) of 67%. Median time on treatment was 20.5 months. In the KRAS mutant NSCLC cohort (n=10), 1 patient achieved a partial response and 8 patients achieved disease control. In this cohort, 70% of patients continued on treatment at least 12 weeks and 30% of patients continued on treatment at least 24 weeks.

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Based on an observation of higher response rates seen in patients with KRASG12V mutations in the investigator-initiated Phase 1 combination study, we conducted a combined analysis with data from the combination study and the prior single-agent study that utilized a twice-weekly dosing schedule of VS-676 [1] to get a more complete picture of activity in KRASG12V mutations.

Combination Analysis
The subsequent, combined analysis (VS-6766 monotherapy and defactinib combination) showed a 57% ORR (4/7 patients); as a single agent (2/5 patients) and in combination with defactinib (2/2 patients) in KRASG12V mutant NSCLC. Similarly, the combined analysis showed a 60% ORR (3/5 patients); as a single agent (1/2 patients) and in combination with defactinib (2/3 patients) in KRASG12V mutant gynecologic cancers.

These additional analyses were conducted by Verastem Oncology to understand the impact that various KRAS variants may have had on response to identify potential signals to pursue in future prospective studies.

Thes additional analysis was not part of the AACR 2020 poster presentation.

“Earlier research has demonstrated MEK inhibitors can cause upregulation of FAK in KRAS mutant tumors, which are notoriously difficult to treat and quite common across solid tumors. The combination of a RAF/MEK and FAK inhibitor can potentially overcome this challenge and opens up an exciting new pathway for treatment,” stated Professor Udai Banerji, MBBS, MD, DNB, Ph.D, FRCP, Professor of Molecular Cancer Pharmacology at The Institute of Cancer Research, London, United Kingdom and Honorary Consultant in Medical Oncology at The Royal Marsden NHS Foundation Trust, London. Banerji is the lead investigator of the clinical study.

“We found that the combination of VS-6766 and defactinib in low-grade serous ovarian cancer (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. The study continues to enroll additional patients into the ovarian, lung and colorectal expansion cohorts with additional responses seen in all cohorts,” Banerji added.

“We are encouraged by these early response rates in KRAS mutant LGSOC and in KRASG12V mutant tumors as they underscore the significant potential of this novel approach in areas of high unmet medical need,” said Brian Stuglik, Chief Executive Officer of Verastem Oncology.

“The potential of the combination of VS-6766 and defactinib is rapidly evolving as we continue to gain more insights and analyze the data. We plan to initiate discussions with regulatory authorities as soon as possible to define a path forward, with the goal of commencing a registration-directed clinical trial during 2020,” Stuglik concluded.

Initial Results
The poster presented during the AACR digital annual meeting describes safety and dose-response data from the dose-escalation portion and expansion cohorts from an open-label, investigator-initiated Phase I study conducted in the United Kingdom assessing the combination of RAF/MEK and FAK inhibitor therapy in patients with LGSOC and KRAS mutant NSCLC.

The study evaluated the combination of VS-6766 and defactinib. VS-6766 was administered using a twice-weekly dose-escalation schedule and was administered 3 out of every 4 weeks. Defactinib was administered using a twice-daily dose-escalation schedule, also 3 out of every 4 weeks. Dose levels were assessed in 3 cohorts: cohort 1 (VS-6766 3.2mg, defactinib 200mg); cohort 2a (VS-6766 4mg, defactinib 200mg); and cohort 2b (VS-6766 3.2mg, defactinib 400mg).

In patients with LGSOC (n=8), the ORR was 50% (n=4). Among the patients with KRAS mutant LGSOC (n=6), the ORR was 67% (n=4). Of the 4 patients who have responded, 3 had a prior MEK inhibitor and as of November 2019 had been on study for a median of 20.5 months (range 7-23 months). In the patients with NSCLC (n=10), all of which had KRAS mutations, 1 patient achieved a partial response, and 1 patient with a 22% tumor reduction still on treatment as of November 2019. Median time on treatment for this cohort was approximately 18 weeks.

Adverse events
The most common side effects seen in the Phase 1 study were rash, creatine kinase elevation, nausea, hyperbilirubinemia and diarrhea, most being NCI CTC Grade 1/2 and all were reversible. The recommended Phase II dose was determined to be cohort 1 (VS-6766 3.2mg, defactinib 200mg).

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 KRASmutant LGSOC and KRASG12V mutant NSCLC, including patients previously treated with a MEK inhibitor. Expansion cohorts remain ongoing.

Clinical trials
Phase I Trial of VS-6063 and RO5126766. (FRAME) – NCT03875820
Study of FAK (Defactinib) and PD-1 (Pembrolizumab) Inhibition in Advanced Solid Malignancies (FAK-PD1) – NCT02758587

[1] Banerji U. Phase 1 study of the combination of a RAF-MEK inhibitor CH5126766 (VS-6766) and FAK inhibitor defactinib in an intermittent dosing schedule with expansions in KRAS mutant cancers. Poster #: CT143; Session: VPO.CT01 – Phase I Clinical Trials; Monday, April 27, 2020; 9:00 a.m. to 6:00 p.m. ET [Poster]
[2] Chénard-Poirier, M. et al. Results from the biomarker-driven basket trial of RO5126766 (CH5127566), a potent RAF/MEK inhibitor, in RAS- or RAF-mutated malignancies including multiple myeloma. Journal of Clinical Oncology 2017: 35. 10.1200/JCO.2017.35.15_suppl.2506.
[3] Gerber D. et al. Phase 2 study of the focal adhesion kinase inhibitor defactinib (VS-6063) in previously treated advanced KRAS mutant non-small cell lung cancer. Lung Cancer 2020: 139:60-67.
[4] Jiang H et al. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat Med 2016: Aug 22(8) 851-60.
[5] Sulzmaier F.J. et al. FAK in cancer: mechanistic findings and clinical applications. Nature Rev Cancer. 2014 14: 598-610.

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