The Phase 1/2 trial will evaluate the safety, tolerability, and efficacy of VS-6766 in combination with sotorasib in patients with KRAS G12C-mutant NSCLC who have not been previously treated with a KRAS G12C inhibitor as well as in patients who have progressed on a KRAS G12C inhibitor. The study will therefore investigate the potential benefits of a more complete vertical blockade of the RAS pathway with the combination of VS-6766 (RAF/MEK blockade) with sotorasib (G12C inhibition) in KRAS G12C-mutant locally advanced or metastatic NSCLC.
“Recent data indicate that acquired resistance to KRAS G12C inhibitors in patients occurs predominantly through additional mutations in the RAS pathway, many of which may be addressed with a downstream inhibitor such as VS-6766,” noted Ramaswamy Govindan, M.D., Professor, Department of Medicine, Oncology Division at Washington University School of Medicine and lead investigator of the study.
“This clinical study of VS-6766 and sotorasib will build on preclinical data showing synergy between these two agents, including tumor regression through deeper blockade of ERK pathway signaling.”
“[This study is important and] could potentially expand treatment options for patients with KRAS G12C-mutant NSCLC,” said Brian Stuglik, Chief Executive Officer of Verastem Oncology.
“This collaboration advances our strategy to fully explore the potential of VS-6766 as a backbone of therapy to treat RAS pathway-driven cancers,” he added.
Verastem Oncology expects to initiate the clinical trial with VS-6766 and sotorasib by the end of 2021.
Earlier this month, in a mini oral presentation, researchers updated data from the ongoing investigator-sponsored Phase 1/2 FRAME study, an adaptive, two-part multicenter, parallel cohort, randomized, open-label study designed to assess safety, dose-response, and preliminary efficacy of the combination of VS-6766, Verastem’s RAF/MEK inhibitor, and defactinib, its FAK inhibitor, in patients with KRAS mutant solid tumors, including low-grade serous ovarian cancer (LGSOC), non-small cell lung cancer (NSCLC) and colorectal cancer (CRC).
Because the combination of VS-6766 and defactinib has been found to be clinically active in patients with KRAS mutant tumors, the FRAME study was expanded to include new cohorts in pancreatic cancer, KRAS mutant endometrioid cancer, and KRAS-G12V NSCLC.
The findings will be presented at the European Society of Medical Oncology (ESMO) Congress, September 16-21, 2021.
“Low-grade serous ovarian cancer is a rare, slow-growing cancer that does not respond well to chemotherapy or hormone therapy, and disproportionately affects younger women. The results presented at ESMO this year show that VS-6766 combined with defactinib continues to demonstrate encouraging response rates in patients with LGSOC, including a 46% partial response rate across the overall patient population and a 64% partial response rate in patients with KRAS-mutated LGSOC, with manageable rates of side-effects,” explained Susana Banerjee, MBBS, MA, Ph.D., FRCP, lead author of the presentation and Team Leader in Women’s Cancers at The Institute of Cancer Research, London, and Consultant Medical Oncologist and Research Lead for The Royal Marsden NHS Foundation Trust Gynaecology Unit. 
“It’s particularly promising that the combination was also effective in patients who had previously received a MEK inhibitor. I am delighted that this drug combination has shown such encouraging results in a group of patients who urgently need new treatments,” she added.
“The investigator-sponsored FRAME study, the initial results of which led the U.S. Food and Drug Administration (FDA) to grant Breakthrough Therapy designation for the VS-6766 and defactinib combination in LGSOC, continues to be instrumental in providing the foundational data for safety, efficacy, and durability in this novel combination for RAS pathway tumors,” Verastem’s Stuglik noted.
“These data indicate that combining VS-6766 with defactinib results in promising response rates and median progression-free survival in patients who have already received MEK inhibitors. Verastem’s company-sponsored, registration-directed Phase 2 RAMP 201 study evaluating VS-6766 both alone and in combination with defactinib in patients with recurrent LGSOC is ongoing and we look forward to reporting top-line results from the selection portion of the study during the first half of 2022.”
Results in Patients with LGSOC
In the FRAME study, VS-6766 was administered using a twice-weekly dose-escalation schedule and is administered 3 out of every 4 weeks. Defactinib is administered using a twice-daily dose-escalation schedule, also 3 out of every 4 weeks. Dose levels are 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). The recommended Phase 2 dose was determined to be cohort 1 (VS-6766 3.2mg, defactinib 200mg).
Among the evaluable patients with LGSOC (n=24), the overall response rate (ORR) was 46% (11 of 24). Among the patients with KRAS mutant LGSOC (n=11), the ORR was 64% (7 of 11). Among the patients with KRAS wild-type LGSOC (n=9), the ORR was 44% (4 of 9). Of the evaluable patients, 10 (42%) received previous MEK inhibitor therapy.
The mPFS across all patients was 23.0 months (95% CI: 10.6- not reached). As of the April 2021 data cutoff date, 13 of 24 patients (54%) remained on study.
For context, for other therapies studied in recurrent LGSOC, response rates have been between 6% and 26% and mPFS was between 7.2 and 13.0 months.
In the FRAME study, the most common Grade 3/4 treatment-related adverse events (AEs) were creatine kinase elevation (12%), rash (8%), diarrhea (4%), mouth ulcer/mucositis/glossitis (4%) and hyperbilirubinemia (4%), with only one discontinuation due to AEs as of the data cutoff.
These updated data suggest that the novel, intermittent dosing schedule used in the FRAME study continues to show encouraging clinical activity in patients with recurrent LGSOC, including in patients previously treated with a MEK inhibitor. Expansion cohorts are also ongoing in pancreatic cancer, KRAS/BRAF mutant endometrioid cancer and KRAS-G12V NSCLC.
A Study of VS-6766 v. VS-6766 + Defactinib in Recurrent Low-Grade Serous Ovarian Cancer With and Without a KRAS Mutation (Raf And Mek Program/RAMP-201/ENGOTov60/GOG3052) – NCT04625270
A Study of VS-6766 v. VS-6766 + Defactinib in Recurrent G12V or Other KRAS-Mutant Non-Small Cell Lung Cancer (RAMP-202) – NCT04620330
Defactinib and VS-6766 for the Treatment of Patients With Metastatic Uveal Melanoma – NCT04720417
Highlights of Prescribing Information
Sotorasib (Lumakras™; Amgen)[Prescription Information]
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