Verastem Oncology and Amgen have signed an agreement to evaluate the combination of VS-6766 (formerly known as CH5126766 and RO5126766), an investigational dual RAF/MEK inhibitor, in combination with KRAS G12C inhibitor sotorasib (Lumakras™; Amgen) in the treatment of patients diagnosed with KRAS G12C-mutant non-small cell lung cancer (NSCLC).
In contrast to other MEK inhibitors in development, VS-6766 blocks both MEK kinase activity and the ability of RAF to phosphorylate MEK. This unique mechanism allows VS-6766 to block MEK signaling without the compensatory activation of MEK that appears to limit the efficacy of other inhibitors.
The U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation for the combination of Verastem Oncology’s investigational RAF/MEK inhibitor VS-6766, with defactinib, its FAK inhibitor, for the treatment of all patients with recurrent low-grade serous ovarian cancer (LGSOC) regardless of KRAS status after one or more prior lines of therapy, including platinum-based chemotherapy.
A single-leading cause of cancer death
Approximately 85% of lung cancers are non-small cell lung cancer (NSCLC), which are the single leading cause of cancer deaths worldwide. [1] KRAS mutation occurs in approximately 25% of NSCLC adenocarcinoma patients.[2]
Two of the most common types of KRAS mutations are G12C, which occurs in approximately 13% of patients with NSCLC adenocarcinoma, as well as G12V, which is present in approximately 7% of NSCLC. [3][4] Currently, there is a high unmet need in the second-line treatment of KRAS mutant NSCLC.[1][5]

Study
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.[6]

“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.

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Verastem Oncology expects to initiate the clinical trial with VS-6766 and sotorasib by the end of 2021.

FRAME Study
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. [8][9][10][11]

“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.

Clinical studies
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]

References
[1] Molina, Julian R., Non–Small Cell Lung Cancer: Epidemiology, Risk Factors, Treatment, and Survivorship. National Institute of Health. Mayo Foundation for Medical Education and Research. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2718421/pdf/nihms121782.pdf. Accessed June 2021.
[2] Roman, Marta, et al. KRAS oncogene in non-small cell lung cancer: clinical perspectives on the treatment of an old target. Molecular Cancer. 2018;17:33.
[3] TCGA PanCancer Atlas (cBioPortal analysis).
[4] American Cancer Society. Key Statistics for Lung Cancer. Available at: https://www.cancer.org/cancer/lung-cancer/about/key-statistics.html. Accessed June 2021.
[5] Pakkala S, et al. Personalized therapy for lung cancer: striking a moving target. JCI Insights. 2018;3:3120858
[6] Awad, Mark, et al. LB002 – Mechanisms of acquired resistance to KRAS G12C inhibition in cancer. Presented at: American Association for Cancer Research Annual Meeting; April 10, 2021.
[7] Coma S, Chowdhury S, Pachter A. J. Dual RAF/MEK Inhibitor VS-6766 Enhances Anti-Tumor Efficacy of KRAS G12C Inhibitors through a Vertical Pathway Inhibition Strategy. Presented at: American Association for Cancer Research Annual Meeting; April 10, 2021.
[8] Siemon J, Gershenson DM, Slomovitz B, Schlumbrecht M. Low grade serous ovarian carcinoma: identifying variations in practice patterns. Int J Gynecol Cancer. 2019 Jan;29(1):174-180. doi: 10.1136/ijgc-2018-000018. PMID: 30640701.
[9] Gershenson DM, Okamoto A, Ray-Coquard I. Management of Rare Ovarian Cancer Histologies. J Clin Oncol. 2019 Sep 20;37(27):2406-2415. doi: 10.1200/JCO.18.02419. Epub 2019 Aug 12. PMID: 31403866.
[10] Monk BJ, Grisham RN, Banerjee S, Kalbacher E, Mirza MR, Romero I, Vuylsteke P, Coleman RL, Hilpert F, Oza AM, et al. MILO/ENGOT-ov11: Binimetinib Versus Physician’s Choice Chemotherapy in Recurrent or Persistent Low-Grade Serous Carcinomas of the Ovary, Fallopian Tube, or Primary Peritoneum. J Clin Oncol. 2020 Nov 10;38(32):3753-3762. doi: 10.1200/JCO.20.01164. Epub 2020 Aug 21. PMID: 32822286; PMCID: PMC7655017.
[11] Banerjee S. Phase I study of the combination of the dual RAF/MEK inhibitor VS-6766 and the FAK inhibitor defactinib: Results of efficacy in low grade serous ovarian cancer. Abstract #725MO Presented on Sunday, September 19, 2021; 17:50-17:55 CEST at the European Society for Medical Oncology (ESMO21), held September 16 – September 21, 2021.[Study]

Featured Image: ESMO 2018. Photo Courtesy: © 2018 – 2021 ESMO. Used with permission.

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