Results from a study published in The LANCET Oncology showed that VS-6766 (formerly known as CH5126766, CKI27 and RO5126766; Verastem Oncology*), a unique inhibitor of the RAF/MEK signaling pathway, with a specific dosing regimen of 4 mg twice weekly, is tolerable and shows antitumor activity in patients with RAS mutant tumors.[1]
VS-6766 is a unique inhibitor of the RAF/MEK signaling pathway, which, in contrast to other MEK inhibitors in development, 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.
Clinical trial in Solid Tumors and Multiple Myeloma
Between June 2013 to January 2019, 58 patients, including 51 patients with solid tumors and seven patients with multiple myeloma, were enrolled in a study conducted at The Institute of Cancer Research (ICR) and The Royal Marsden Hospital in the United Kingdom.
The study consisted of two parts. The first part was a dose escalation part to determine the recommended dosage (29 patients) and the second part was a basket expansion part to investigate efficacy and safety of the recommended dosage determined in the dose escalation part (29 patients).
Based on the outcome, four mg twice weekly was established as the recommended Phase II dose for VS-6766 monotherapy and was deemed tolerable based on clinician’s assessment with several patients remaining on study for more than six months.
In the subsequent basket expansion part, seven (26.9%) of 26 response-evaluable patients with RAS mutations in the basket expansion achieved objective responses, with response rates in patients with NSCLC, gynecological malignancies, colorectal cancer (CRC), melanoma, and multiple myeloma being 3/10 (30%), 3/5 (60%), 0/4 (0%), 0/1 (0%), and 1/6 (16.7%), respectively. In all six responders with solid tumors, tumor shrinkage was observed at the time of the first restaging scan after two cycles of treatment, with partial responses confirmed after two to four cycles. Five of the six responses lasted more than six months.
Among the 57 safety-evaluable patients, the most common Grade 3/4 treatment related adverse events (TRAEs) were rash (19%), CPK elevation (11%), hypoalbuminemia (11%), and fatigue (7%). Five (9%) patients experienced treatment-related serious adverse events. In the study, TRAEs were manageable, resolved spontaneously or reversed with dose modification. There were no treatment-related deaths. The study also confirmed a long half-life of 55 hours and target engagement in the form of reduction of both p-ERK and p-MEK in three patients who underwent paired biopsies, supporting intermittent dosing schedules.
First to evaluate
This investigator-initiated Phase I study was the first to evaluate a dual RAF/MEK inhibitor using innovative intermittent dosing schedules in patients harboring RAS/RAF pathway mutations. Based on the results, a Phase II trial will commence in December 2020.
An intermittent dosing schedule of VS-6766 informed further testing as both a single agent in RAS/RAF-mutant cancers such as KRAS mutant (KRASmt) non-small cell lung cancer (NSCLC) or in combination with small molecules including the FAK inhibitor defactinib (NCT03875820) in KRASmt solid tumors. In this dose-escalation study, tolerability and antitumor activity were observed across various cancers with RAS/RAF/MEK pathway mutations.
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.
Combination therapies
RAS mutant tumors are present in 30% of all human cancers and have historically presented a difficult treatment challenge and are often associated with significantly worse prognosis.
Challenges associated with identifying new treatment options for these types of cancers include resistance to single agents, identifying tolerable combination regimens with MEK inhibitors and new RAS inhibitors in development addressing only a minority of all RAS mutated cancers.
The combination of VS-6766 and defactinib (VS-6063, previously known as PF-04554878), an oral small molecule, ATP-competitive, focal adhesion kinase (FAK) and PYK2 inhibitor, in that is currently being evaluated as a potential combination therapy for various solid tumors, has been found to be clinically active in patients with KRAS mutant tumors.
Defactinib inhibits FAK, which may prevent the integrin-mediated activation of several downstream signal transduction pathways, including those involving RAS/MEK/ERK and PI3K/Akt, thus inhibiting tumor cell migration, proliferation, survival, and tumor angiogenesis
The investigational agent received Orphan Drug designation in ovarian cancer and mesothelioma in the United States, the European Union and Australia. Preclinical research has described the effect of FAK inhibition to enhance immune response by decreasing immuno-suppressive cells, increasing cytotoxic T-cells, and reducing stromal density, which allows tumor-killing immune cells to enter the tumor.[2][3]
The tyrosine kinase FAK, a signal transducer for integrins, is normally activated by binding to integrins in the extracellular matrix (ECM) but may be upregulated and constitutively activated in various tumor cell types.
Frame Study
In an ongoing investigator-initiated Phase I/II FRAME study, the combination of VS-6766 and defactinib is being evaluated in patients with Low-Grade Serous Ovarian Cancer (LGSOC), a type of ovarian cancer that disproportionately affects younger women, KRAS mutant NSCLC and colorectal cancer (CRC). Updated interim data from this study presented at the 2nd Annual RAS-Targeted Drug Development Summit in September 2020 demonstrated a 56% overall response rate and long duration of therapy among patients with KRAS-G12 mutant LGSOC.
Based on an observation of higher response rates seen in NSCLC patients with KRAS-G12V mutations in the study, Verastem will also be further exploring the role of VS-6766 and defactinib in KRAS-G12V NSCLC. The FRAME study was expanded in August 2020 to include new cohorts in pancreatic cancer, KRAS mutant endometrial cancer and KRAS-G12V NSCLC.
Rapid evaluation
“These results support the potential of VS-6766 as a treatment for a variety of cancers where conventional approaches have been sub-optimal and there is significant unmet need. We believe VS-6766 has the potential to be the backbone of RAS therapy by addressing the multiple points of resistance and toxicity issues that have made advancing new options difficult,” said Brian Stuglik, Chief Executive Officer of Verastem Oncology.
“Our Phase II registration-directed trials with VS-6766 in low grade serous ovarian cancer and KRAS mutant NSCLC are scheduled to begin by the end of this year. These adaptive design trials are a capital efficient approach to rapidly evaluate VS-6766 alone or in combination with defactinib to determine which regimen to take forward into the expansion phase of the trial.”
Note
* Verastem in-licensed VS-6766 from Chugai Pharmaceutical Co. in January 2020.
Clinical trials
Phase I Trial of VS-6063 and RO5126766. (FRAME) – NCT03875820
Phase I Trial of RO5126766 Alone and in Combination With Everolimus (DDU RAF/MEK) – NCT02407509
A Study Of PF-04554878 In Patients With Advanced Non-Hematologic Malignancies (B0761001) – NCT00787033
Reference
[1] Guo C, Chénard-Poirier M, Roda D, Miguel M, Harris SJ, Moreno Candilejo I, et al. Intermittent schedules of the oral RAF–MEK inhibitor CH5126766/VS-6766 in patients with RAS/RAF-mutant solid tumours and multiple myeloma: a single-centre, open-label, phase 1 dose-escalation and basket dose-expansion study. Lancet Oncol. 2020 Oct;28(20):1470-2045.DOI:https://doi.org/10.1016/S1470-2045(20)30464-2
[2] 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.
[3] 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.
Featured Image: Doctor discussing treatment options with a patient. Photo courtesy: © 2019 Fotolia/Adobe. Used with permission.
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