Investigators Explore the Role of VS-6766 and Defactinib in KRAS-Mutant NSCLC

D. Ross Camidge, MD, PhD

Patients with non-small cell lung cancer (NSCLC) harboring KRAS mutations have been an underserved population with few treatment options, specifically those with G12V mutations. Investigators hope to build on early efficacy data in this patient population with a novel combination approach and address this unmet need with the commencement of the phase 2 RAMP 202 trial (NCT04620330).

RAMP 202 will evaluate the safety and efficacy of VS-6766, a RAF/MEK inhibitor, alone and in combination with defactinib, a FAK inhibitor, in adult patients with KRAS-mutant NSCLC following treatment with an appropriate platinum-based regimen and an approved immune checkpoint inhibitor.¹

Finding the Correct Roadblocks for KRAS

Approximately 30% of patients with NSCLC harbor a KRAS mutation, and agents targeting various components of the RAS pathway have met hurdles. For example, MEK inhibitors have been limited in their ability to impede ERK signaling because of possible feedback reactivation of RAF, which results in MEK phosphorylation.² Investigators have determined that the bypassing mechanisms and resistance in the blockade of the RAS pathway may be circumvented through the inhibition of parallel pathways in the extracellular matrix, namely the FAK-signaling pathway.³

“There’s a signaling pathway that is partially in a straight line that goes RAS, RAF, MEK, ERK,” explained D. Ross Camidge, MD, PhD, a professor of medicine and medical oncology, director of the Thoracic Oncology and Clinical Research Programs at the University of Colorado (CU) School of Medicine, and CU Cancer Center member in Aurora, in an interview with OncologyLive®. “[The pathway] is commonly used by many different cancers and it’s so important to some cancers that there are often mutations in that pathway. We know there were some cancers driven by BRAF mutations and ARAF mutations [and] we know there are some cancers driven by RAS mutations.

“One of the problems is that it’s a bit like a tree; lots of these branches come off at each of these points. The question is how do you shut down signaling without some bypass loop going around it. VS-6766 is hitting it at 2 separate points, hitting it at the RAF level and at the MEK level.”

The investigational agent VS-6766 blocks MEK kinase activity and also prevents the process of RAF to phosphorylate MEK. The mechanism of VS-6766 allows for more effective inhibition of ERK signaling and may lead to greater therapeutic activity against ERK-dependent RAS- or BRAF-mutant tumors. In preclinical models, the agent showed synergy with G12C inhibitors in KRAS-mutant NSCLC and colorectal cancer. In mouse models, VS-6766 has also demonstrated the ability to enhance the antitumor effects of PD-1–targeted therapies in KRAS-mutant NSCLC.⁴

Further, VS-6766 has demonstrated significant tumor regression in KRAS G12Vmutant NSCLC, one of the second most common codon 12 variants identified with KRAS. KRAS G12V–mutant disease has been shown to be more reliant on CRAF, and preclinical models have shown that CRAF ablation with VS-6766 improved the survival of mice with mutant disease over BRAF ablation in vivo.⁵

Defactinib, an oral small molecule inhibitor of FAK and PYK2, promoted stronger tumor regression when combined with VS-6766, according to results from in vivo models.⁵ The agent has been granted an orphan drug designation for the treatment of patients with ovarian cancer and mesothelioma in the United States, the European Union, and Australia. Preclinical models of KRAS-mutant solid tumors treated with defactinib and VS-6766 show the combination to be synergistic in several KRAS-mutant tumor cell lines.⁶

Figure: Study of Dual RAK/MEK Inhibitor as a Single Agent and in Combination With FAK Inhibitor in Patients With Recurrent KRAS-Mutant NCSLC

Initial Safety and Efficacy Data of VS-6766 and Defactinib

The combination of VS-6766 and defactinib is currently under investigation in the phase 1/2 FRAME study (NCT03875820), a basket trial enrolling patients with solid tumors with KRAS mutations. Patient populations include those with low-grade serous ovarian cancer, KRAS-mutant NSCLC, and KRAS-mutant colorectal cancer.

In FRAME, VS-6766 and defactinib were administered using a twice-weekly and twice-daily dose-escalation schedule, respectively, in week 3 of a 4-week cycle. Investigators determined the recommended dose for phase 2 of the study as being VS-6766 3.2 mg and defactinib 200 mg.⁷

Preliminary results showed the combination displayed activity in patients with KRAS-mutant NSCLC included in the study analysis (n = 10). Patients were refractory to conventional treatment or had no conventional treatment options available to them; they had received a median of 2 prior lines of therapy and a majority had prior anti–PD-1 therapy. An analysis showed that 1 patient experienced a partial response and 8 patients achieved disease control. Patients in this cohort continued on treatment for at least 12 weeks at a rate of 70%, and 30% continued on treatment for at least 24 weeks. Of note, the patient who achieved a partial response had KRAS G12Vmutant disease and remained on therapy for more than 3 months.^3,7

In a subsequent combined analysis of the FRAME study and a prior VS-6766 single-agent study, patients with NSCLC harboring the specific KRAS G12V mutation (n = 7) experienced an overall response rate (ORR) of 57% when treated with VS-6766 either as a single agent or in combination with defactinib.

The most common adverse events observed in FRAME, most of which were grade 1 or 2, were rash, creatine kinase elevation, nausea, hyperbilirubinemia and diarrhea.⁴

“[Verastem Oncology did] a study which combined the drug with a FAK inhibitor, and also [examined it] as a monotherapy,” Camidge said. “In that dose-escalation, dose-expansion study, there were a number of patients with a specific KRAS mutation called KRAS G12V, who mostly all had ovarian cancer. They responded. Some of them responded to the combination and some of them responded to monotherapy, so we don’t know whether you actually need the combination. I saw the data and G12V is also present in NSCLC. I reached out to them and said, ‘You know, you should really also develop this in lung cancer.’ That’s what led to the RAMP 202 study.”

Details of the RAMP 202 Trial

RAMP 202 is a multicenter, parallel cohort, randomized, open-label trial that will enroll approximately 100 patients in the United States and the European Union. In part 1 of this adaptive 2-part study, investigators will determine the optimal regimen of VS-6766 either as a monotherapy or in combination with defactinib, with patients randomized 1:1 in each arm. Once they have determined the optimal regimen, the investigators will evaluate the safety and efficacy in part 2.¹

To be eligible for the trial, patients must be at least 18 years old with histologic or cytologic evidence of NSCLC, have a known KRAS mutation, and have received appropriate prior therapy. Participants must have an ECOG performance status of at least 1, adequate organ function, and adequate recovery from toxicities related to prior treatments.⁸

The primary end points of the study are to determine the optimal regimen and to determine the efficacy of the optimal regimen. Secondary end points include ORR as assessed by the investigator, duration of response, disease control rate, progression-free survival, and overall survival.⁸

“If we see reproducible, robust, and durable responses in KRAS G12V, or other subtypes, it certainly puts a target on the back of G12V as something that could lead to regulatory approval of this specific approach for that specific mutation,” Camidge said. “If it shows more modest activity, that still opens up the idea that this could be an ingredient that could be combined with other drugs. We have some leads in ovarian cancer, but we have to prove it in lung cancer.”

References

1. Verastem Oncology initiates phase 2 registration-directed trial of VS-6766 and defactinib in previously treated KRAS mutant non-small cell lung cancer. News release. Verastem Oncology. December 15, 2020. Accessed July 8, 2021. https://www.biospace.com/article/releases/verastem-oncology-initiates-phase-2-registration-directed-trial-of-vs-6766-and-defactinib-in-previously-treated-kras-mutant-non-small-cell-lung-cancer I
2. shii N, Harada N, Joseph EW, et al. Enhanced inhibition of ERK signaling by a novel allosteric MEK inhibitor, CH5126766, that suppresses feedback reactivation of RAF activity. Cancer Res. 2013;73(13):4050-4060. doi:10.1158/0008-5472.CAN-12-3937
3. Addressing RAS pathway blockade & resistance. Verastem, Inc. April 27, 2020. Accessed July 8, 2021. https://investor.verastem.com/static-files/93835009-c4b6-4818-907516cb64237930
4. VS-6766. Verastem Oncology. Accessed July 8, 2021. https://www.verastem.com/research/raf-mek-inhibition/ vs-6766
5. Corporate presentation. Verastem, Inc. May 2021. Accessed July 8, 2021. https://investor.verastem.com/ static-files/0dec46c2-5d9e-406b-958e-4225eab078c2
6. Defactinib. Verastem Oncology. Accessed July 8, 2021. https://www.verastem.com/research/fak-inhibition/ defactinib-fak-inhibitor
7. 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 July 7, 2020.
8. A study of VS-6766 v. VS-6766 + Defactinib in recurrent G12V or other KRAS-mutant non-small cell lung cancer. ClinicalTrials.gov. Updated June 15, 2021. Accessed July 8, 2021. https://clinicaltrials.gov/ct2/show/NCT04620330