Personalizing Therapy With VS-6766, Defactinib for Patients With KRAS+ NSCLC

Seeking to expand the armamentarium of personalized treatment regimens for patients with recurrent, KRAS-positive, non–small-cell lung cancer (NSCLC), D. Ross Camidge, MD, PhD, Director of Thoracic Oncology, University of Colorado School of Medicine and University of Colorado Cancer Center, and colleagues are conducting the RAMP (Raf And Mek Program) 202 clinical trial, which is now enrolling patients.

Tailoring Therapy for Patients With KRAS-Positive NSCLC

The purpose of this study is to assess the efficacy, tolerability, and safety of the dual RAF/MEK inhibitor VS-6766 from Verastem Oncology administered alone or in combination with defactinib, a FAK inhibitor, in this patient population.

“All of the big successes in treating NSCLC have come from personalizing therapy,” explained Dr Camidge.

“Even with the KRAS biomarker present in about 25% of patients with NSCLC, current recommendations for treatment have yet to suggest anything other than basic chemotherapy and immunotherapy options. Sometimes patients with KRAS-positive NSCLC can do well with these options [but] sometimes they do not,” he continued.

According to Dr Camidge, a series of drugs are currently in the advanced development stage for the most common KRAS-positive subtype, G12C; however, >50% of KRAS-positive are not G12C. The second most common subtype of KRAS-positive disease is G12V, for which no specific treatments currently exist.

“We can treat patients with KRAS-positive tumors with the current standard chemotherapies and immunotherapies, but something specific to this or that KRAS mutation has always been the goal,” he said.

The RAMP 202 Clinical Trial

The RAMP 202 study is unique in that it will broadly examine all KRAS mutations but specifically focus on patients with the G12V subtype.

“A drug or combination treatment shown to be significantly active in patients with G12V mutations would represent a major step forward,” Dr Camidge explained.

Data from the trial, which includes men and women aged ≥18 years with KRAS-G12V-positive NSCLC who have received appropriate prior therapy, will determine which regimen is taken forward into the expansion phase of the trial.

The first phase of RAMP 202 will determine an ideal regimen of VS-6766 alone or in combination with defactinib in patients with KRAS-G12V-positive NSCLC. A separate cohort within this phase will evaluate the efficacy and safety parameters in patients with recurrent KRAS-positive tumors.

“Because RAMP’s focus on G12V mutations is unique, we very much look forward to opening this study to a patient population that has never had a precision treatment option,” Dr Camidge said.

Previous studies of VS-6766 in combination with defactinib have shown that RAF and MEK inhibitors slow tumor growth, and that the addition of a FAK inhibitor induced tumor regression.

The RAMP 202 study, which began in December 2020, has built upon data from the phase 1/2 FRAME study, data for which were presented at the American Association for Cancer Research Annual Meeting in April 2020. These data showed that among 10 patients with KRAS-positive NSCLC, there was an overall response rate (ORR) of 10%, with 8 patients achieving disease control.

Among patients in the FRAME trial who achieved disease control, 70% and 30% continued therapy for at least 12 weeks and at least 24 weeks, respectively.

A subsequent analysis of VS-6766 alone and in combination with defactinib in patients with G12V mutations showed a combined ORR of 57% (4 of 7 patients).

“Our wish is that results will build on preclinical data that showed substantial anti-tumor efficacy with this treatment combination in patients with NSCLC. We also hope RAMP 202 expands upon the positive trends seen in the FRAME study, which showed both response and durable duration of benefits in patients with G12V NSCLC, potentially providing a novel targeted treatment option for these patients who have high unmet needs and high mortality rates,” Dr Camidge stated.

“In this study, we hope to advance our understanding of a potential new option for patients with KRAS mutant NSCLC by targeting the RAF/MEK and FAK pathways,” said Dr Camidge.

 “Some key advances have come from looking at specific KRAS mutations and by also focusing on G12V mutations, allowing us to build upon the areas that have shown particular promise and determine an optimal path forward,” Dr Camidge said.

“We'll be looking closely at potential toxicities and how to best manage those throughout the trial so we can safely administer these medicines to our patients, giving them the best chances for durable benefit,” he concluded.—Emily Bader