Phase I trial of the RAF/MEK clamp VS-6766 in combination with everolimus using an intermittent schedule with expansion in NSCLC across multiple KRAS variants.

Abstract

9018 Background: VS-6766 is a small molecule RAF/MEK clamp that results in the reduction of p-MEK and p-ERK. Preclinical data show synergy of VS-6766 with the mTOR inhibitor everolimus across a panel of KRAS mutated (mt) NSCLC cell lines. This clinical trial evaluated the safety and efficacy of a novel intermittent regimen of VS-6766 and everolimus with an expansion in KRAS mt NSCLC (NCT02407509). Methods: The trial used a 3+3 dose escalation design with an intermittent once a week schedule A, and if tolerated, twice a week schedule B (Mon-Thu or Tue-Fri) for both drugs on a 3 weeks on/1 week off, 28 day cycle. Patients with RAS or RAF mt cancers were eligible for the dose escalation cohort, and 20 patients with KRAS mt NSCLC will be treated in the dose expansion cohort. Toxicity was evaluated by NCI CTC V4 and efficacy was evaluated using RECIST 1.1. Results: A total of 28 patients have been treated; median age 60 yrs (range 36-78), and median lines of previous treatment 3 (range 0-7). Sixteen patients have been treated in the dose escalation (3 in schedule A and 13 in the schedule B). The doses of 4 mg of VS-6766 and 5 mg everolimus (once weekly) were tolerated with no dose limiting toxicities (DLTs) and the dose intensity escalated to schedule B (twice weekly). At 4 mg VS-6766 twice weekly, DLTs were observed in two out of six patients and included grade 4 CPK elevation and grade 3 rash. Thus, the dose in schedule B (twice weekly) was de-escalated to 3.2 mg VS-6766 and the dose of everolimus was kept at 5 mg. No DLTs were reported in 6 patients and thus this was declared as the recommended phase 2 dose (RP2D). At the RP2D, the grade 3-4 drug related AE were rash (18%) and pruritus (7%). In the dose escalation cohorts, 3 partial responses (PRs) were reported (2 KRAS G12D low grade serous ovarian cancer and 1 NRAS Q61K mt thyroid cancer). In the KRAS mt NSCLC expansion cohort, 10 patients are evaluable for efficacy and 2 confirmed responses were reported ( KRAS mutations G12V and G13A) with an objective response rate (ORR) 20% to date. The disease control rate (PR + SD) at the first scheduled evaluation was 90%. The median progression free survival (PFS) in the KRAS mt NSCLC cohort is 6.35 months (95% CI 3.52 – not reached). Updated ORR and PFS data will be presented. Conclusions: A tolerable intermittent dosing schedule targeting both the MAPK and PI3K pathways has been established. The combination of VS-6766 with everolimus has shown activity in patients with a variety of KRAS mutation variants including responses in KRAS mt NSCLC.

Emerging Targeted Therapies in Advanced Non-Small-Cell Lung Cancer

“…The KRAS mutation was G12D in these two patients, and PFS was 35.8 and 41.8 months with treatment ongoing. The median PFS was 6.35 months (95% CI 3.52-not reached), a promising result in this heavily pre-treated cohort [79]. The combination of VS-6766 and everolimus is tolerable and has an encouraging preliminary clinical efficacy across different KRAS mutation variants.…”

RAF and MEK Inhibitors in Non-Small Cell Lung Cancer

“…The combination of avutometinib plus sotorasib is being further evaluated in the phase I/II RAMP 203 study (NCT05074810, Table 1) [96]. Additionally, the combination of avutometinib with the mTOR inhibitor everolimus in KRAS-mutant NSCLC patients has shown promising results and is being tested in another clinical trial (NCT02407509, Table 1) [97].…”

Targeted therapy for lung cancer: Beyond EGFR and ALK

“…In addition, off‐target mechanisms of resistance have been identified, such as bypass signaling though mutations or amplifications in downstream effectors or histologic subtype transformation caused by cell plasticity 73 . Beyond KRAS G12C‐selective inhibitors, there is a lack of specific inhibitors for other codon 12 mutations, for which the RAF/MEK inhibitor VS‐6766 is currently under investigation, 74 although a successful strategy has not yet been stablished. To overcome ineffectiveness because of upstream guanine nucleotide exchange factor activation, new KRAS‐inhibition strategies with SHP2 (TNO155, RMC‐4630) and SOS inhibitors (BI 1701963) are currently under clinical development (Table 2).…”