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.

• DOI: 10.1200/jco.2022.40.16_suppl.9018
• Publication Date: 2022-06-06T18:04:22Z
• Authors: Anna Rachel Minchom; Vicky Sanchez Perez; Cienne Morton; Thubeena Manickav...; George Nintos; Julia Elizabeth L...; Christina Guo; Nina Tunariu; Tom Parker; Toby Prout; Mona Parmar; Alison Joanne Turner; Laura Finneran; Emma Hall; Jonathan A. Pachter; Louis J. Denis; James F. Spicer; Udai Banerji
• Keywords: Everolimus; Regimen

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