MEK inhibitors (MEKi) lack single agent clinical efficacy in RAS mutant cancers, likely because MEKi produce only a cytostatic response in preclinical RAS mutant cancer models. BCL-XL is an anti-apoptotic BCL2 family protein identified by a synthetic lethal shRNA screen as a key suppressor of apoptotic response to MEKi. BCL-XL was found to bind and inhibit BIM, the key pro-apoptotic protein induced by MEKi. Combined BCL-XL/MEK inhibition led to tumor regressions in mouse models of RAS mutant cancers.
In dose escalation, N (150, 200, 250, 300mg daily) was given d1-28 (after a 7d lead at 150mg daily). T (1, 1.5, 2mg daily) was given d1-28 in schedules A and B, or d1-14 only of a 28d cycle in schedule C. Pre-treatment and d15 on-treatment biopsies and serial cell-free (cf)DNA were obtained.
To date, 43 patients (pts) (median age 60) initiated treatment (A [n = 9]; B [n = 11]; C [n = 23]), 38 in dose escalation; 66.7% had ≥4 prior therapies. 9/43 (20.9%) had colorectal cancer (CRC), 8/43 (18.6%) pancreatic, 9/43 (20.9%) NSCLC and 11/43 (25.6%) gynecologic (GYN) cancers. 14/43 (32.6%) were KRAS G12D, 7/43 (16.3%) G12C, 7/43 (16.3%) G12V.Recommended phase 2 dose (RP2D) was established as T 2mg d1-14 + N 250mg d1-28.Gr 3-4 treatment related AEs occurred in 40% pts, with AST increase, diarrhea, decreased platelets most common. At RP2D, 2/13 evaluable pts had confirmed PR (15.4%) with disease control rate (DCR; PR + SD) 46.2%. Early potential disease-specific differences in efficacy were noted. In GYN pts at all doses, overall DCR = 63.6%, with 2/11 (18.1%) with ongoing confirmed PR (-60% and -51% by RECIST), including one >20 mos. By contrast no PRs were seen in 9 CRC pts, with overall DCR only 22%. Evidence of MAPK pathway inhibition was observed in on-treatment tumor biopsies. Pts with PR/SD had a median decrease in mutant KRAS levels in cfDNA of 64% by 4 wks.
Combination of N+T was tolerable, and R2PD was established. Initial signs of efficacy were noted, with favorable DCR and durable PRs in RAS mutant GYN pts. Expansion cohorts are currently enrolling in GYN, NSCLC, pancreatic pts, and NRAS mutant cancers. Updated efficacy and correlative data will be presented.
Clinical trial identification
Legal entity responsible for the study
R.B. Corcoran: Honoraria (self): Array Biopharma; Honoraria (self): Astex Pharmaceuticals; Honoraria (self): BMS; Honoraria (self): FOG Pharma; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Fount Therapeutics; Honoraria (self): N-of-one; Honoraria (self): Revolution Medicines; Advisory / Consultancy, Shareholder / Stockholder / Stock options: nRichDx; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Avidity Biosciences; Honoraria (self): Novartis; Honoraria (self): Taiho. L.G. Ahronian: Full / Part-time employment: Tango Therapeutics. All other authors have declared no conflicts of interest.