A phase I dose escalation (DE) study of ERK inhibitor, LY3214996, in advanced (adv) cancer (CA) patients (pts).

3001 Background: LY3214996 is a selective and potent ERK1/2 inhibitor that has demonstrated tumor growth inhibition in several pre-clinical tumor models with BRAF, RAS, or MAP2K1 mutations. This is the first-in-human Phase 1 Study of LY3214996 in adv CA pts. Methods: The goals of this DE study were to determine a recommended Phase 2 dose (RP2D), safety, pharmacokinetic (PK), and preliminary efficacy of LY3214996 (NCT02857270; I8S-MC-JUAB; Eli Lilly & Co.). Pts with adv CA, ≥18 yrs of age, ECOG ≤1, and with adequate organ function were eligible. Pharmacodynamic (PD) biomarkers including pRSK were evaluated in blood and paired tumor tissue. The DE phase evaluated PO doses using the Bayesian model-based toxicity band method. Results: A total of 51 pts with median age of 62 yrs (range: 21-81) received at least 1 dose of LY3214996 with a median of 3 cycles (range: 1-12). Most pts had a mutation in RAS (N = 33) or BRAF (N = 16) and had a median of 4 prior lines of treatment. The DLTs observed in the study include grade (G) 3 cough and fatigue, G3 dehydration, increased creatinine (Cr), G3 increased CPK, G3 rash > 7 days, and 1 pt with renal failure. TRAEs to LY3214996 occurring in ≥10% of pts included nausea, vomiting, diarrhea, dermatitis acneiform, fatigue, pruritus, and blurred vision. LY3214996 exposures increased with dose. Tumor regression was observed in 7 pts with BRAF/non -BRAF mutant CA including 5 pts who failed prior IO/MAPK inhibitors. Four pts achieved stable disease (2 BRAF, 1 RAS and 1 CRAF mutation) that lasted > 4 mos. Up to 100% pRSK decrease from baseline in tumor was observed. Conclusions: LY3214996 had an acceptable safety profile, favorable PK, and potent tumor PD inhibition at RP2D. This supports further exploration of LY3214996 as monotherapy and in combination in CA pts with activating MAPK pathway alterations. Clinical trial information: NCT02857270.