SPYK04, a novel RAF-MEK molecular glue: Dose escalation (DE) in first-in-human study for MAPK pathway-altered solid tumors.

3100 Background: SPYK04 is a novel MEK1/2 inhibitor designed to enhance RAF-MEK binding and potentially inhibit feedback activation of MEK1/2. This approach was developed to address the limited efficacy of conventional MEK inhibitors in RAS-mutated cancers, which is thought to be due to feedback activation of the MAPK pathway. Methods: This first-in human study of SPYK04 is conducted in the US and Japan (NCT04511845). Patients with locally advanced or metastatic solid tumors harboring MAPK pathway alterations were eligible in its DE part. The primary endpoints included assessment of pharmacokinetics, adverse events (AEs) and dose-limiting toxicities (DLTs); the secondary endpoint was objective response rate (ORR). SPYK04 was administered orally once daily in continuous 28-day cycles. Results: A total of 23 patients were enrolled in DE. SPYK04 was evaluated at doses ranging from 0.1 to 1.3 mg/day. An accelerated titration design was employed for doses of 0.1, 0.2, and 0.4 mg/day, followed by a transition to a 3+3 design starting from 0.8 mg/day. Over the dose range of 0.1 to 1.3 mg/day, systemic exposure demonstrated a dose-dependent increase. Grade 3 or higher treatment-related adverse events (TRAEs) were observed in 30.4% of patients. TRAEs observed in >= 20% of patients were: dermatitis acneiform and blood creatinine phosphokinase increased (60.9% each); AST increased (30.4%); nausea and stomatitis (26.1%, each). DLTs were observed in one patient each at dose levels of 0.8, 1.0 and 1.3 mg/day. All DLTs were due to receiving <75% of the planned dose. A decision was made to not escalate beyond 1.3 mg/day. The ORR was 8.7% (n = 2 of 23), with both partial responses (PRs) occurring amongst the 5 enrolled ovarian cancer patients. The disease control rate (DCR; PR+SD) was 52.2% (n = 12 of 23). Conclusions: SPYK04 was tolerated at doses up to 1.3 mg/day in patients with advanced solid tumors. PRs were observed in two patients with ovarian cancer. Further evaluation of safety and efficacy will occur in the expansion part of this study. Clinical trial information: NCT04511845 . SPYK04 dose, mg/day 0.1 0.2 0.4 0.8 1 1.3 Patients, n 1 1 1 8 6 6 Safety, n (%) TRAE 0 1 (100.0) 1 (100.0) 8 (100.0) 6 (100.0) 6 (100.0) Grade 3 or higher TRAE 0 0 0 1 (12.5) 4 (66.7) 2 (33.3) TRAE leading to discontinuation of study treatment 0 0 0 0 1 (16.7) 0 Confirmed best response, n (%) Responders 0 0 0 1 (12.5) 1 (16.7) 0 Partial Response 0 0 0 1 (12.5) 1 (16.7) 0 Stable Disease 0 0 1 (100.0) 2 (25.0) 3 (50.0) 4 (66.7)