A phase 1b/2 study of VS-6766 in combination cetuximab in patients (pts) with advanced KRAS mt colorectal cancer (CRC).

Abstract

TPS219 Background: KRAS mutations (mts) are present in about 45% of CRC and predict lack of response to anti-EGFR therapy like cetuximab. Limited therapy options exist for pts after prior 5-FU based regimens. Regorafenib or TAS-102 is commonly used however, the modest clinical benefit, and toxicity limit their use. Novel therapies are needed for pts at this point in their disease course. KRAS G12D and G12V mts occur in 11-12% and 9-10% of CRC, respectively, whereas G12C mts occur in 3-4% of CRCs . KRAS G12C mts occur in 3-4% of CRCs. Recently, results of phase 1/2 KRYSTAL-1 study were reported. Adagrasib (a KRAS G12C inhibitor) was used with/without cetuximab in heavily pretreated CRC pts harboring KRAS G12C mts. The objective response rate (ORR) and disease control rate (DCR) was 43% and 100% (resp.) in pts receiving cetuximab and adagrasib (28 evaluable pts), and 22% and 87%, resp., in those receiving adagrasib alone (42 evaluable pts). Phase 1b CodeBreaK101 study evaluating sotorasib ( KRAS G12C inhibitor) and panitumumab (anti-EGFR) combination in KRAS G12C mt CRC showed 15.4% confirmed ORR and 26.9% unconfirmed ORR. These data are encouraging, suggesting EGFR inhibition in combination with downstream KRAS inhibition may represent important therapeutic strategy for this disease. KRAS mts lead to constitutive activation of the MAPK pathway signaling and cell activation. VS-6766 is a novel dual RAF/MEK inhibitor which has shown activity in KRAS mutated tumors. Combination of EGFR inhibition and VS-6766 may overcome resistance of KRAS mt CRC cancers to EGFR inhibition alone. Preclinically, VS-6766 and EGFR inhibition showed synergy in KRAS mt CRC cell lines, including cell lines harboring KRAS G12D and G12V mts, and CRC PDX of KRAS G12V mt CRC showed tumor regression with this combination. These data support the development of VS-6766 with anti-EGFR therapy in KRAS mt CRC warranting this phase 1 study to evaluate safety and efficacy of this combination in clinical settings. Methods: This is an open label, single arm study evaluating VS-6766 with cetuximab in pts with KRAS mt advanced CRC. Phase 1b primary endpoints include safety and tolerability, and maximum tolerated dose and recommended phase 2 dose determination. ORR is the primary endpoint of the Phase 2 study. Secondary endpoints include OS and PFS. There will be upto 4 dose levels tested. Three de-escalation doses to find the optimal cetuximab dose, and one dose escalation of VS-6766, are planned. Eligible pts include those with metastatic CRC and progression after 5-FU, oxaliplatin, irinotecan and VEGFi therapy. Based on prior studies, dermatologic, gastrointestinal, ocular and CPK elevation have been the main toxicities noted with VS-6766. The study is funded by research grants from Verastem Oncology. Cetuximab will be supplied by Eli Lilly.