EXTH-45. DEVELOPMENT OF COMBINATION THERAPIES OF KRAS^G12C INHIBITOR ADAGRASIB IN PRECLINICAL MODELS OF BRAIN METASTASIS Free

The highly selective KRAS^G12C inhibitor adagrasib (MRTX849) is FDA-approved for KRAS^G12C+ advanced non-small cell lung cancer (NSCLC). We recently provided preclinical evidence of MRTX849 brain penetration and activity, allowing MRTX849 inclusion in a national genomically-guided multicenter clinical trial (NCT03994796) for patients with brain metastasis (BM). However, multiple genetic alterations such as CDKN2A/B deletions, a common driver of NSCLC BM, can limit MRTX849 efficacy. Furthermore, although MRTX849 can sensitize extracranial tumors to immune checkpoint inhibitors (ICI), its intracranial immune benefit is unknown. Our objective was to improve MRTX849 monotherapy, evaluating combination therapies with CDK4/6 inhibitor abemaciclib or anti-PD-1 in preclinical models of BM.

We tested in vitro sensitivity of MRTX849 and abemaciclib, using KRAS^G12C+, CDKN2A-deleted human lung cancer cell lines SW1573 and H2122. The efficacy of a 5-week treatment of MRTX849 and abemaciclib was evaluated in an intracranial NSCLC BM model in nude mice. Additionally, we utilized a syngeneic murine Kras^G12C colorectal cancer BM model (CT26^G12C) to test different MRTX849 dosages and assess its therapeutic effects in combination with anti-PD-1 antibody.

MRTX849 and abemaciclib demonstrated mild synergy in reducing cell viability in vitro. Combination treatment of MRTX849 and abemaciclib significantly improved both survival and intracranial tumor control relative to controls in SW1573 NSCLC BM model. In a syngeneic colorectal BM model, we identified benefit of a 2-week MRTX849 single treatment at 100 mg/kg (BID) in controlling brain tumor growth. In a dual subcutaneous intracranial BM model with CT26^G12C, MRTX849 alone and combination therapy mediated complete regression of extracranial tumors. Although monotherapies reduced intracranial tumor growth, MRTX849 combination with anti-PD-1 resulted in a greater benefit. Both MRTX849 monotherapy and the combination therapy extended animal survival.

MRTX849 combination therapies with abemaciclib or anti-PD-1 demonstrate intracranial activity, inhibiting BM progression and prolonging survival, in preclinical models of KRAS^G12C+ BM.