Work

Combining the KRASG12C inhibitor adagrasib with anti-PD-1 immunotherapy improves overall survival and prevents recurrence in preclinical models of brain metastasis

Year: 2026

Type: article

Abstract: Background: inhibitor active in patients with BM. KRAS mutations are linked with immune escape and may contribute to the limited clinical benefit from single-agent immune checkpoint inhibitors (ICI) targeting PD-1/PD-L1 in BM. Although adagrasib sensitizes extracranial tumors to ICI, its intracranial benefit combined with immunotherapy remains unknown. Here, we evaluate adagrasib with ICI in mouse models that mimic the BM immune microenvironment. Methods: . Murine BM models resembling the immunologic characteristics of BM were established by subcutaneous and intracranial injection of these cells. Animals were treated with adagrasib combined with anti-PD-1 and monitored for intracranial tumor growth and survival. Disease-free mice after 11-13 weeks were rechallenged with a higher tumor cell dose to assess tumor-specific memory. Results: Three-week adagrasib monotherapy and combination therapy with ICI demonstrated benefit in colorectal and lung cancer BM models. Adagrasib alone and in combination demonstrated similarly potent anti-tumor effects against extracranial tumors. While monotherapies reduced intracranial tumor growth, adagrasib with ICI showed the most favorable outcome. Although both adagrasib monotherapy and combination therapy extended survival, long-term intracranial disease control after rechallenge was the greatest with combination therapy. Conclusions: Adagrasib with ICI improved long-term survival and blocked CNS progression in dual extra- and intracranial BM models. These findings support investigation of adagrasib with ICI in patients with KRASG12C-mutant BM.

Source: Neuro-Oncology Advances

DOI: 10.1093/noajnl/vdag107