Enhanced Therapeutic Synergy of ABSK071 with Various Agents in KRASG12C Mutated Cancers

The KRAS gene mutation is prevalent in various human cancers, with the KRASG12C variant present in a significant proportion of lung, colorectal, and pancreatic cancers. Although sotorasib and adagrasib, two KRASG12C inhibitors, have been approved for treating NSCLC with this mutation, their efficacy is limited, and drug resistance is a concern. There is a need for next-generation inhibitors with improved activity and combination therapies to enhance their effectiveness.

ABSK071 is a novel KRASG12C inhibitor that has shown superior inhibitory activity against multiple KRASG12C-mutated cell lines compared to sotorasib and adagrasib. It also exhibits enhanced in vivo anti-tumor efficacy in xenograft models that are less responsive to sotorasib. The study evaluated the combination of ABSK071 with various targeted agents, including EGFR inhibitors, FGFR inhibitors, SHP2 inhibitors, and SOS1 inhibitors, as well as immuno-oncology agents like anti-PD-1/L1, CSF-1R inhibitor, and CD73 inhibitor.

In cellular experiments, ABSK071 combined with agents such as cetuximab, afatinib, AZD4547, TNO-155, RMC-4630, and BI3406 resulted in synergistic effects on cell growth inhibition. The in vivo study confirmed these synergistic anti-tumor effects, with superior activities observed when these agents were combined with ABSK071 compared to sotorasib. Additionally, ABSK071 demonstrated synergy with anti-PD-1/L1 antibodies and other immuno-oncology reagents in mouse syngeneic models with KrasG12C mutations.

The findings suggest that ABSK071 has the potential to be a more effective KRASG12C inhibitor, with a broad range of synergistic effects when combined with targeted and immuno-oncology therapies. This indicates its promise for treating a variety of KRASG12C-dependent cancers and addresses the need for more effective treatment options.