Beyond a Single KRAS Inhibitor: China-Originated Therapeutics and the Rise of Resistance-Directed Combinations

For decades, KRAS was the archetype of an "undruggable" oncogene.The success of covalent KRAS G12C inhibitors overturned that paradigm, but it also exposed the limitations of simply matching one mutation with one drug.Responses are often incomplete, resistance emerges through pathway reactivation and tumor-microenvironmental adaptation, and therapeutic sensitivity differs across alleles and tumor lineages [1][2][3][4][5] .The next phase of KRAS therapeutics will therefore depend on both new inhibitors and mechanism-based, biomarker-informed combinations.China-originated drug discovery and clinical translation are increasingly contributing to this shift.Garsorasib (D-1553) provides a useful starting point and exemplifies this transition.Developed in China, this selective KRAS G12C inhibitor moved from preclinical discovery into phase 1 and phase 2 studies in Chinese patients with non-small-cell lung cancer (NSCLC), and was subsequently approved in China [6][7][8] .The program matured through international presentations, including AACR and WCLC, before longerterm publication.In a pooled analysis of 189 patients led by Zhengbo Song and colleagues, garsorasib achieved an objective response rate (ORR) of 48.1%, a median duration of response of 12.45 months, and a median progression-free survival (PFS) of 9.07 months [8] .These results established more than another active G12C inhibitor: they created a China-originated clinical platform on which combination strategies could be built.