Covalent inhibitors of KRASG12C have shown antitumor activity against advanced/metastatic KRAS G12C-mutated cancers, though resistance emerges and additional strategies are needed to improve outcomes. JDQ443 is a structurally unique, covalent inhibitor of GDP-bound KRASG12C that forms novel interactions with the switch II pocket. JDQ443 potently inhibits KRASG12C-driven cellular signaling and demonstrates selective antiproliferative activity in KRAS G12C-mutated cell lines, including those with G12C/H95 double mutations. In vivo, JDQ443 induces AUC exposure-driven antitumor efficacy in KRAS G12C-mutated cell-derived (CDX) and patient-derived (PDX) tumor xenografts. In PDX models, single-agent JDQ443 activity is enhanced by combination with SHP2, MEK or CDK4/6 inhibitors. Notably, the benefit of JDQ443 plus the SHP2 inhibitor TNO155 is maintained at reduced doses of either agent in CDX models, consistent with mechanistic synergy. JDQ443 is in clinical development as monotherapy and in combination with TNO155, with both strategies showing antitumor activity in patients with KRAS G12C-mutated tumors.

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Patients may encounter process barriers in acquiring oral therapy, particularly because of pharmacy processing time, as well as high copays. Time to treatment initiation may have implications for patients' clinical outcomes. Adequate staff with dedicated time to facilitate this process should be used in the ambulatory oncology practice setting.

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