RNK08954 shows unconfirmed responses in KRASG12D-mutant NSCLC and PDAC in Phase Ia trialNew drug shows promise for KRASG12D lung and pancreatic cancers

UNLABELLED: KRAS G12D is the most prevalent subtype of KRAS mutation across solid tumors, but no drug is available in the clinic. RNK08954 is a potent and selective KRASG12D inhibitor that inhibits proliferation of KRASG12D-mutant cells and demonstrates significant tumor regressions in mouse xenograft models while inhibiting KRAS-mediated signaling. The in vivo effects of RNK08954 are explained by its unique pharmacokinetic (PK) profile and significantly prolonged retention time in tumor tissues. RNK08954 shows synergy with immune checkpoint blockade (ICB). In a phase Ia study, the median follow-up was 4.85 months for 36 evaluable patients. In patients with non-small cell lung cancer (NSCLC), the objective response rate (ORR; unconfirmed) was 58.33%, and in patients with pancreatic ductal adenocarcinoma (PDAC), the ORR (unconfirmed) was 33.33% in the 1,000- to 1,200-mg cohort. This study supports the clinical potential of RNK08954 in patients with KRASG12D mutation either as a single agent or in combination. SIGNIFICANCE: RNK08954 is potentially the first orally bioavailable KRASG12D inhibitor, distinguished by unique PK properties, preclinical efficacy, preliminary clinical activity with encouraging results in patients with NSCLC and PDAC, and synergistic potential with ICB. RNK08954 may address a critical unmet need by targeting the most prevalent KRAS mutation across solid tumors.