Turning Point Therapeutics, Inc. announced initiation of the first cohort of its Phase 1b/2 TRIDENT-2 combination study of lead investigational drug repotrectinib. The initial cohort will investigate repotrectinib in combination with MEK-inhibitor trametinib in KRAS G12D mutated advanced solid tumors. The Phase 1b portion of the study will examine the safety, tolerability, pharmacokinetics, and any early signals of efficacy of repotrectinib in combination with trametinib in patients with KRAS G12D mutated advanced solid tumors. After determination of a recommended Phase 2 combination dose, the study includes a Phase 2 dose expansion portion with the primary endpoint of objective response rate. Results from preclinical studies presented at the 2021 American Association for Cancer Research annual meeting found that repotrectinib in combination with trametinib was more effective than single-agent trametinib in patient-derived KRAS mutant G12D lung cancer models. The repotrectinib-trametinib combination suppressed a broad range of downstream mutant KRAS G12D signaling, increased cell cycle arrest and induction of apoptosis, and was more active in multiple KRAS G12D dependent models compared to either single-agent treatment. The frequently mutated Kirsten Rat Sarcoma (KRAS) viral oncogene is associated with a broad range of human cancers, including approximately 30% of non-small cell lung, 40% of colorectal and more than 90% of pancreatic cancers. KRAS G12D mutations are known to occur across multiple tumors types, including an estimated 30% of pancreatic, 15% of colorectal and 5% of both endometrial and non-small cell lung cancers. Therapeutic targeting of KRAS has proven challenging, in part due to resistance and adaptive upregulation of alternative signaling pathways that promote tumor cell survival, as well as concurrent secretion of various cytokines and growth factors.