On August 16, 2021 Turning Point Therapeutics, Inc. (NASDAQ: TPTX), a precision oncology company developing next-generation therapies that target genetic drivers of cancer, reported initiation of the first cohort of its Phase 1b/2 TRIDENT-2 combination study of lead investigational drug repotrectinib (Press release, Turning Point Therapeutics, AUG 16, 2021, View Source [SID1234586647]). The initial cohort will investigate repotrectinib in combination with MEK-inhibitor trametinib in KRAS G12D mutated advanced solid tumors.
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"We are pleased to initiate the TRIDENT-2 study and explore a potential new treatment option for patients with KRAS-driven solid tumors," said Mohammad Hirmand, executive vice president and chief medical officer. "With preclinical studies demonstrating repotrectinib’s ability to inhibit JAK2, SRC and FAK, our goal is to help improve the effectiveness of KRAS-targeting agents by suppressing known pathways of tumor resistance."
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 (AACR) (Free AACR Whitepaper) 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.