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Turning Point Therapeutics Begins Study of Repotrectinib, Mekinist in KRAS G12D-Mutated Cancers

NEW YORK – Turning Point Therapeutics on Monday said that it has begun a Phase Ib/II clinical trial evaluating its investigational drug repotrectinib combined with the MEK inhibitor trametinib (Novartis' Mekinist) for patients with KRAS G12D-mutated advanced solid cancers.

The Phase Ib portion of the study, dubbed TRIDENT-2, is designed to evaluate the combination's safety, tolerability, pharmacokinetics, and early efficacy signals. Following the Phase Ib portion, Turning Point will continue on to the Phase II portion, in which it will evaluate objective response rates, among other key endpoints, using the recommended dose determined in the first portion.

TRIDENT-2 follows in the wake of preclinical data suggesting that combining repotrectinib with trametinib could benefit patient-derived lung cancer models harboring KRAS G12D mutations to a greater extent than trametinib alone. The reason for this, according to the preclinical results, was that the combination therapy suppressed a range of downstream mutant KRSA G12D signaling, in turn leading to increased cell cycle arrest and apoptosis.

Separately, Turning Point is also evaluating repotrectinib in patients with advanced solid tumors characterized by ALK, ROS1, and NTRK1/2/3 rearrangements in the Phase I/II TRIDENT-1 trial. The firm has already begun talks with the US Food and Drug Administration seeking approval for the agent in ROS1-positive non-small cell lung cancer based on the results of that trial.

"We are pleased to initiate the TRIDENT-2 study and explore a potential new treatment option for patients with KRAS-driven solid tumors," Mohammad Hirmand, Turning Point's chief medical officer and executive VP, said in a statement. "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."