Trethera Corporation received US FDA Fast Track designation for its deoxycytidine kinase (dCK) inhibitor TRE-515 in combination with KRAS G12C inhibitors for previously treated KRAS G12C-mutated non-small cell lung cancer (NSCLC).
The designation covers patients whose disease has progressed following treatment with an anti-PD-(L)1 antibody and platinum-based chemotherapy. Trethera said the combination is intended to address resistance to KRAS G12C inhibitors, which can produce responses in previously treated NSCLC but are commonly followed by disease progression.
TRE-515 is an oral inhibitor of dCK, the rate-limiting enzyme in the nucleoside salvage pathway. Trethera is testing the hypothesis that KRAS-inhibited tumors become increasingly dependent on this pathway under therapeutic stress. In preclinical positron emission tomography studies, dCK activity remained detectable following KRAS inhibitor treatment and was subsequently suppressed by TRE-515.
Clinical experience with TRE-515 to date comes from a first-in-human Phase I dose-escalation study (NCT05055609) in patients with advanced or metastatic solid tumors. The drug was evaluated across a 36-fold dose range without dose-limiting toxicities, and Trethera reported signs of clinical activity at the 40-mg and 80-mg dose levels, including one patient who maintained disease control for more than 250 days.
Those data were generated with TRE-515 outside the proposed KRAS G12C inhibitor combination, which has not yet been clinically established. The combination strategy is supported by an NIH SBIR award for preclinical TRE-515/KRAS inhibitor studies in NSCLC, which Trethera valued at USD 2.7 million when it announced the funding in December 2025.