FDA Grants Fast Track Designation to TRE-515 for KRAS G12C NSCLC

The FDA has granted fast track designation (FTD) to TRE-515 for use in combination with KRAS G12C inhibitors in patients with KRAS G12C mutation-positive non–small cell lung cancer (NSCLC) previously treated with an anti-PD-(L)1 antibody and platinum-based chemotherapy.¹

This marks the second FTD for TRE-515, following a prior designation in metastatic castration-resistant prostate cancer. TRE-515 has demonstrated favorable safety and antitumor activity in an ongoing first-in-human trial in advanced solid tumors (NCT05055609).¹

“For decades, oncology has focused heavily on targeting oncogenic signaling pathways, including KRAS,” Owen N. Witte, MD, cofounder of Trethera Corporation and professor of microbiology, immunology, and molecular genetics at UCLA, stated a news release. “The next frontier is understanding how cancer cells adapt metabolically to survive those therapies. If successful, TRE-515 could represent a first-in-class approach by targeting the nucleoside salvage pathway, a key metabolic support system that tumors may use under therapeutic stress.”

Mechanism, Preclinical, and Early-Phase Rationale

TRE-515 is an orally administered, first-in-class inhibitor of deoxycytidine kinase (dCK), the rate-limiting enzyme in the nucleoside salvage pathway, 1 of 2 biosynthetic pathways that generate DNA precursors. Based on preclinical data, targeting KRAS in tumors could increase dependence on the salvage pathway, making a combination effective. Specialized PET imaging demonstrated dCK activity following KRAS inhibitor treatment in mouse models, which could then be blocked by subsequent TRE-515 treatment.^1,2

In the phase 1 dose-escalation trial, there were no dose-limiting toxicities up to a dose of 1440 mg, and the investigators focused on collecting biomarker samples that could aid in dose optimization and patient selection for further investigation.^1-3 The sponsor reported a 47% disease control rate in this heavily pretreated population.³ Over 35 patients have been dosed, and the phase 1 portion completed enrollment in September 2025.^2,3 A trial of up to 72 healthy volunteers is being used to provide pharmacokinetic and biomarker data for the development of TRE-515.⁴

Regulatory Context and Next Steps

FTD is intended to facilitate development and expedite FDA review of drugs addressing serious conditions with unmet medical need, including potential eligibility for more frequent FDA communication, accelerated approval, and priority review if relevant criteria are met.

Two KRAS G12C inhibitors, adagrasib (Krazati) and sotorasib (Lumakras), are indicated for use in patients with advanced NSCLC with the appropriate mutation after progression on first-line systemic therapy.⁵

Researchers have also proposed based on preclinical data that TRE-515 could be used to treat autoimmune diseases including multiple sclerosis, Crohn disease, and optic neuritis, and an expanded access program has made it available for patients with amyotrophic lateral sclerosis.³

“For patients with advanced NSCLC, the central challenge is not only achieving an initial response but also making that response more durable,” Evan Abt, PhD, UCLA assistant professor and co-investigator for the preclinical studies, stated in the news release.¹ “This [FTD] underscores the importance of rapidly evaluating innovative, rational combination strategies that may extend the benefit of KRAS-targeted therapies to more patients.”

REFERENCES

1. FDA Grants Fast Track Designation for TRE-515 in Combination with KRAS G12C Inhibitors for the Treatment of Non-Small Cell Lung Cancer. News release. Trethera Corporation. October 1, 2026. Accessed October 2, 2026. https://tinyurl.com/4fvj4x72
2. Clark PM, Thompson CB, Schultz KA. Deoxycytidine kinase inhibition: Rewiring tumor nucleotide metabolism for therapeutic gain. Nucleosides Nucleotides Nucleic Acids. 2026;45(11):1203-1215. doi:10.1080/15257770.2026.2647890
3. Pipeline. Trethera Corporation. Accessed October 2, 2026. https://trethera.com/pipeline/
4. FDA Provides Trethera Clearance to Initiate TRE-515 Clinical Trial in Healthy Volunteers to Study Food Effect and Biomarkers. News release. Trethera Corporation. July 30, 2025. Accessed October 2, 2026. https://tinyurl.com/js8c6wr
5. NCCN. Clinical practice guidelines in oncology. Non–small cell lung cancer, version 9.2026. Accessed October 2, 2026. https://tinyurl.com/56akmfyn