FDA Grants Fast Track Designation to TRE-515 Plus KRAS Inhibitors in Pretreated KRAS G12C+ NSCLC

The FDA has granted fast track designation to TRE-515 in combination with KRAS inhibitors for the treatment of 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

Trethera Corporation, the developer of TRE-515, stated that its approach is based on the observation that tumors treated with KRAS inhibitors may increase their reliance on the nucleoside salvage pathway as a metabolic support system under therapeutic stress. In preclinical studies, specialized PET imaging showed persistent deoxycytidine kinase (dCK) activity following KRAS inhibitor treatment, whereas subsequent TRE-515 treatment completely blocked tumor dCK activity, according to the company.

Trethera also reported that TRE-515 has demonstrated favorable safety and antitumor activity in an ongoing first-in-human phase 1 trial (NCT05055609), which is evaluating TRE-515 in patients with advanced solid tumors.^1.2

“KRAS G12C inhibitors have transformed the NSCLC treatment landscape, but resistance and incomplete responses remain major challenges. We believe TRE-515 has the potential to address a key metabolic escape pathway used by cancer cells and improve outcomes for patients with this devastating disease,” Ken Schultz, MD, chairman and chief executive officer of Trethera, stated in a news release.¹

The designation marks the second fast track designation for TRE-515, following a prior designation in metastatic castration-resistant prostate cancer. The agent has also received orphan drug designation for 2 autoimmune neurologic diseases.

What is the mechanism of action of TRE-515?

TRE-515 is an orally administered, first-in-class small molecule inhibitor of dCK, the rate-limiting enzyme in the nucleoside salvage pathway, which is one of two biosynthetic pathways that generate DNA precursors.Rapid, upregulated DNA replication in cancer cells creates high replication stress, which renders these cells more susceptible than normal cells to perturbations in nucleotide metabolism.²

According to Trethera, some cancers may be preferentially dependent on the salvage pathway to support tumor growth, and the salvage pathway can become activated and essential for abnormal cell growth in cancer.¹ The company is developing TRE-515 as monotherapy and as part of combination regimens.

How is the first-in-human phase 1 trial of TRE-515 designed?

TRE-515 is being evaluated in an open-label, multicenter, nonrandomized, first-in-human phase 1 dose-escalation study with expansion, which is enrolling an estimated 94 adult patients with advanced solid tumors.² 

Eligible patients must be at least 18 years of age with a histologically or cytologically confirmed solid tumor and advanced refractory cancer for which standard curative or palliative measures do not exist or are no longer effective, with no limit on the number or type of prior therapies. Measurable disease per RECIST 1.1 criteria is required, except in patients with a positive biomarker of progression such as prostate-specific antigen or CA-125. Patients must also have an ECOG performance status of 0 to 2 and adequate organ function, including a creatinine clearance of at least 60 mL/min, a platelet count of at least 75,000/mm³, and a neutrophil count of at least 1500/mm³. Key exclusion criteria comprise candidacy for potentially curative therapy, prior organ transplant, QTcB prolongation greater than 470 msec, and known HIV or active hepatitis B or C infection.²

Patients are receiving oral TRE-515 once daily in continuous 21-day cycles. Dose escalation follows a conventional 3+3 design, with dose-limiting toxicities (DLTs) assessed over the first 21 days; the maximum tolerated dose (MTD) is defined as the highest dose at which fewer than 2 of 6 patients experience a DLT. A safety review committee will define the recommended phase 2 dose (RP2D), at which an additional 6 patients will be treated. Tumor response is assessed by investigators per RECIST criteria 1.1 every 8 weeks, and a substudy is examining the effect of an acid-reducing agent on TRE-515 exposure.

The primary end points are safety and tolerability, as measured by the number of patients with adverse effects (AEs) per NCI-CTCAE v5.0 criteria, and the incidence of DLTs. Secondary end points include pharmacokinetic parameters, the RP2D, and preliminary antitumor activity per RECIST 1.1 criteria. Exploratory objectives include assessing on-target dCK knockdown with an [¹⁸F]-clofarabine PET probe and plasma deoxynucleoside concentrations.

“For decades, oncology has focused heavily on targeting oncogenic signaling pathways, including KRAS,” said Owen Witte, MD, UCLA Professor and co-founder of Trethera, stated in a news release.¹ “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.”

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://trethera.com/fda-fast-track-tre-515-kras-g12c-nsclc/
2. Open-label, dose-escalation with expansion to assess the safety, tolerability, and PK of TRE-515 in subjects with solid tumors. ClinicalTrials.gov. Accessed October 2, 2026. https://clinicaltrials.gov/study/NCT05055609