The first-in-human phase 1/2 study of TSN1611, a highly selective KRAS G12D inhibitor, in patients with advanced solid tumors.

3083 Background: TSN1611 is a novel small molecule KRAS G12D inhibitor targeting both active (GTP-bound) and inactive (GDP-bound) forms of KRAS G12D protein. TSN1611 showed high potency and selectivity against KRAS G12D mutant tumor cells in vitro and effectively inhibited tumor growth in several pancreatic ductal carcinoma (PDAC), colorectal cancer (CRC) and non-small cell lung cancer models (NSCLC) in vivo. Methods: A phase 1/2 study of TSN1611 was developed to enroll patients (pts) with advanced solid tumors harboring KRAS G12D mutation. The study comprised a phase 1a dose escalation part following a BOIN design with accelerated titration to determine the maximum tolerated dose (MTD), recommended phase 2 dose and pharmacokinetics (PK), followed by a phase 1b part for dose optimization to compare different recommended doses and a phase 2 part to evaluate the efficacy of TSN1611 across various tumor types. Alternative dose levels or regimens could be explored based on the emerging data. Pts received oral TSN1611 twice daily (BID), until disease progression, unacceptable toxicity, or patient withdrawal. Here we report the preliminary data from phase 1a part. Results: As of Jan 05, 2025, 18 pts received TSN1611 from 50 to 600 mg BID (9 with CRC, 5 PDAC, 2 NSCLC, and 1 each with ampullary cancer and gallbladder cancer, all with pre-identified KRAS G12D mutation). Median age was 61 years (range 36-81). The median prior lines of systemic therapy were 3 (range 1-6). No dose-limiting toxicity was reported and MTD was not reached. The most common (≥ 10%) treatment related adverse events (TRAEs) were grade 1 or 2 vomiting (44.4%), nausea and diarrhea (38.9% each), fatigue (16.7%), ALT increased, blood CPK increased, hyperkalemia and hyperuricemia (11.1% each). No treatment related grade 3 or higher AE or SAE was reported. Four (30.8%) out of the 13 evaluable pts demonstrated stable disease per RECIST v1.1. Tumor reductions were observed in 3 pts (CRC, PDAC, and NSCLC, n = 1 each) at 200 or 400 mg BID, with treatment ongoing. Serial assessment of plasma ctDNA revealed declines in KRAS G12D variation allele frequency at 200 mg BID and above, echoing that the exposure at 200 mg BID reached that of ED 90 in the CRC GP2D model. TSN1611 was rapidly absorbed with T max around 2 hours and half-life around 15 hours. The PK profile indicated a general dose proportionality in exposure across the evaluated dose ranges and low to moderate accumulation after multiple BID dosing. Dose escalation is ongoing, and more data will be available at the conference presentation. Conclusions: TSN1611 was well tolerated, demonstrating acceptable PK characteristics as predicted, with preliminary tumor shrinkage observed in pts with refractory KRAS G12D mutant tumors. Phase 1b/2 studies are planned to evaluate TSN1611 both as a monotherapy and in combination with standard of care and/or novel agents treating cancer. Clinical trial information: NCT06385925 .