Updated results of the phase 1/2 study of TSN1611, a highly selective KRAS G12D inhibitor, in patients with advanced solid tumors.

Abstract

710 Background: TSN1611 is a novel small molecule KRAS G12D inhibitor targeting both the active (GTP-bound/On) and inactive (GDP-bound/Off) 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 initiated 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 (RP2D) 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. Pts received oral TSN1611 tablets twice daily (BID), until disease progression, unacceptable toxicity, or patient withdrawal. Results: As of Aug 29, 2025, 76 pts received TSN1611 from 50 to 1200 mg BID in Phase 1 part (46 in Phase 1a and 30 in Phase 1b). Median age was 61 yrs (range 22-81). The median prior lines of systemic therapy were 2 (range 0-7). No dose-limiting toxicity was reported and MTD was not reached. The RP2D was established as 1200 mg BID. Patients were randomized to 800 mg and 1200 mg BID for dose optimization in Phase 1b part. Overall, the most common (≥ 10% out of 76 pts) treatment-related adverse events (TRAEs) were nausea (52.6%), vomiting (43.4%), diarrhea (40.8%), anemia (18.4%), decreased white blood cell count (14.5%), fatigue and decreased neutrophil count (11.8% each), and increased ALT and decreased appetite (10.5% each). All TRAEs were Grade 1 or 2 (CTCAE v5.0), except for one case each (1.3%) of Grade 3 decreased WBC count and Grade 3 anemia. No serious TRAE was observed. TRAEs led to dose interruption in 9 pts (11.8%) and dose reduction in 3 pts (3.9%); however, no treatment discontinuation due to TRAEs occurred. Tumor response was observed at doses ≥ 600 mg BID; among the 7 evaluable pts with NSCLC who had post-baseline tumor evaluation, the objective response rate (ORR) was 42.9% (3/7 PR) and the disease control rate (DCR) was 100% (all 7 pts achieved stable disease or better). Among evaluable pts at 800 mg and 1200 mg BID, the ORR was 36.4% (4/11 PR) and DCR was 72.7% (8/11) in PDAC pts who had received 1-2 prior lines of therapy. Enrollment into the Phase 2 portion of the study is ongoing, and more data will be available at the conference presentation. Conclusions: TSN1611 demonstrated promising clinical efficacy in pts with KRAS G12D mutant tumors, with a well-tolerated safety profile. These results support further evaluation of TSN1611 as a monotherapy and in combination therapies in KRAS G12D mutant tumors. Clinical trial information: NCT06385925 .