A phase 1/2 study of TSN1611, a highly selective oral KRAS G12D inhibitor, in solid tumors: Efficacy and safety in KRAS G12D–mutated NSCLC patients.

8516 Background: There remains an unmet clinical need for effective therapies targeting KRAS G12D mutation in patients (pts) with advanced non-small cell lung cancer (NSCLC) refractory to prior treatments. TSN1611 is a novel oral small-molecule inhibitor designed to bind both the active GTP-bound (ON) and inactive GDP-bound (OFF) conformations of KRAS G12D, providing a differentiated mechanism of action and broad antitumor activity in preclinical models. Methods: This multi-regional Phase 1/2 study enrolled pts with advanced solid tumors harboring KRAS G12D mutation. Phase 1a dose-escalation part evaluated TSN1611 at 50–1200 mg twice daily (BID). A subsequent Phase 1b dose-optimization part evaluated 800 mg and 1200 mg BID. In Phase 2, efficacy is being further explored across multiple tumor types at the recommended Phase 2 dose of 1200 mg BID. Results: As of Jan 23, 2026, 117 pts received TSN1611 across all dose levels in Phase 1/2. Tumor types included NSCLC (n = 26), pancreatic adenocarcinoma (n = 50), colorectal cancer (n = 35), and others (n = 6). Median age was 62 yrs (range 22-81). The median prior lines of systemic therapy were 2 (range 0-7). The most common (≥10%) treatment-related adverse events (TRAEs) in all treated pts were diarrhea (53.0%), nausea (48.7%), vomiting (46.2%), anemia (17.9%), decreased white blood cell count (16.2%), decreased neutrophil count (13.7%), increased ALT (12.8%), decreased appetite (12.0%), decreased platelets (11.1%), fatigue and increased AST (10.3% each). Grade 3 TRAEs occurred in 9.4% of pts; these were all single events (0.9% each) except for anemia, diarrhea, and asymptomatic lipase elevation, which occurred in 1.7% of pts each. TRAEs led to dose interruption in 17.1% pts and dose reduction in 7.7% pts; no treatment discontinuations due to TRAEs occurred. Among 26 NSCLC pts, all had stage IV metastatic disease; 22 (84.6%) had received prior chemotherapy and/or PD-1/PD-L1 inhibitors, and 9 (34.6%) had received prior anti-angiogenic therapy. Among 20 response-evaluable NSCLC pts treated with TSN1611 at 600–1200 mg BID, 10 achieved partial response, 8 had stable disease, and 2 had progressive disease, yielding an objective response rate (ORR) of 50% (95% CI 27.2–72.8) and a disease control rate (DCR) of 90% (95% CI 68.8–98.3). Median time to response was 1.4 months (range 1.2–3.5). In addition to extracranial responses, rapid intracranial responses were observed. Median progression-free survival (PFS) was not mature yet (range 1.3+ to 12.9+ months), with a 9-month PFS rate of 54.5% (95% CI 24.4–77.0). Enrollment continues and updated data will be presented at the conference. Conclusions: TSN1611 demonstrated a favorable safety profile and clinically meaningful antitumor activity in pts with KRAS G12D mutated NSCLC. Further development of TSN1611 as monotherapy and in combination regimens is ongoing. Clinical trial information: NCT06385925 .