Preliminary phase 1 results of INCB161734, a novel oral Kirsten rat sarcoma (KRAS) G12D inhibitor, as monotherapy or in combination with chemotherapy for advanced/metastatic pancreatic duct adenocarcinoma (PDAC).

654 Background: KRAS G12D is the most common KRAS mutation, occurring in ~40% of patients (pts) with PDAC. INCB161734, a novel, selective ON/OFF KRAS G12D small molecule inhibitor, is being evaluated in a phase 1 trial. Here we report results in pts with advanced/metastatic PDAC, including safety and efficacy of INCB161734 monotherapy, and preliminary safety results of combinations. Methods: This multi-center, first-in-human dose escalation/expansion study is enrolling adult pts with advanced/metastatic solid tumors and KRAS G12D mutation (NCT06179160). The study is evaluating INCB161734 monotherapy including a PDAC-specific expansion cohort and INCB161734 combination therapies, including with mFOLFIRINOX or GEMNabP in pts with PDAC and ≤1 prior treatment (tx) in the metastatic setting. The primary endpoint is safety. Secondary endpoints include pharmacokinetics and preliminary efficacy (per RECIST v1.1). Translational assessments include longitudinal ctDNA analyses. Results: As of August 1, 2025, 136 pts, including 83 with PDAC, had received INCB161734 monotherapy at daily doses of 200 mg to 1600 mg in escalation and at recommended doses for expansion (RDEs) of 600mg QD and 1200mg QD in expansion. Tx-related AEs (TRAEs) in ≥15% of pts were nausea (58%), diarrhea (51%), vomiting (46%), and fatigue (18%); mostly grade 1/2; 4 (3%) pts had serious TRAEs. No pt had a fatal TRAE or a TRAE leading to tx discontinuation. INCB161734 monotherapy efficacy and ctDNA analyses in PDAC at RDEs are summarized in the Table. INCB161734 dose escalation combined with chemotherapies has begun (starting dose 600 mg daily). Among pts with PDAC who received INCB161734 600 mg in combination with GemNabP (n=6) or mFOLFIRINOX (n=4), no dose limiting toxicities were observed, allowing further INCB161734 dose escalation with both chemotherapies. INCB161734 showed comparable steady state exposures as monotherapy or in combination with either chemotherapy. Further data from combination therapies will be presented. Conclusions: INCB161734 monotherapy has a manageable safety profile, with promising early clinical efficacy and evidence of molecular response in pts with advanced/metastatic PDAC harboring KRAS G12D mutation. Ongoing dose escalation of INCB161734 in combination with chemotherapy shows an encouraging safety profile. Clinical trial information: NCT06179160 . INCB161734 monotherapy outcomes at selected doses in pts with PDAC and ≥1 post-baseline scan. 600 mg Dailyn = 22 1200 mg Daily † n = 29 PR, n (%) 5 (23) 10 (34) Disease control*, n (%) 16 (73) 25 (86) Molecular response ‡ , % (n) 41 (7/17 § ) 72 (13/18 § ) Includes pts enrolled in escalation or expansion. *PR + stable disease; † total daily dose as QD or BID; ‡ ≥90% reduction in ctDNA G12D variant allele frequency; § Pts with detectable baseline G12D. PR, partial response.