Phase Ia study of VRN101099, a brain-penetrant, highly selective covalent HER2 inhibitor, in HER2-positive or HER2-mutant advanced solid tumors.

1048 Background: Despite advances in HER2-targeted therapies, including trastuzumab deruxtecan (T-DXd), unmet needs remain in patients with HER2-driven solid tumors who develop treatment resistance, particularly those with central nervous system (CNS) metastases. VRN101099 is an orally bioavailable, brain-penetrant covalent HER2 inhibitor that irreversibly inhibits HER2 and induces receptor internalization and degradation. Preclinical studies demonstrated antitumor activity in subcutaneous and intracranial xenograft models of HER2-positive breast and gastric cancers. Methods: This open-label phase Ia study assesses the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of VRN101099 in patients with HER2 IHC 1+/2+/3+ or HER2-activating mutant advanced solid tumors. A standard 3+3 dose-escalation design determines the maximum tolerated dose and recommended phase 2 dose (RP2D), with dose-limiting toxicities assessed during the first 21-day cycle. VRN101099 is given orally once daily in continuous 21-day cycles. Optional backfill cohorts may enroll up to 12 patients at tolerated dose levels to characterize safety, PK, and PD further. Data are descriptive as of the 18 January 2026 cutoff and inform ongoing dose escalation, backfill enrollment, and RP2D selection; early reporting reflects emerging safety and activity. Safety is overseen by a Safety Review Committee defined by protocol. Results: As of January 2026, 17 patients received VRN101099 (80–320 mg). Median age was 63 years; 65% were female, and 35% had breast cancer. HER2 IHC 3+ expression was seen in 29% of patients; 35% were ISH-positive, and 24% had HER2-activating mutations. Patients had received a median of 3 prior systemic therapies (range 0–10); 58% had prior anti-HER2 therapy, including T-DXd (47%). No Grade ≥3 treatment-related adverse events occurred. The most common treatment-related adverse event was Grade 1–2 diarrhea. Among eleven patients with at least one post-baseline tumor assessment at data cutoff, five with HER2 IHC 3+ expression or HER2-activating mutations experienced tumor size reduction after two cycles. Confirmed partial responses were observed in two patients previously treated with T-DXd: one with HER2 IHC 3+ breast cancer and one with HER2 S310Y-mutant NSCLC. PK analyses showed dose-dependent exposure, with trough concentrations at 240 mg exceeding preclinically defined HER2 inhibitory thresholds. Conclusions: VRN101099 was well tolerated across evaluated dose levels and demonstrated encouraging antitumor activity in heavily pretreated HER2-driven solid tumors, including patients previously treated with T-DXd. These findings support continued dose escalation and expansion to define the RP2D and further characterize the therapeutic potential of VRN101099. Clinical trial information: NCT06806982 .