VRN101099 / Voronoi - LARVOL DELTA

Early Clinical Outcomes of VRN101099 in ERBB2-Mutated Advanced Non-Small Cell Lung Cancer: A Case Series From a Phase 1A Study (IASLC-WCLC 2026) - P1 | "Trastuzumab deruxtecan (T-DXd) has shown activity in HER2-mutant NSCLC but with limited durability; poziotinib and pyrotinib provide incomplete mutational coverage with dose-limiting toxicities; and current agents exhibit poor CNS penetration...All had progressed on prior HER2-targeted therapies including T-DXd (n=3) and tucatinib/trastuzumab (n=1)...Conclusions : In this Phase 1a case series, VRN101099 demonstrated preliminary antitumor activity across multiple ERBB2 mutation types and tumor histologies, including patients with CNS disease and those refractory to prior HER2-targeted therapies. These findings support the continued evaluation in planned dose-expansion cohorts to further characterize the efficacy and safety of VRN101099 in ERBB2-mutant malignancies."

Clinical • Clinical data • Metastases • P1 data • Breast Cancer • CNS Disorders • HER2 Breast Cancer • HER2 Positive Breast Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • HER-2 • KRAS • PIK3CA • TP53

VRN101099: A Potential Best-in-Class HER2 TKI With Strong Potency Against HER2 Ex20ins and BBB Penetration. (IASLC-WCLC 2026) - "In HER2-amplified intracranial models, VRN101099 achieved superior tumor regression and survival compared to comparator HER2 TKIs, including zongertinib. Together, these data support further development of VRN101099 for HER2 ex20ins NSCLC, particularly in patients with CNS involvement or prior ADC exposure. Updated data from subcutaneous, orthotopic brain metastasis, leptomeningeal, and patient-derived xenograft models will be presented."

HER2 exon 20 • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • EGFR • HER-2

Early Clinical Antitumor Activity of VRN101099 Across Diverse HER2-Mutants in Solid Tumors (ESMO 2026) - No abstract available

Clinical • Oncology • Solid Tumor • HER-2

Study to Evaluate the Effect of Food and a Proton Pump Inhibitor on the Pharmacokinetics of VRN101099 in Healthy Adult Participants (clinicaltrials.gov) - P1 | N=24 | Recruiting | Sponsor: Voronoi, Inc | Not yet recruiting ➔ Recruiting

Enrollment open

Phase Ia study of VRN101099, a brain-penetrant, highly selective covalent HER2 inhibitor, in HER2-positive or HER2-mutant advanced solid tumors. (ASCO 2026) - P1 | "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)."

Metastases • P1 data • Breast Cancer • Gastric Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Study to Evaluate the Effect of Food and a Proton Pump Inhibitor on the Pharmacokinetics of VRN101099 in Healthy Adult Participants (clinicaltrials.gov) - P1 | N=24 | Not yet recruiting | Sponsor: Voronoi, Inc

New P1 trial

Mechanistic and early clinical characterization of VRN101099, a selective HER2 inhibitor with receptor degradation activity (AACR 2026) - "Beyond catalytic activity, HER2 signaling is regulated by receptor dimerization, trafficking, and degradation, indicating that therapeutic strategies combining kinase inhibition with receptor downregulation may achieve more complete pathway suppression.Several HER2-directed tyrosine kinase inhibitors (TKIs), including tucatinib, zongertinib, and sevabertinib, have demonstrated clinical activity in HER2-driven cancers. Consistently, flow cytometry demonstrated reduced cell-surface HER2 following VRN101099 treatment, whereas tucatinib and zongertinib increased surface HER2 levels.Given that HER2-directed antibody-drug conjugates (ADCs), including trastuzumab deruxtecan (T-DXd) and trastuzumab emtansine (T-DM1), require receptor internalization and lysosomal processing for activity, VRN101099 showed synergistic antitumor activity with these ADCs in HER2-driven xenograft models.A first-in-human, phase 1 dose-escalation study of VRN101099 monotherapy is ongoing. As of January..."

Clinical • First-in-human • Late-breaking abstract • Oncology • Solid Tumor • EGFR

VRN101099: A novel treatment option for HER2-driven cancer patients, overcoming T-DXd resistance and brain metastases (AACR 2025) - "In intracranial xenograft models, VRN101099 demonstrated superior anti-tumor efficacy to tucatinib, neratinib, zongertinib, trastuzumab, and T-DXd. In conclusion, VRN101099 is a promising HER2-selective TKI with a favorable profile including potency, tolerability, and brain permeability. This identifies VRN101099 as a potential novel systemic treatment option for patients with HER2-driven cancers, particularly those with brain metastases or those who have progressed after or failed with T-DXd."

Clinical • Late-breaking abstract • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • EGFR • HER-2

Combinatory treatments of VRN101099 with antibody therapies for HER2-driven breast cancer (SABCS 2025) - "In BT474 or SKBR3, HER2 amplified breast cancer cells, xenograft models with subcutaneous or intracranial implantation, VRN101099 showed combinatory and synergistic anti-tumor effects with Trastuzumab, Pertuzumab, T-DM1, T-DXd, and Zanidatamab. The first-in-human dose escalation study of VRN101099 monotherapy will determine the maximal tolerable dose, and an optimal dose finding study for the combination will be followed."

Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • EGFR • HER-2

Preclinical and Clinical Activity of VRN101099, a Novel Covalent HER2 TKI for Metastatic HER2-Driven Solid Tumors (AACR-NCI-EORTC 2025) - "Although HER2-targeted therapies such as T-DXd and Zongertinib have demonstrated favorable outcomes in HER2-driven tumors, their efficacy remains limited, particularly in patients with brain metastasis and in those harboring specific activating mutations (e.g. S310F/Y). Pharmacokinetic analysis showed that VRN10 achieves sufficient target engagement at an 80mg Ctrough, and remains well tolerated up to 160mg, with no treatment-related adverse events (TRAEs). Together, preclinical and emerging clinical findings demonstrate VRN101099's promise as a therapeutic option for patients with HER2-positive or HER2-mutant solid tumors, including those with difficult-to-treat metastatic sites such as the brain and bone."

Late-breaking abstract • Metastases • Preclinical • Bladder Cancer • Brain Cancer • Breast Cancer • Gastric Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Pancreatic Cancer • Solid Tumor • HER-2

A Phase 1, First-in-Human, Dose-Escalation Study of VRN101099, a Brain-Penetrant HER2 TKI, in Patients with Advanced HER2 Alteration Solid Tumors (AACR-NCI-EORTC 2025) - P1 | "While HER2-targeted therapies such as trastuzumab, pertuzumab, tyrosine kinase inhibitors (TKIs), and the antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) have improved patient outcomes, major unmet medical needs persist. The primary endpoints are the incidence of DLTs and the overall safety profile. Secondary endpoints include PK parameters, PD biomarkers, and preliminary anti-tumor activity as assessed by Objective Response Rate (ORR) according to RECIST v1.1 (ClinicalTrials.gov Identifier: NCT06806982)."

Clinical • First-in-human • Late-breaking abstract • Metastases • P1 data • Gastric Cancer • Lung Cancer • Oncology • Solid Tumor • HER-2

VRN101099_01: A Study of VRN101099 in Patients With HER2-Positive Solid Tumors (clinicaltrials.gov) - P1 | N=72 | Recruiting | Sponsor: Voronoi, Inc | Not yet recruiting ➔ Recruiting

Enrollment open • HER2 Positive Breast Cancer • Solid Tumor

A Phase 1 Study of VRN101099 in Patients With HER2-Positive Solid Tumors (clinicaltrials.gov) - P1 | N=72 | Not yet recruiting | Sponsor: Voronoi, Inc

New P1 trial • Oncology • Solid Tumor

Voronoi, solid tumor target 'VRN101099' Australian clinical phase 1 IND approved [Google translation] (Yakup Shinmoon) - "Voronoi has received approval for the phase 1 clinical trial plan for 'VRN101099' from the Australian Human Research Ethics Committee...the clinical trial will be conducted at five institutions in Australia and Korea with 72 patients with HER2-positive solid tumors...In this clinical trial, the company plans to confirm the maximum tolerated dose and dose-limiting toxicity of the drug and establish the recommended phase 2 dose (RP2D)...'The 'expected end date of the clinical trial' is approximately 36 months from the date of approval of the clinical plan.'....The company applied for the clinical trial on November 19, 2024."

New P1 trial • Trial completion date • Solid Tumor • HER-2

VRN101099: a novel oral treatment option for patients with advanced solid tumors including brain metastasis driven by HER2 amplification or HER2-activating mutations even with T-DXd resistance (EORTC-NCI-AACR 2024) - "Thanks to its high brain permeability and non-substrate of BCRP, VRN101099 exhibited superior intracranial anti-tumor efficacy compared to current therapeutic options, such as tucatinib, neratinib, trastuzumab, and T-DXd. VRN101099 presents a novel systemic treatment option for patients with HER2-driven cancer, particularly those with brain metastasis or who have progressed after or discontinued T-DXd. The first-in-human study of VRN101099 is expected at the end of 2024."

Clinical • Late-breaking abstract • Metastases • Breast Cancer • Colon Cancer • Colorectal Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • HER-2

Preclinical study of VRN101099, a Brain Permeable HER2-Selective Irreversible Kinase Inhibitor for HER2 Positive Metastatic Breast Cancer (SABCS 2023) - No abstract available

Metastases • Preclinical • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor

VRN101099, Brain Permeable HER2 Kinase Inhibitor, Shows the Anti-tumor Activity in Preclinical Models of HER2-positive Cancers (SABCS 2022) - "While T-DXd showed positive results in HER2-positive breast cancer brain metastasis (BCBM), its activity and blood-brain barrier (BBB) permeability in active BCBM need to be further validated (TUXEDO-1 included 15 patients with active brain metastasis). Tucatinib plus Trastuzumab and Capecitabine triplet showed efficacy in patients with brain metastasis, but Tucatinib alone has poor BBB penetration...In summary, VRN101099 is a brain penetrant, orally bioavailable, irreversible, and highly selective inhibitor of HER2 with therapeutic potential in HER2-positive BCBM. These data support the clinical development of VRN101099 in HER2-driven cancers."

Preclinical • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • EGFR • HER-2