tamnorzatinib (ONO-7475) / Ono Pharma - LARVOL DELTA

A PhaseⅠStudy of ONO-7475 in Combination With ONO-4538 and Gemcitabine Plus Nab-paclitaxel (GnP), the Standard of Care, and ONO-7475 in Combination With GnP in Patients With Pancreatic Cancer (clinicaltrials.gov) - P1 | N=87 | Active, not recruiting | Sponsor: Ono Pharmaceutical Co. Ltd | Recruiting ➔ Active, not recruiting

Enrollment closed • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • CA 19-9

Development of an initial triple combination therapy targeting EGFR, AXL, and FGFR for EGFR-mutated non-small cell lung cancer (AACR 2025) - "Our findings demonstrate that the FGF2-FGFR1 signaling pathway contributes to adaptive resistance to the combination of osimertinib and ONO-7475 in EGFR-mutated NSCLC with high AXL expression. The triple combination therapy of osimertinib, ONO-7475, and BGJ398 showed safety and prevented tumor regrowth in CDX models, suggesting that this regimen has the potential to improve outcomes for patients with EGFR-mutated NSCLC."

Combination therapy • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AXL • EGFR • FGF2 • FGFR • FGFR1 • MYC

Study of ONO-7475 in Combination With Osimertinib in EGFR Gene Mutation-positive Non-small Cell Lung Cancer (clinicaltrials.gov) - P1 | N=78 | Active, not recruiting | Sponsor: Ono Pharmaceutical Co. Ltd | Trial completion date: Apr 2025 ➔ Oct 2025 | Trial primary completion date: Apr 2025 ➔ Oct 2025

Combination therapy • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

A PhaseⅠStudy of ONO-7475 in Combination With ONO-4538 and Gemcitabine Plus Nab-paclitaxel (GnP), the Standard of Care, and ONO-7475 in Combination With GnP in Patients With Pancreatic Cancer (clinicaltrials.gov) - P1 | N=87 | Recruiting | Sponsor: Ono Pharmaceutical Co. Ltd

Combination therapy • Metastases • New P1 trial • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor

ONO-7475-03: ONO-7475 Phase I Study An Open-label, Uncontrolled Study of ONO-7475 in Combination With Osimertinib in EGFR Gene Mutation-positive Non-small Cell Lung Cancer (clinicaltrials.gov) - P1 | N=78 | Active, not recruiting | Sponsor: Ono Pharmaceutical Co. Ltd

Combination therapy • New P1 trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Triple combination therapy comprising osimertinib, an AXL inhibitor, and an FGFR inhibitor improves the efficacy of EGFR-mutated non-small cell lung cancer. (PubMed, Cancer Lett) - "Cell-based assays showed that triple therapy with osimertinib, ONO-7475, and the FGFR inhibitor BGJ398 significantly increased apoptosis by increasing expression of proapoptotic factor Bim and reduced cell viability compared with that observed for the osimertinib-ONO-7475 therapy. Xenograft models showed that triple therapy considerably suppressed tumor regrowth. A novel therapeutic strategy of additional initial FGFR1 inhibition may be highly effective in suppressing the emergence of osimertinib- and ONO-7475-resistant cells."

Combination therapy • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • FGF2 • MYC

A phase 1 study of tamnorzatinib (ONO-7475), an Axl/Mer dual inhibitor, alone and in combination with nivolumab in patients with advanced or metastatic solid tumors (AACR 2024) - P1 | "ONO-7475 was tolerated at repeated once-daily oral doses up to 10 mg as a monotherapy and in combination with NIVO in pts with advanced or metastatic solid tumors."

Clinical • Combination therapy • IO biomarker • Metastases • P1 data • Oncology • Solid Tumor • AXL

Phase 1 Study of ONO-7475 With and Without ONO-4538 in Subjects Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1 | N=24 | Completed | Sponsor: Ono Pharmaceutical Co. Ltd | Suspended ➔ Completed | N=84 ➔ 24 | Trial completion date: Apr 2023 ➔ Nov 2022

Enrollment change • Metastases • Monotherapy • Trial completion • Trial completion date • Oncology • Solid Tumor

A Study of ONO-7475 in Patients With Acute Leukemias (clinicaltrials.gov) - P1/2 | N=42 | Terminated | Sponsor: Ono Pharmaceutical Co. Ltd | N=67 ➔ 42 | Trial completion date: Sep 2024 ➔ Jan 2023 | Active, not recruiting ➔ Terminated | Trial primary completion date: Nov 2023 ➔ Dec 2022; Protocol defined futility criteria

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Circulating small extracellular vesicles promote proliferation and migration of vascular smooth muscle cells via AXL and MerTK activation. (PubMed, Acta Pharmacol Sin) - "Pretreatment with BSM777607 (pan-TAM inhibitor), bemcentinib (AXL inhibitor) or UNC2250 (MerTK inhibitor) blocked csEV-induced proliferation and migration of VSMCs. Finally, we demonstrated that dual inhibition of AXL/MerTK by ONO-7475 (0.1 µM) effectively hindered csEV-mediated proliferation and migration of VSMCs in ex vivo mouse aorta injury model. Based on these results, we propose an essential role for csEVs in proliferation and migration of VSMCs and highlight the feasibility of dual AXL/MerTK inhibitors in the treatment of vascular diseases."

Journal • Cardiovascular • AXL • MERTK

A Study of ONO-7475 in Patients With Acute Leukemias (clinicaltrials.gov) - P1/2 | N=67 | Active, not recruiting | Sponsor: Ono Pharmaceutical Co. Ltd | Recruiting ➔ Active, not recruiting

Enrollment closed • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

A Study of ONO-7475 in Patients With Acute Leukemias (clinicaltrials.gov) - P1/2 | N=67 | Recruiting | Sponsor: Ono Pharmaceutical Co. Ltd | Trial completion date: Feb 2023 ➔ Sep 2024 | Trial primary completion date: Apr 2022 ➔ Nov 2023

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Identification of ADRN-specific, MES-specific, and pan-subtype therapeutic targets in neuroblastoma (AACR 2022) - "MES neuroblastoma cell lines are more sensitive to small molecule AXL inhibitors (Cabozantinib, NPS-1034, and ONO-7475) compared to ADRN cell lines. Here we have identified and prioritized ADRN-specific, MES-specific, and pan-subtype neuroblastoma therapeutic targets and suggest AXL-targeted therapy may eliminate both MES-dominant neuroblastoma cells and immune cell populations that contribute to an immunosuppressive microenvironment."

IO biomarker • Neuroblastoma • Oncology • Solid Tumor • CD276 • GAS6 • L1CAM • PD-L1 • PRRX1

Phase 1 Study of ONO-7475 With and Without ONO-4538 in Subjects Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1; N=84; Suspended; Sponsor: Ono Pharmaceutical Co. Ltd; Recruiting ➔ Suspended

Clinical • Monotherapy • Trial suspension • Oncology • Solid Tumor

AXL/MERTK inhibitor ONO-7475 potently synergizes with venetoclax and overcomes venetoclax resistance to kill FLT3-ITD acute myeloid leukemia. (PubMed, Haematologica) - "Compared to ONO-7474 monotherapy, the combination of ONO- 7475/ABT-199 was even more potent in reducing leukemic burden and prolonging survival of mice in both model systems. These results suggest the ONO-7475/ABT-199 combination may be effective for acute myeloid leukemia therapy."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • AXL • FLT3 • MERTK

A novel Axl and Mertk dual inhibitor ONO-7475: A new therapeutic agent for the treatment of FLT3-ITD and -wild-type acute myeloid leukemia (AML) overexpressing (AACR 2018) - P1; "Our data suggest that Mertk may play an important role in survival signaling in FLT3-WT AML. Therefore, targeting both Axl and Mertk by ONO-7475 could be a new strategy for the treatment of FLT3-WT patients with AML in addition to FLT3-ITD. Additional work to investigate and clarify for target populations in both FLT3-ITD and -WT AML is currently under way."

Acute Myelogenous Leukemia

Phase 1 Study of ONO-7475 With and Without ONO-4538 in Subjects Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1; N=84; Recruiting; Sponsor: Ono Pharmaceutical Co. Ltd; Trial completion date: Apr 2021 ➔ Apr 2023; Trial primary completion date: Apr 2021 ➔ Apr 2023

Clinical • Monotherapy • Trial completion date • Trial primary completion date • Oncology • Solid Tumor

A Study of ONO-7475 in Patients With Acute Leukemias (clinicaltrials.gov) - P1/2; N=67; Recruiting; Sponsor: Ono Pharmaceutical Co. Ltd; Active, not recruiting ➔ Recruiting

Clinical • Enrollment open • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

A Study of ONO-7475 in Patients With Acute Leukemias (clinicaltrials.gov) - P1/2; N=67; Active, not recruiting; Sponsor: Ono Pharmaceutical Co. Ltd; Phase classification: P1 ➔ P1/2; N=42 ➔ 67; Trial completion date: Mar 2021 ➔ Feb 2023; Trial primary completion date: Sep 2020 ➔ Apr 2022

Clinical • Enrollment change • Phase classification • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

A Study of ONO-7475 in Patients With Acute Leukemias (clinicaltrials.gov) - P1; N=42; Recruiting; Sponsor: Ono Pharmaceutical Co. Ltd; Trial primary completion date: Dec 2019 ➔ Mar 2020

Clinical • Trial primary completion date • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

A Study of ONO-7475 in Patients With Acute Leukemias (clinicaltrials.gov) - P1; N=42; Recruiting; Sponsor: Ono Pharmaceutical Co. Ltd; Trial primary completion date: Mar 2020 ➔ Sep 2020

Clinical • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

A Study of ONO-7475 in Patients With Acute Leukemias (clinicaltrials.gov) - P1; N=42; Active, not recruiting; Sponsor: Ono Pharmaceutical Co. Ltd; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

ONO-7475, a novel AXL inhibitor, suppresses the adaptive resistance to initial EGFR-TKI treatment in EGFR-mutated non-small lung cancer. (PubMed, Clin Cancer Res) - "These results demonstrate that ONO-7475 suppresses the emergence and maintenance of tolerant cells to the initial EGFR-TKIs, osimertinib or dacomitinib, in AXL-overexpressing EGFR-mutated NSCLC cells, suggesting that ONO-7475 and osimertinib is a highly potent combination for initial treatment."

Journal • EGFR

AXL/Mertk Inhibitor ONO-7475 Potently Synergizes with BCL2 Inhibitor ABT-199, Overcomes ABT-199 Resistance Mechanisms, and Kills FLT3 ITD AML Cells (ASH 2019) - "These results suggest that ONO-7475 in combination with ABT-199 is an effective therapeutic strategy for treating FLT3-ITD-dependent AML, including those that are resistant to the BCL2 specific inhibitors. Critically, these results indicate that inhibition of AXL/MERTK axis overcomes survival advantages conferred by MCL-1, a common mechanism of Venetoclax resistance. The ability of ONO-7475/ABT-199 combination to eliminate Molm13 cells without completely suppressing MCL-1 suggests that drug combination involves MCL-1 independent targets."

IO Biomarker • BCL2 • FLT3

A Study of ONO-7475 in Patients With Acute Leukemias (clinicaltrials.gov) - P1; N=42; Recruiting; Sponsor: Ono Pharmaceutical Co. Ltd; Trial completion date: Nov 2019 ➔ Mar 2021; Trial primary completion date: Jan 2019 ➔ Dec 2019

Clinical • Trial completion date • Trial primary completion date