dubermatinib (TP-0903) / Sumitomo Pharma - LARVOL DELTA

Beat AML: Study of Biomarker-Based Treatment of Acute Myeloid Leukemia (clinicaltrials.gov) - P2/3 | N=3000 | Recruiting | Sponsor: Beat AML, LLC | Phase classification: P1/2 ➔ P2/3 | Trial completion date: Dec 2028 ➔ Dec 2032 | Trial primary completion date: Dec 2028 ➔ Dec 2032

Biomarker • Phase classification • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • NPM1

A phase 1b/2 study of TP-0903 and decitabine targeting mutant TP53 and/or complex karyotype in patients with untreated acute myeloid leukemia ≥ age 60 years: Phase 1b interim results. (ASCO 2022) - P1/2 | "Initial results with DL1 suggest that TP-0903/dec shows preliminary clinical activity in the prognostically poor TP53m/complex karyotype AML sub-group, with 4 pts achieving MRD negative status out of 6 patients who achieved a CR/CRh/CRi (66%). After further patients were treated on DL1, the toxicity profile and correlative data supported the de-escalation to DL-1 as the RP2D. The Ph2 study is ongoing to determine the clinical activity of this new RP2D (DL-1)."

Clinical • P1/2 data • Acute Myelogenous Leukemia • Anemia • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Oncology • Solid Tumor • Transplantation • AXL • CHEK1 • GAS6 • TP53

Discovery of NTQ2494, a potent and orally bioavailable inhibitor of AXL kinase for the treatment of human tumors. (PubMed, Eur J Med Chem) - "NTQ2494 (5p) exhibited favorable ADMET properties and demonstrated significantly enhanced in vivo efficacy in an MV-4-11 xenograft model compared to TP-0903. NTQ2494 is currently under Phase I clinical evaluation for the treatment of advanced hematological malignancies and solid tumors."

Journal • Hematological Disorders • Hematological Malignancies • Oncology • Solid Tumor • AXL

c-Met/AXL crosstalk in mediating therapeutic resistance in renal cell carcinoma (AACR 2024) - "We have also found that prolonged treatment of c-Met inhibitor Cabo, (including Crizotinib and PF-4217903) induced c-Met and AXL overexpression in RCC cells...Furthermore, either silencing of AXL (using siRNA) or inhibiting AXL (using TP0903) induced significant apoptosis in these Cabo-resistant cells. Together, our data suggest that inhibition of AXL along with c-Met can be beneficial in preventing acquired therapeutic resistance in RCC."

Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • AXL • KDR • KRAS • MET

Beat AML: Study of Biomarker-Based Treatment of Acute Myeloid Leukemia (clinicaltrials.gov) - P1/2 | N=3000 | Recruiting | Sponsor: Beat AML, LLC | N=2000 ➔ 3000 | Trial completion date: Dec 2026 ➔ Dec 2028 | Trial primary completion date: Dec 2026 ➔ Dec 2028

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

Profiling drug sensitivity in CLL B cells after BTK inhibitor progression using a novel drug panel (ASH 2025) - " Using the Mayo Clinic CLL Database and the Mayo Clinic CLL Tissue Bank, we identified 47 patients with RR CLL, all of whom experienced disease progressionon a BTKi (35 ibrutinib +/- CD20 antibody, 10 acalabrutinib +/- CD20 antibody, 2 other)...We also observed that RR CLL cohort exhibited significantly increased drug resistance to most of the tested drugs in the presence of BMSCs with corresponding increases in IC50s (with vs. without BMSCs, fold-change respectively): LP-118 3.92-fold, venetoclax 1.98-fold, carfilzomib 2.58-fold, TP-0903 1.65-fold, panobinostat 204.23-fold, TCIP1 1.91-fold, crenolanib 1.31-fold, idasanutlin 1.69-fold, belinostat 6.14-fold, LP-168 1.29-fold, eprenetapopt 3.44-fold and GTE 1.08-fold (11 out of 12 with p -values <0.05 except for GTE which was not significant, Mann-Whitney U test)... Our results highlight the spectrum of currently available drugs that show promise for therapeutic use in patients with RR CLL who experience disease..."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • AXL • BCL2 • STAT6 • TP53

Targeting AXL can effectively overcome c-Met-induced therapeutic resistance in renal cancer and promote tumor cell death through increased oxidative stress. (PubMed, Cancer Lett) - "Importantly, inhibition of AXL either using a potent inhibitor, TP-0903, or through genetic silencing resensitized the resistant cells to Cabo-induced cell death. Together, our findings highlight AXL as a key driver of therapeutic resistance to c-Met inhibitors. A combination therapy targeting both c-Met and AXL in renal cancer could be a promising strategy to overcome the acquired resistance to c-Met inhibitors through increased oxidative stress."

Journal • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • AXL • HMOX1 • MET

AXL tyrosine kinase inhibitor TP-0903 induces ROS trigger neuroblastoma cell apoptosis via targeting the miR-335-3p/DKK1 expression. (PubMed, Cell Death Discov) - "Finally, we demonstrated that TP-0903 significantly diminished the tumor growth and DKK1 expression in xenograft mice. Collectively, our findings indicate that TP-0903 triggers apoptotic cell death of NB cells, attributing to the ROS-mediated miR-335-3p upregulation and the consequent DKK1 downregulation."

Journal • Neuroblastoma • Oncology • Solid Tumor • AXL • DKK1 • MIR335

Axl receptor tyrosine kinase inhibition ameliorates murine lupus diffuse alveolar hemorrhage by regulating macrophage activation. (PubMed, Int Immunopharmacol) - "AxlTK is involved in the development of DAH by regulating the activation of macrophages and might be a potential therapeutic target for SLE with DAH."

Journal • Preclinical • Hematological Disorders • Immunology • Inflammatory Arthritis • Lupus • AXL • MRC1

TP-0903 Suppresses Aurora A-PLK1 Signaling to Inhibit Proliferation of a Myelodysplastic Syndrome-Derived Cell Line. (PubMed, Cancer Sci) - "These findings suggest the activation of an atypical ferroptosis pathway mediated through the TGF-β1/SMAD3 signaling pathway. Overall, these data indicate that TP-0903 may offer a novel therapeutic strategy for the treatment of refractory hematological malignancies."

Journal • Preclinical • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Solid Tumor • HMOX1 • MET • PLK1 • SMAD3 • TGFB1

In vitro synergistic effect of AXL, FAK and ErbB receptors inhibitors for head and neck cancer. (PubMed, Biol Direct) - "To this end, this study aims to evaluate the antitumor efficacy of a combined treatment with low doses of different molecular targeted drugs, i.e. Y15, a FAK inhibitor, Afatinib (AFA) an ErbB inhibitor and TP-0903, an Axl inhibitor, on HNC. Moreover, as compared to the individual inhibitors and their pairwise combinations, the triple drug combination was the only able to simultaneously downregulate Axl, FAK, and N-cadherin while upregulating E-cadherin expression levels. The results reported herein provide compelling preliminary evidence supporting the combined use of Y15, AFA and TP-0903 as a novel therapeutic strategy for HNCs."

Journal • Preclinical • Head and Neck Cancer • Oncology • Solid Tumor • AXL • CDH1 • CDH2

A Phase 1b/2 Study of TP-0903 and Decitabine Targeting Mutant TP53 and/or Complex Karyotype in Patients with Untreated Acute Myeloid Leukemia (AML) ≥ Age 60 years. (PubMed, Cancer Res Commun) - P1/2 | "The combination of TP-0903 and decitabine was reasonably tolerated and had activity in this patient population. Further research and novel treatment strategies are necessary to improve outcomes for patients with these high-risk subtypes of AML."

Journal • P1/2 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • TP53

AXL promotes inflammatory breast cancer progression by regulating immunosuppressive macrophage polarization. (PubMed, Breast Cancer Res) - "AXL signaling promotes IBC growth by inducing M2 macrophage polarization and driving the secretion of immunosuppressive molecules and cytokines via STAT6 signaling, thereby contributing to an immunosuppressive TME. Collectively, these findings highlight the potential of targeting AXL signaling as a novel therapeutic approach for IBC that warrants further investigation in clinical trials."

Journal • Breast Cancer • Inflammatory Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • AXL • CCL20 • EREG • MRC1 • STAT6

RNAi Screen Identifies AXL Inhibition Combined with Cannabinoid WIN55212-2 as a Potential Strategy for Cancer Treatment. (PubMed, Pharmaceuticals (Basel)) - "Moreover, in addition to tumor suppression, the combination therapy of TP-0903 and WIN55212-2 induced the infiltration of cytotoxic CD8+ T cells and significantly reduced mTOR and STAT3 activation in tumor tissues of C57BL/6J mice bearing MC-38 cells. This study demonstrated that targeting AXL could sensitize cannabinoids to cancer therapy by interfering with tumor cells and tumor-infiltrating CD8+ T cells."

Journal • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor • CD8 • STAT3

DSP-0509, a TLR7 agonist, exerted synergistic anti-tumor immunity combined with various immune therapies through modulating diverse immune cells in cancer microenvironment. (PubMed, Front Oncol) - "In summary, our study elucidated the effects of DSP-0509 on immune activity within the tumor microenvironment. These findings provided valuable insights that pave the way for the development of novel combination immunotherapy strategies."

Immune cell • Journal • Oncology • CD4 • CD8 • CTLA4 • GZMB • ICOS • IL10 • PRF1 • TNFA

Inhibition of AXL along with c-Met potentially halts resistance development in renal cell carcinoma (KCRS 2024) - "We found that prolonged treatment with c-Met inhibitors Cabo, Crizotinib, and PF4217903, induced c-Met and AXL overexpression in RCC cells...Finally, silencing AXL (using siRNA) or inhibiting AXL (using TP0903) in CaboR cells, induced significant apoptosis. Conclusions Together, our data suggest that CaboR cells have a distinct epigenomic and transcriptomic profile, and that targeting AXL along with c-Met inhibition can be beneficial in preventing acquired therapeutic resistance in RCC."

Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • ETV1 • GAS6 • HOXA9 • MET

Beat AML: Study of Biomarker-Based Treatment of Acute Myeloid Leukemia (clinicaltrials.gov) - P1/2 | N=2000 | Recruiting | Sponsor: Beat AML, LLC | Trial completion date: Dec 2023 ➔ Dec 2026 | Trial primary completion date: Dec 2023 ➔ Dec 2026

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

Mesenchymal-epithelial transition and AXL inhibitor TP-0903 sensitise triple-negative breast cancer cells to the antimalarial compound, artesunate. (PubMed, Sci Rep) - "Thus, TP-0903 and ZEB1 knockdown sensitised TNBC cells to ART, likely via different pathways. Synergistic interactions between TP-0903 and ART indicate that combination approaches involving these compounds can have therapeutic prospects for TNBC treatment."

Journal • Breast Cancer • Infectious Disease • Oncology • Solid Tumor • Triple Negative Breast Cancer • GPX8 • SOD2 • ZEB1

First-in-human Study of Oral TP-0903 (a Novel Inhibitor of AXL Kinase) in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=177 | Completed | Sponsor: Sumitomo Pharma America, Inc. | Phase classification: P1a ➔ P1

Metastases • Phase classification • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • KRAS

TARGETING THE RESPONSE OF LAM CELLS TO EXTRACELLULAR MATRIX COULD PROVIDE NEW THERAPIES FOR LYMPHANGIOLEIOMYOMATOSIS (BTS WM 2023) - "Inhibitors of these molecules (Samuraciclib/CDK7, Dubermatinib/AXL, IPR-803/UPAR) proved effective against TSC2-/- LAM-derived cells, significantly reducing proliferation in vitro. Conclusion LAF-derived ECM enhances TSC2-/- cell proliferation in vitro and may contribute to disease progression by providing a pro-proliferative microenvironment for LAM cells in vivo. A number of pro-proliferative molecules are upregulated when TSC2-/- LAM-derived cells are grow on decellularised ECM in vitro, and targeting these pathways may provide novel therapies for LAM patients with reduced response to rapamycin."

Oncology • Pulmonary Disease • Respiratory Diseases • Solid Tumor • AXL • CDK1 • CDK2 • CDK4 • CDK6 • CDK7 • GAS6 • PLAU • TSC2 • VTN

Impact of nucleotide metabolism on CLL B-cell pathobiology and CLL disease progression (IWCLL 2023) - "When we treated high and low PNP expressing CLL B-cells from untreated patients with drugs known to be active in CLL, interestingly we found high PNP expressing CLL B-cells are sensitive to Bcl2 inhibitor venetoclax and AXL kinase inhibitor TP-0903 versus low PNP expressing CLL B-cells...However treatment of CLL B-cells from untreated patients cultured alone or co-cultured with BMSCs with TYMS inhibitor raltitrexed did not show any killing indicating an alternate role of TYMS in BMSC cultured CLL B-cells...In conclusion, these results indicate that active purine and pyrimidine metabolism in CLL B-cells augmented by the BM environment can support CLL B-cell survival and drug resistance and possible induction of EMT components. Future studies are underway to understand the role and regulation of PNP and TYMS in CLL disease progression and drug resistance for both untreated and treated CLL patients."

IO biomarker • Chronic Lymphocytic Leukemia • AXL • TYMS

AXL-initiated paracrine activation of pSTAT3 enhances mesenchymal and vasculogenic supportive features of tumor-associated macrophages. (PubMed, Cell Rep) - "We also found that AXL-STAT3 inhibition can impede the recruitment of TAMs in a xenograft mouse model, thereby suppressing tumor growth. These findings suggest the potential application of AXL-STAT3-related markers to quantitatively assess metastatic potential and inform therapeutic strategies in lung cancer."

Journal • Lung Cancer • Oncology • Solid Tumor • AXL • CD163 • CD44

A PHASE 1B/2 STUDY OF TP-0903 AND DECITABINE TARGETING MUTANT TP53 AND/OR COMPLEX KARYOTYPE IN PATIENTS WITH UNTREATED ACUTE MYELOID LEUKEMIA (AML) ≥ AGE 60 YEARS: FINAL RESULTS (EHA 2023) - P1/2 | "Although the 1 st stage in the Ph2 portion of the trial was terminated early after treating only 11 patients with 25 mg TP-0903 + dec, the trial still achieved 3 of the 4 required CR responses needed to move onto the 2 nd stage. Additionally, 3 other patients in this group achieved responses of CRh (1) and CRi (2). This combination regimen is encouraging, considering the high risk and poor outcome of patients with TP53 m and/or CK AML."

Clinical • P1/2 data • Acute Myelogenous Leukemia • Anemia • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Leukemia • Leukopenia • Lymphoma • Neutropenia • Oncology • Thrombocytopenia • AXL • CHEK1 • TP53

TBK1 inhibition potentiates the efficacy of AXL-targeted therapy by modulating tumor microenvironment in aggressive breast cancers (AACR 2023) - "We assessed the activity of AXL inhibitor TP-0903 in reducing tumor growth... Targeting TBK1 enhances the efficacy of AXL-targeted therapy in aggressive breast cancer by suppressing the paracrine effect of CCR5/CCL5 axis. This combination represents a novel and effective therapy modulating the TME of aggressive breast cancer, which warrants further investigation in the clinical setting."

Biomarker • Clinical • Tumor microenvironment • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • AXL • CD8

Targeting AXL can effectively inhibit c-Met-induced therapeutic resistance in renal cancer (AACR 2023) - "We have also utilized murine model(s) of renal cancer growth (both xenograft and syngeneic), and found that Cabo treatment increases the levels of c-Met and AXL in tumor tissues, and the inhibition of AXL using TP-0903 can markedly inhibit the expression levels of total c-Met and AXL...Interestingly, we found increased levels of total c-Met and AXL in tumor tissues following Cabo treatment. Together our data suggest that AXL plays a critical role in mediating therapeutic resistance against c-Met inhibitor; and a combination of Cabo and an AXL/other RTK inhibitor can effectively block the resistance."

Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • AXL • HGF • KDR • MET • STAT3