bemcentinib (BGB324) / Rigel Pharmaceuticals, Oncoinvent - LARVOL DELTA

Predicting Targeted and Immunotherapeutic Response Outcomes in Melanoma With Single-Cell Raman Spectroscopy and Artificial Intelligence. (PubMed, JCO Precis Oncol) - "Single-cell Raman spectroscopy combined with ML offers a scalable, prognostic platform to predict therapeutic resistance likelihood, with further potential to advance clinical, multiomic biomarker efforts for melanoma. Our approach may improve first- and second-line therapy selection assessments for precision medicine by providing rapid, nondestructive prediction of therapeutic response based on cellular spectral profiles."

IO biomarker • Journal • Melanoma • Oncology • Solid Tumor

Tumour Extrinsic Regulation of Neutrophils Sensitize Mesotheliomas to AXL and PD1 Inhibition inMIST3, a Phase II Clinical Trial (IASLC-WCLC 2026) - P2 | "Introduction : Immune checkpoint blockade (ICB) with ipilimumab and nivolumab is a front-line standard of care in patients with mesothelioma...We evaluated AXL and programmed death 1 (PD1) inhibition (AXL-PD1) with bemcentinib and pembrolizumab respectively, in a phase IIA clinical trial in patients with ICB naïve-relapsed mesothelioma (MIST3, NCT03654833 )...Gut microbiota predicted tumour responsiveness (ROC AUC=0.959, p=0.0004), and positively correlated with neutrophil infiltration, IRF3 and TLR2. Conclusions : In summary, a gut microbiota-neutrophil axis regulates sensitivity to AXL-PD1, highlighting opportunities to improve ICB therapeutic effectiveness through promotion of innate anti-tumour immunity."

Clinical • P2 data • Mesothelioma • Oncology • Solid Tumor • AXL • FLI1 • NAB2 • NF2 • SPI1 • TLR2

Therapeutic Effects of Inhibitors to Putative DTP-associated Pathways in EGFR-mutant Lung Cancer PDX Models (IASLC-WCLC 2026) - "Our goal is to assess the efficacy of inhibitors targeting these DTP markers in osimertinib (osi)-induced DTPs of EGFR -mutant PDX models. Methods : DTPs were induced in PDX models with EGFR ex19del (PHLC137) by oral gavage with osi (25 mg/kg QD) and osi combination treatment with bemcentinib (AXL inhibitor, 50 mg/kg BID), BI-847325 (AURK inhibitor, 10 mg/kg QD), valemetostat (EZH1/2 inhibitor, 100 mg/kg QD), tazemetostat (EZH2 inhibitor, 500mg/kg QD), or selinexor (XPO1 inhibitor, 10 mg/kg QD)...Conclusions : In patient-derived models, AXL pathway and epigenetic regulators may represent additional vulnerabilities in osi-induced DTPs. However, despite delay in regrowth, all single agent combination treatments with osi did not achieve complete eradication of the DTP cells, suggesting that multiple combinatorial strategies may be required to overcome DTPs."

IO biomarker • Lung Cancer • Oncology • Solid Tumor • EGFR • EZH2

Phase 1 trial of bemcentinib (BGB324), a first-in-class, selective AXL inhibitor, with docetaxel in patients with previously treated advanced non-small cell lung cancer. (PubMed, Lung Cancer) - "Bemcentinib plus docetaxel with G-CSF support demonstrates anti-tumor activity in previously treated, advanced NSCLC. The role of AXL inhibition in the treatment of NSCLC remains under investigation."

Journal • Metastases • P1 data • Fatigue • Febrile Neutropenia • Hematological Disorders • Lung Cancer • Neutropenia • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Bemcentinib and pembrolizumab in patients with relapsed mesothelioma: MIST3, a phase IIa trial with cellular and molecular correlates of efficacy. (ASCO 2023) - P2 | "MiST3 met its primary endpoint and warrants further evaluation. Analysis of the cellular and molecular correlates of response are ongoing and will be presented. Clinical trial information: NCT03654833."

Clinical • P2a data • Fatigue • Hematological Disorders • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Sarcoma • Solid Tumor

Final top-line results of the BGBC008 phase II, multicenter study of bemcentinib and pembrolizumab (bem+pembro) in second-line (2L) advanced non-squamous (NS) non-small cell lung cancer (NSCLC) (NCT03184571) (ESMO 2023) - P2 | "Survival benefit was observed in pts with AXL >5, regardless of prior therapy or PD-L1 status. The promising efficacy signal observed in KRASMT pts warrants further validation."

Clinical • IO biomarker • Metastases • P2 data • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

AXL is associated with STAT3 activation in breast cancer. (PubMed, Mol Clin Oncol) - "It was found that the overexpression of AXL in MCF7 and 293T cells enhanced STAT3 phosphorylation and transcriptional activity, whereas AXL knockdown using short hairpin RNA or pharmacological inhibition with R428 suppressed STAT3 activation...Bioinformatics analysis of clinical BC datasets (GSE102484, GSE9893 and The Cancer Proteome Atlas) validated a positive correlation between AXL expression and STAT3 signaling activation. Collectively, these findings demonstrate that AXL is associated with STAT3 activation in BC, providing insight into the molecular pathways driving BC progression and uncovering candidate therapeutic targets."

Journal • Breast Cancer • Oncology • Solid Tumor • AXL • IL6 • STAT3

Identifying molecular signatures underpinning treatment responses to novel therapeutics influencing COVID-19 outcomes. (PubMed, J Immunol) - "The ACCORD trial evaluated 3 investigational treatments-bemcentinib, tozorakimab, and zilucoplan-in patients hospitalized with COVID-19, each of which has demonstrated clinical efficacy. These insights support the need for adaptive precision medicine approaches tailored to individual, evolving immune trajectories. Moreover, the immunological mechanisms targeted by these repurposed immunomodulatory therapies may inform treatment strategies across a broader spectrum of immune-mediated diseases beyond COVID-19."

Journal • Infectious Disease • Inflammation • Novel Coronavirus Disease

Mesothelioma Stratified Therapy (MiST) : A Multi-drug Phase II Trial in Malignant Mesothelioma (clinicaltrials.gov) - P2 | N=186 | Completed | Sponsor: University of Leicester | Active, not recruiting ➔ Completed

Trial completion • Mesothelioma • Oncology • Solid Tumor • PD-L1

NLRC5-Deficient Macrophages Promote a Tumor-Permissive Phenotype via AXL- and MERTK-Mediated Efferocytosis. (PubMed, FASEB J) - "Pretreatment of macrophages with AXL and MERTK inhibitors (R428, UNC2025) resulted in reduced efferocytosis and phosphorylation of downstream signaling molecules, STAT3 and ERK1/2. We propose that defective NLRC5 signaling in macrophages leads to tumor-permissive responses, thereby promoting the development of gastric lymphoid neogenesis to Helicobacter infection."

Journal • B Cell Lymphoma • Gastric Cancer • Hematological Malignancies • Infectious Disease • Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • AXL • CD8 • IL10 • MERTK • NLRC5 • SOCS1 • SOCS3 • STAT3 • TGFB1

Inhibition of AXL receptor tyrosine kinase increases osteoblast function and bone mass. (PubMed, Bone Res) - "siRNA-mediated knockdown of Axl or pharmacological inhibition with the small molecule BGB324 significantly enhanced osteoblast differentiation and mineralization in vitro...Consistently, double knockdown experiments demonstrated that simultaneous loss of Axl with either Isg15 or Mapk1, but not other interferon-related genes, reversed the Axl knockdown-induced increase in osteoblast differentiation, reinforcing their mechanistic involvement. Collectively, our study identifies Axl as a promising therapeutic target for osteoporosis and other bone-related disorders."

Journal • Musculoskeletal Diseases • Orthopedics • Osteoporosis • Rheumatology • AXL • MAPK1

AXL-Driven TNFR1 Upregulation Connects EMT to Inflammatory Signaling in Melanoma (EACR 2026) - "AXL function was inhibited with bemcentinib (BGB324)... Our study identifies a previously unrecognized regulatory axis in melanoma: AXL-driven control of TNFR1 links EMT process to TNF/NF-κB activation. This discovery positions TNFR1 as a central node through which AXL amplifies inflammation, providing a novel mechanistic insight and a potential therapeutic vulnerability."

Cutaneous Melanoma • Melanoma • Solid Tumor • AXL • CDH2 • CTNNB1 • MMP9 • TNFRSF1A

CTSK+ macrophages drive fibrotic stenosis in benign airway stenosis via the PROS1-AXL pathway. (PubMed, Int Immunopharmacol) - "This work defines a pro-fibrotic cellular module in BAS CTSK+ macrophages and CD82+ fibroblasts interacting via PROS1-AXL and establishes a rationale for targeting this pathway, supported by both patient-relevant primary cell and in vivo evidence, to disrupt fibrosis and mitigate recurrence."

Journal • Fibrosis • Immunology • AXL • CTSK • PROS1 • TNFRSF11A • TNFSF11

Study of Bemcentinib Plus Pacritinib In Patients With Advanced Lung Adenocarcinoma (clinicaltrials.gov) - P1/2 | N=4 | Terminated | Sponsor: The University of Texas Health Science Center at San Antonio | N=44 ➔ 4 | Trial completion date: Sep 2027 ➔ May 2026 | Recruiting ➔ Terminated | Trial primary completion date: Sep 2027 ➔ May 2026; Investigational drug limitations

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PD-L1

Dual Blockade of PD-L1 and AXL: A Novel Immunotherapeutic Approach for Ovarian and Cervical Cancer. (PubMed, Iran J Allergy Asthma Immunol) - "In this study, we targeted PD-L1 using an siRNA and AXL using a blocker (R428) in OVACAR-3 and CaSki cells, ovarian and cervical cancer cell lines, respectively, in the following groups: Scramble-siRNA, PD-L1-siRNA, Scramble-siRNA in conjunction with R428, PD-L1-siRNA in conjunction with R428, R428 monotherapy and untreated controls. Cell viability was assessed by MTT assay after 48 hours of treatment, and cisplatin sensitization was evaluated in resistant OVACAR-3 cells...The results showed a significant decrease in cell proliferation, suppression of EMT-regulating genes, reduction of stemness in cancer cells, increased apoptosis and disruption of the cell cycle in the studied cell lines. These findings suggest that simultaneous blockade of PD-L1 and AXL could serve as a novel tumor-suppressive strategy, especially for cancer patients resistant to ICBs."

IO biomarker • Journal • Platinum resistant • Cervical Cancer • Oncology • Ovarian Cancer • Solid Tumor • ANXA5 • AXL

AXL receptor tyrosine kinase regulates Golgi organization and function via an adhesion-Arf1 signalling axis in breast and lung cancer cell lines. (PubMed, Biol Open) - "AXL is prominently localized to the Golgi and is displaced upon inhibition with R428, which disrupts Golgi organization...This impacts Golgi-associated functions, tubulin acetylation in MDAMB231 cells, and cell-surface glycosylation in A549 cells. Together, our findings identify an adhesion-AXL-AMPK-GBF1-Arf1 pathway governing Golgi organization and function in cancer cells."

Journal • Preclinical • Breast Cancer • Lung Cancer • Oncology • Solid Tumor • AXL

Knowledge Discovery and Drug-Repurposing Framework for Pancreatic Ductal Adenocarcinoma: Molecular Networking and Computational Docking. (PubMed, Comput Struct Biotechnol J) - "These proteins exhibited high-affinity interactions with zavegepant (a clinically approved CGRP receptor antagonist), omilancor, bemcentinib, conivaptan, and APTO-253...Thus, we suggest a systems-level platform for nominating ligandable PDAC targets and clinically actionable compounds. The framework highlights opportunities for rational drug repurposing and motivates future mechanistic studies at the intersection of proteomics and structure-based screening for targets to PDAC."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • AHNAK2 • ANXA2 • EIF2A • EIF2S1

Bemcentinib and pembrolizumab may overcome exhaustive immune phenotypes in patients with treatment refractory lung adenocarcinoma and reveals a potential STAT3 bypass mechanism (AACR 2025) - P2 | "Separately, we tested whether adding targeting of the JAK2/STAT3 pathway (an AXL bypass mechanism) with pacritinib, a selective JAK2 inhibitor with no JAK1 activity, can further inhibit tumor growth compared with targeting AXL-PD1 alone, in a C57BL/6 syngeneic mouse D19.1 LAC model. BEM + PEM led to immune cell responses following cycle 1 treatment in LAC patients previously treated with chemo-immunotherapy. CyTOF data suggest that AXL-PD1 drug targeting may overcome immune cell exhaustion and re-activate CD8+ T cell, cDC1 and NKT cells in treatment refractory LAC patients treated with BEM+PEM. Granzyme B expression in PBMCs may serve as a biomarker of treatment response. Furthermore, in vivo drug targeting of AXL-PD1-STAT3 axis demonstrates significant synergy in a syngeneic LAC mouse model, showing a strong potential for future clinical trials."

Clinical • IO biomarker • Late-breaking abstract • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD123 • CD163 • CD40 • CD8 • GZMB • IL3RA • JAK1 • MRC1 • STAT3

Targeted polymeric nanoconjugates for BBB penetration and time specific delivery of PDL1 blocking small peptides via LRP1 targeting in melanoma brain metastases (AACR 2026) - "In subcutaneous melanoma models, the combination of P-12 (anti-PD-L1)- based peptides with the AXL inhibitor Bemcentinib yielded greater tumor burden reduction than anti-PD-1 monotherapy, suggesting the potential to circumvent ICB resistance in MBM settings. Our data indicate that BBB transcytosis of INCs via LRP-1 mediates enhanced delivery of PD-L1 blocking peptides to the TiME, supporting improved therapeutic exposure for MBM. Our data indicate that BBB transcytosis of INCs via LRP-1 mediates enhanced delivery of PD-L1 blocking peptides to the TiME, supporting improved therapeutic exposure for MBM. AXL emerges as a critical therapeutic target and a rational axis for combination strategies with targeted nanoplatforms to treat resistant MBM. Ongoing studies across additional MBM-relevant models aim to validate these findings and further optimize second-generation bispecific INCs approaches."

IO biomarker • Brain Cancer • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • LRP1

AXL mRNA overexpression in CTCs as a new potential liquid biopsy biomarker in NSCLC (AACR 2026) - "Nowadays, clinical trials are investigating the efficacy of AXL-inhibitors such as bemcentinib, that has already received US FDA fast-track designation for the treatment of advanced or metastatic NSCLC combined with a PD-L1 inhibitor. In this study we evaluated AXL mRNA expression in circulating tumor cells (CTCs) isolated at different time points from two groups of NSCLC patients: a) under osimertinib treatment and b) under immunotherapy... This is the first time that AXL overexpression is detected in CTCs of NSCLC patients undergoing immunotherapy. Our results indicate that NSCLC patients with overexpression of AXL in CTCs could benefit from combination therapies with AXL-inhibitors to either overcome resistance to targeted therapies or enhance immune responses. The role of AXL as a potential biomarker and therapeutic target in advanced NSCLC needs to be further confirmed through larger clinical studies including liquid biopsy approach."

Biomarker • Biopsy • IO biomarker • Liquid biopsy • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AXL • CTCs • EGFR

CD39 restrains ATP–P2X7-driven inflammatory cell death and neuroinflammation during neonatal Zika virus infection (IMMUNOLOGY 2026) - "Inflammatory readouts and eATP release were assessed, including evaluations with soluble apyrase or Axl-antagonist bemcentinib (R428)... Our data identify CD39 as an upstream brake on eATP signaling that limits P2X7-linked inflammatory cell death and neuroinflammation during neonatal ZIKV infection, while shaping antiviral IFN responses. Targeting the CD39–P2X7 axis may provide therapeutic opportunities to mitigate neuroinflammatory damage in neurotropic viral infections."

Inflammatory cell • Late-breaking abstract • Infectious Disease • Inflammation • AXL • CASP3 • CASP8 • ENTPD1 • IFNB1 • IGF2BP1 • IL1B • IL6 • STAT1 • ZBP1

LRP1-Targeted Polymeric Nanoconjugates for BBB Penetration and Time-Specific Delivery of PD-L1–Blocking Peptides in Melanoma Brain Metastases (IMMUNOLOGY 2026) - "In subcutaneous melanoma, combining P-12–based peptides with Bemcentinib yielded greater tumor reduction than anti-PD-1 alone, suggesting circumvention of ICB resistance... LRP-1–mediated INC delivery enhances PD-L1 blockade exposure in MBM TiME, supporting a strategy to treat resistant MBM. AXL is a key target for rational combination with nanoplatforms. Further validation in MBM models is planned, and ongoing preclinical testing."

IO biomarker • Brain Cancer • Cutaneous Melanoma • Melanoma • Solid Tumor • LRP1

AXL tyrosine kinase inhibition restores anti-PD-1 efficacy in melanoma through tumor-associated macrophage–dependent mechanisms (IMMUNOLOGY 2026) - "ICB-resistant melanoma models (Yumm1.7, B16F10) were treated with warfarin or bemcentinib (AXL inhibitors) alone or with anti-PD-1, with or without macrophage depletion. AXL is a dominant TAM-driven regulator of ICB resistance in melanoma. AXL inhibition restores functional PD-1:PD-L1 blockade and rebalances macrophage signaling toward immunostimulation in a microenvironment-specific manner. These findings support AXL as both a biomarker and therapeutic target to overcome ICB resistance, with implications for tailoring macrophage-targeted strategies in refractory melanoma."

Clinical • IO biomarker • Melanoma • Oncology • Solid Tumor • AXL • CSF1R • CXCL9 • GAS6 • IL10 • IL12A • IL23A

Postoperative Radiotherapy Combined With Nimotuzumab Followed by Benmelstobart in High-Risk Patients With Head and Neck Squamous Cell Carcinoma (clinicaltrials.gov) - P3 | N=370 | Recruiting | Sponsor: Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University | Not yet recruiting ➔ Recruiting

Enrollment open • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Thyroid Gland Carcinoma • EGFR • PD-L1

Development and evaluation of orthotopically and subcutaneously implanted luciferase-labeled prostate cancer xenograft models for therapeutic assessment (AACR 2024) - "As a first step, these studies evaluate the effect of standard of care cytotoxic agents paclitaxel and carboplatin and the newer AXL kinase inhibitor bemcentinib alone and in combination on tumor growth kinetics and agent tolerability. PC3M-luc and DU145-luc cells were implanted subcutaneously on right flank or orthotopically into the prostate of NCG triple immunodeficient mice (Charles River). The development of orthotopic and subcutaneous PC3M-luc and DU145-luc prostate cancer models provides a valuable platform for assessing the effectiveness of established and novel therapies. These models mimic various clinical presentations of prostate cancer and promise to offer insights into disease progression and therapeutic strategies. Future studies will focus on durable responses and the assessment of other combination therapies for improved treatment outcomes."

Preclinical • Genito-urinary Cancer • Lung Cancer • Oncology • Prostate Cancer • Solid Tumor • AXL