bemcentinib (BGB324)

Additionally, the AXL inhibitor Bemcentinib effectively inhibited the proliferation organoids and enhanced the immunotherapeutic efficacy of Atezolizumab. Furthermore, neural crest-like cells were observed in the glial reactive tissue surrounding finger-like protrusions. Overall, our results revealed that the AXL might be a potentially effective therapeutic target for ACPs.

Instead, pharmacological blockade with the AXL inhibitors bemcentinib (BGB324), cabozantinib and NPS-1034 rapidly killed RMS cells in an AXL-independent manner, and augmented the efficacy of the chemotherapeutics vincristine and cyclophosphamide. In vivo administration of the combination of bemcentinib and vincristine exerted strong anti-tumoral activity in a rapidly progressing PDX mouse model, significantly reducing tumor bruden compared to single-agent treatment. Collectively, our data identify bemcentinib as a promising drug to improve chemotherapy efficacy in RMS patients.

P1, N=23, Completed, University of Texas Southwestern Medical Center | Active, not recruiting --> Completed | Trial completion date: May 2027 --> Apr 2023

P1, N=10, Terminated, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | N=20 --> 10 | Suspended --> Terminated; NCI decided to terminate ABTC Consortium due to NCI moving in different direction for Brain Cancer - official close date is 10/31/23

P1, N=20, Suspended, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Dec 2024 --> Dec 2023

More importantly, compound 59 oral administration showed good pharmacokinetic profile and in vivo antitumor efficiency, in which we observed significant AXL phosphorylation suppression, and its antitumor efficacy at 20 mg/kg (qd) was comparable to that of BGB324 at 50 mg/kg (bid), the most advanced AXL inhibitor. Taken together, this work provided a valuable lead compound as a potential AXL inhibitor for the further antitumor drug development.

We report on a novel mechanism of AXL-MAPK-driven escape from type II JAK2 inhibition, which is targetable at different nodes. This highlights AXL as mediator of acquired resistance warranting inhibition to enhance sustainability of JAK2 inhibition in MPN.

Such patients benefit from hypomethylating agents and venetoclax but frequently develop resistance to this treatment regimen. Additionally, extended research on TNFα and cytotoxic immune cells may lead to a better understanding of what mechanisms cause a treatment response. This may ultimately enable an accurate selection of patients who will benefit from bemcentinib-LDAC.

P1, N=20, Suspended, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Active, not recruiting --> Suspended

Recent trials explore drugs like bemcentinib, everolimus, talazoparib, and others for potential approaches to targeting these mutations. Therapeutically relevant gene alterations were detected in the analyzed real-world patient cohort. The loss of STK11 or KEAP1 should be interpreted in the context of KRAS mutational and could be a clinical biomarker for poor response to targeted therapy in patients with advanced NSCLC. The data highlight that in addition to established biomarkers such as PD-L1, new potential marker of resistance such as STK11 or KEAP1 should be considered in molecular analysis prior to therapy initiation.

Combined radiotherapy with Axl inhibition by treatment with R428 and small interfering RNA lentivirus targeting Axl infection significantly reduced cell viability, colony formation ability, DNA double-stranded break repair, and the invasive and migratory ability of 4T-1/IRR cells...The results of western blotting showed that the critical molecular mechanism involved in the radioresistance of TNBC cells was the PI3K/Akt/mTOR signaling pathway induced by Axl activation. Thus, it is hypothesized that targeted Axl therapy combined with radiotherapy may have significant potential for the treatment of TNBC.

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.

Conclusions Bem was well tolerated in combinations with Pem or D/T in melanoma, but did not increase responses or survival in the efficacy population nor in biomarker defined subgroups. High FOXP3 count in tumour infiltrating inflammatory cells was a strong predictive marker for response to Pem.

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.

In addition, AXL- and SAM68-deficiency or R428 treatment induced elevated levels of cholesterol and upregulated genes in the cholesterol biosynthesis pathway. There might be a protective role of cholesterol in shielding cancer cells against DNA damage induced by AXL inhibition or SMA68 deficiency.

Therapeutically, pre-clinical studies using a xenograft mouse model of MCL indicated that bemcentinib is more effective than ibrutinib in reducing the tumour burden and to increase the overall survival. Our study highlights the importance of a previously unidentified AXL splice variant in cancer and the potential of bemcentinib as a targeted therapy for MCL.

The top four compounds were used to treat HPV- and HPV+ cervical cancer cell lines, three of which (Ropitoin, R428 and Ketoconazole) reduced NFX1-123 protein levels, inhibited cellular growth, survival, and migration, and enhanced the cytotoxicity of Cisplatin. These findings highlight cancers expressing high levels of NFX1-123, and drugs that target it, may reduce cellular growth, survival, and migration, making NFX1-123 a potential novel therapeutic target.

MTE induces endoplasmic reticulum stress-associated immunogenic cell death in NSCLC cells. The anti-tumor effects of MTE are dependent upon endoplasmic reticulum stress. MTE triggers endoplasmic reticulum stress-associated immunogenic cell death by inhibiting AXL activity. Kaempferol is an active component that inhibits AXL activity in MTE. The present research revealed the role of AXL in regulating endoplasmic reticulum stress and enriched the anti-tumor mechanisms of MTE. Moreover, kaempferol may be considered a novel AXL inhibitor.

P1, N=20, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial primary completion date: Apr 2023 --> Oct 2023

EudraCT 2019‐003806‐28/NA/124645. Clinical trial information: NCT05469178.

P1b/2a, N=64, Recruiting, BerGenBio ASA | Not yet recruiting --> Recruiting

Knockdown of Axl by siRNA or the treatment with Axl-specific inhibitor R428 dramatically inhibits the migration and invasion of both IgR3 and WM852 in vitro. These findings suggest that Axl enhances the invasion of melanoma cells.

P1/2, N=64, Ongoing, BerGenBio ASA

In a syngeneic model of SCLC, the combination of bemcentinib, ceralasertib and an anti-PDL1 antibody induced significant tumor regression. Together, these promising findings demonstrate that AXL inhibition may be an effective strategy to target the RS vulnerability common in SCLC.

Furthermore, administration of BGB324 as a neoadjuvant sensitives brain metastatic lesions to targeted therapy. Our findings suggest targeting AXL is a viable option to eradicate residual brain metastatic cells and limit relapses in HER2+ breast cancer patients.

Treatment of STK11m NSCLC cell lines with the AXL inhibitor bemcentinib led to a reduction in the STK11-associated DDR signature and increase in inflammatory signatures demonstrating the impact of AXL targeting on tumor cells.Due to the high unmet medical need in individuals harboring a STK11 mutation, the encouraging efficacy in the NCT03184571 clinical trial and the high incidence of AXL protein expression in STK11m tumors, a global, open-label Phase 1b/2a trial to determine the safety, tolerability and anti-tumor activity of bemcentinib with SOC (pembrolizumab, pemetrexed and carboplatin) in 1L advanced/metastatic non-squamous NSCLC patients with STK11 mutations and no actionable mutations is currently enrolling. The Phase 1b part of the study will evaluate the safety and tolerability of bemcentinib regardless of STK11 status, whereas the Phase 2a part will assess the efficacy in NSCLC patients with STK11 mutations.1 Li et al., 2022; Cell Rep Med., PMID: 35492873

P1, N=23, Active, not recruiting, University of Texas Southwestern Medical Center | Trial primary completion date: May 2024 --> Feb 2023

Up to 24 and 40 patients will be enrolled in the phase Ib and IIa, respectively. The trial is currently enrolling patients in the phase Ib in the US; patients’ recruitment for the phase IIa is planned to open in Q2 2023 in Europe, UK, and US.

P2, N=186, Active, not recruiting, University of Leicester | Recruiting --> Active, not recruiting | Trial completion date: Mar 2023 --> Oct 2023 | Trial primary completion date: Mar 2023 --> Oct 2023

P2, N=106, Completed, BerGenBio ASA | Recruiting --> Completed

PROS1 and its downstream receptor AXL expression were significantly higher in PTC than in normal thyroid cells. AXL expression was also higher in human PTC tissues than in normal thyroid tissues. Inhibiting the PROS1-AXL-mediated TAM signaling pathway via the AXL blocker R428 suppressed the proliferation and migration of human PTC cells, highlighting the role of this cascade in human PTC development and progression.

To investigate the clinical significance of this finding, the current well-known AXL inhibitor R428 was tested, demonstrating that R428 significantly inhibited resistance to erlotinib, colony formation, epithelial-mesenchymal transformation and cell migration induced by integrin β3. In conclusion, integrin β3 could promote resistance to EGFR-TKI in NSCLC by upregulating the expression of AXL through the YAP pathway. Patients with advanced NSCLC, who are positive for integrin β3, might benefit from a combination of AXL inhibitors and EGFR-TKI therapy.

P1, N=23, Active, not recruiting, University of Texas Southwestern Medical Center | Trial completion date: May 2022 --> May 2027 | Trial primary completion date: May 2022 --> May 2024

Translational research showed activation of CD8+T cells and B/Plasma cells in response to treatment, indicating that BEM elicits activation of two major adaptive immune cell populations responsible for anti-AML immune responses. B EM +L DAC warrants further evaluation in this population.

NSCLC-affected individuals with identified STK11/LKB1 mutations receiving bemcentinib and pembrolizumab demonstrated objective clinical response to combination therapy. We conclude that AXL is a critical targetable driver of immune suppression in STK11/LKB1 mutant NSCLC.

P1, N=20, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Recruiting --> Active, not recruiting | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Apr 2022 --> Apr 2023

In the current study, we investigated the therapeutic potential of the AXL inhibitor (AXLi) BGB324 alone or in combination with the clinically relevant BRAF inhibitor (BRAFi) vemurafenib. When searching for mechanistic insights, AXLi was found to potentiate BRAFi-induced apoptosis, stimulate ferroptosis and inhibit autophagy. Altogether, our findings propose AXLi as a promising treatment in combination with standard therapy to improve therapeutic outcome in metastatic melanoma.

Combined expression of OPCML and AXL shows potential value as a prognostic marker and OPCML as an agent enhancing the effect of R428 may contribute to better prognosis for patients with CCA.

P2, N=200, Recruiting, University of Leicester | Trial completion date: Mar 2022 --> Mar 2023 | Trial primary completion date: Mar 2022 --> Mar 2023