Abstract: 9098 Background: AXL is an RTK implicated in epithelial-to-mesenchymal transition and as a resistance mechanism to multiple therapies including anti-PD1. Bemcentinib (BGB324) is a first-in-class, oral, highly selective and potent AXL inhibitor which has been demonstrated to enhance anti-PD1 therapy in the pre-clinical setting. Methods: This is a Phase II single-arm, two-Stage study with bemcentinib (200mg/d) and pembrolizumab (200 mg/q3wk) for previously treated, IO naïve pts (n = 48 in total) with Stage IV lung adenocarcinoma. The primary endpoint was ORR according to RECIST 1.1 with pre-defined minimum requirement for 18% RR in the first Stage (n = 24) to proceed to Stage 2. Secondary endpoints included DCR, PFS, OS and safety. Tumour biopsies were analysed for PD-L1 (22C3 pharmDx), AXL, and infiltrating immune cells. Results: Stage 1 completed enrolment in Apr ‘18. As of Feb ‘19, 38 pts (24 and 14 in Stage 1 and 2, respectively) have been dosed with the combination; median age 66 (range 39-79) yr, 59% male, all previously received one prior line of platinum-based chemotherapy or a licensed EGFR/ALK-directed therapy. The most common TRAEs (occurring in 〉 15% of pts) were transaminase increases (37%), diarrhoea (29%), and asthenia (17%). All cases of transaminase increase were reversible and resolved with concomitant administration of systemic corticosteroids and interruption of study treatments. At time of writing, Stage 1 had met the efficacy threshold to proceed to Stage 2 with continued enrolment. Among 29 pts evaluable for response 7 PRs were reported (24%). For AXL positive pts (10/21 with available biopsies), ORR was 40%. PD-L1 status was known for 5 responders: 4 pts (80%) were PD-L1 negative or weakly positive. In Stage 1, mPFS was 4.0 months (95% CI 1.9 – NR) and 5.9 months in AXL positive pts (n = 10; 3.0 - NR). mOS was not mature. Conclusions: Overall, bemcentinib in combination with pembrolizumab was well tolerated and promising clinical activity was seen, particularly in pts with AXL positive disease. Updated results will be reported at the meeting, incl 12-month OS for Stage 1 and preliminary efficacy of Stage 2. Clinical trial information: NCT03184571.

Abstract: 7043 Background: The RTK AXL represents a therapeutic target promoting AML cell proliferation and survival by pleiotropic mechanisms and is a negative regulator of anti-tumour immunity. Bemcentinib is a first-in-class, highly selective, oral AXL inhibitor that has previously shown encouraging anti-leukaemic activity as a monotherapy in r/r AML and hr-MDS. Methods: A monotherapy dose-escalation and expansion part of this trial is complete. In this second, phase II part of the study, 11 and 15 AML pts unfit for intensive chemotherapy received bemcentinib at RP2D (200 mg po/d) in combination with low-dose cytarabine (LDAC) and decitabine, respectively. Median age was 77 yr (range: 50-83), median screen myeloblast count 39% (3-95%) and 2/19 (11%) of pts evaluable for FLT3 were FLT3+. Plasma protein biomarker levels were measured using the DiscoveryMap v3.3 panel (Myriad RBM) at screen and following treatment. Results: The most common TRAEs (≥ 15% of pts) were ECG QT prolongation (35%) and diarrhoea (15%). Among these, 3 were Grade 3, and none 4 or 5. All TRAEs were manageable and/or reversible. As of Feb ‘19, 9 pts (2 de novo, 1 secondary, 6 r/r) in the bemcentinib + LDAC group were evaluable for response and 4 (44%; 2 de novo + 2 relapsed) achieved rapid CRi at C2D1. Responses were durable (range: 7 – 11 cycles) in 3 of the 4 responders. A further 2 pts (22%, 1 secondary + 1 relapsed) achieved durable SD (5 and 6 cycles). mPFS among the 5 pts with durable CRi or SD was 5 months (range: 3.5-7.7). Further, at the time of writing, 11 pts (8 de novo, 3 r/r) in the bemcentinib + decitabine group were evaluable for response of which 4 (36%, all de novo) achieved CRi after ≥ 4 cycles. One additional de novo pt achieved durable SD lasting for 5 cycles. Conclusions: Bemcentinib in combination with LDAC exerted early durable responses in patients with both de novo and relapsed AML whilst the combination of bemcentinib + decitabine exerted comparably fewer and later responses in de novo AML. Soluble biomarker correlations will be presented at the meeting. Both combinations were generally well-tolerated and further exploration is warranted. Clinical trial information: NCT02488408.

Abstract: Background Standard low dose cytarabine (LDAC) monotherapy in elderly previously-treated relapsed and primary resistant/refractory (R/R) AML patients unfit for intensive chemotherapy shows limited response (CR rate of up to 17%) and survival benefit (mOS 4-6 mos, Sarkozy, 2013). Hence this vulnerable patient population has significant unmet need for well tolerated and efficacious new treatments. Bemcentinib (BEM) is a selective small molecule inhibitor of AXL, a surface membrane protein kinase receptor mediating resistance to chemotherapeutic agents and decreased antitumor immune response. AXL is overexpressed on leukemic cells, especially in the stem cell compartment, and represents a potential novel target in patients with AML. The ongoing BGBC003 phase II trial includes newly diagnosed (ND), and previously treated R/R AML patients unfit for intensive chemotherapy receiving BEM+LDAC combination treatment. A previously-treated AML patient cohort was selected for expansion, with the objective to explore safety and efficacy and to undertake translational biomarker analysis. Here, we report on preliminary efficacy together with a safety overview for all patients treated with the combination. Methods and Patient Disposition AML patients unfit for intensive therapy received BEM at the RP2D (200mg PO/d) + 10-day LDAC in 21-day cycles. Efficacy endpoints included objective response (OR: CR, CRi, PR) and clinical benefit (CB: OR + SD for ≥ 3 treatment cycles). Secondary objectives include overall survival (OS) and exploratory biomarker analyses. The BEM+LDAC cohorts (n=24); with a data cut-off date of 21 July 2020, comprised 7 newly diagnosed and 17 previously-treated (10 relapsed, 7 refractory) AML patients; with a median of 2 prior therapies (ranges: 1-8 relapsed; 1-4 refractory). Median age was 76 years for previously-treated R/R (range 66-81), and 78 for ND patients (range 75-83). Six (35%) R/R and 0% ND pts had a poor cytogenetic risk profile. Median bone marrow (BM) myeloblasts at screening for R/R AML patients was 33.5% (range 3-94%) and 34% (range 3-54) for ND patients. Plasma protein biomarker levels including soluble AXL (sAXL) were measured at screening and following treatment. Single cell RNA sequencing and T-cell repertoire analysis are being conducted to determine the effect of BEM + LDAC on direct tumor-cell killing and antitumor immunity. Results At the time of data cut off, previously-treated relapsed patients (n=8) were evaluable for response (as per BM assessment at C2D1; 4/8 (50%) relapsed patients achieved objective response (2 CR, 1 CRi, 1PR) and 6/8 (75%) showed clinical benefit. mDOR was 12.1 wks (range 11.9-16.1 wks, ongoing) with a median time-on-trial of 20.4 wks. Notably responses were reported between wk20 (C5) - wk28 (C7). These later onset responses may reflect the importance of AXL-related immunological mechanisms for relatively chemo-resistant relapsed patients and contribute to a longer time-on-treatment. Three relapsed patients remain on study treatment. In contrast, no refractory patients showed response (0/7) with 2/7 (28%) reporting clinical benefit; median time on trial was 8.6 wks. For evaluable newly-diagnosed patients, response was observed in 3/7 (48%, all CR), and clinical benefit in 5/7 (71%). The mDOR was 69.3 wks (range 62.9-105.1 wks, ongoing) and 2 patients remain on study. Overall, the combination was well tolerated, and in keeping with the known safety profile of LDAC. Treatment related AEs of ≥ Grade 3 observed in ≥ 5% of pts (n=24) across all cohorts were anemia, 4 (16%), thrombocytopenia, 3 (12%), febrile neutropenia 2, (8%) and QTcF prolongation, 1 (4%). Conclusions These data show that BEM+LDAC is efficacious and well tolerated in the unfit previously-treated relapsed and newly diagnosed AML populations. No activity was seen in primary resistant/refractory AML patients. An in-depth translational research program aiming to identify predictive molecular and biological factors associated with response in ongoing. Thus, the BEM+LDAC combination warrants further investigation and development in randomized trials with the potential to improve survival outcomes for elderly and unfit AML patients. Disclosures Loges: BerGenBio ASA: Research Funding. Heuser:Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Stemline Therapeutics: Consultancy; PriME Oncology: Honoraria; Karyopharm: Research Funding; Amgen: Research Funding; Bayer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; BerGenBio ASA: Research Funding; Janssen: Consultancy; Roche: Research Funding; Astellas: Research Funding; Abbvie: Consultancy. Chromik:BerGenBio ASA: Research Funding. Vigil:BerGenBio ASA: Research Funding. Paschka:BerGenBio ASA: Research Funding; Sunesis Pharmaceuticals: Consultancy; AbbVie: Other: Travel, accommodation or expenses, Speakers Bureau; Amgen: Other; Astellas Pharma: Consultancy, Speakers Bureau; Astex Pharmaceuticals: Consultancy; Celgene: Consultancy, Other: Travel, accommodations or expenses; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Otsuka: Consultancy; Janssen Oncology: Other; Agios Pharmaceuticals: Consultancy, Speakers Bureau. Re:BerGenBio ASA: Research Funding. Di Renzo:BerGenBio ASA: Research Funding. Lemoli:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; BerGenBio ASA: Research Funding; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mattei:BerGenBio ASA: Research Funding. Ben-Batalla:BerGenBio ASA: Research Funding. Hellesoy:BerGenBio ASA: Research Funding. Lorens:BerGenBio ASA: Current Employment. Birkett:BerGenBio ASA: Consultancy. McPherson:BerGenBio ASA: Current Employment. Nautiyal:BerGenBio ASA: Current Employment. Micklem:BerGenBio ASA: Current Employment. Gabra:BerGenBio ASA: Current Employment. Lorens:BerGenBio ASA: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Patents & Royalties. Fiedler:Gilead: Honoraria; Daiichi Sankyo Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accomodations; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: support in medical writing; Ariad/Incyte: Membership on an entity's Board of Directors or advisory committees; BerGenBio ASA: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: support in medical writing; Celgene: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accomodations, support in medical writing, Research Funding; Servier: Honoraria, Other; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accomodations; BMS: Honoraria. Alvarado:Tolero Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding; Jazz Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Research Funding; BerGenBio ASA: Research Funding; MEI Pharma: Research Funding; Sun Pharma: Research Funding; FibroGen: Research Funding. Gjertsen:Alden Cancer Therapy AS: Current equity holder in private company; Pfizer Inc: Consultancy; BerGenBio AS: Consultancy, Research Funding; Novartis: Consultancy; KinN Therapeutics AS: Current equity holder in private company.

Abstract: Epithelial-to-mesenchymal transition (EMT) endows carcinoma cells with migratory, survival and stem cell-like attributes that facilitate therapeutic resistance and metastasis. Expression of the Axl receptor tyrosine kinase in breast cancer correlates with EMT, poor survival and is prevalent in patient metastases. Axl upregulation in mammary epithelial cells by EMT-transcription factors, TGFbeta or hypoxia, establishes an autocrine-signaling loop with its ligand, Gas6. Inhibition of Axl signaling blocks EMT/ cancer stem cell traits including invasiveness, drug resistance, mammosphere formation, in vivo tumor initiation, and prevents spontaneous metastasis in orthotopic breast cancer models. Congruently, we show that Axl is expressed on mammary epithelial stem/progenitor cells and regulates multipotent progenitor activity. Thus Axl signal transduction represents a novel regulatory pathway linking normal mammary stem/progenitor cells and breast cancer stem cell activity. Clinical Axl-inhibitors represent a novel therapeutic opportunity to treat aggressive breast cancer. Citation Format: Crina Tiron, Fanny Pelissier, Katarzyna Wnuk-Lipinska, Ingunn Stefansson, Reeta Virtakoivu, Masaru Miyano, Tone Sandal, David Micklem, James Garbe, Martha Stampfer, Johanna Ivaska, Lars Akslen, Mark LaBarge, James Lorens. Axl signaling is required for stem cell traits and metastasis in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C76.

Abstract: Epithelial-to-mesenchymal transition (EMT) endows carcinoma cells with migratory, survival and stem cell-like attributes that facilitate therapeutic resistance and metastasis. Expression of the Axl receptor tyrosine kinase in aggressive breast cancer correlates with EMT, poor survival and is prevalent in patient metastases. Induction of EMT in immortalized mammary epithelial cells by EMT-transcription factors, TGFbeta or hypoxia upregulates Axl and establishes an autocrine-signaling loop with its ligand, Gas6. Axl receptor signaling is required to maintain EMT-related invasive, drug resistance and cancer stem cell (CSC) traits of malignant breast cancer cells. Targeting Axl signaling with RNAi or pharmacological agents blocks the EMT/CSC gene program and inhibits malignant functions including invasiveness, drug resistance, mammosphere formation, in vivo tumor initiation, and spontaneous metastasis in orthotopic breast cancer models. These results suggest that Axl expression is requisite for the maintenance of EMT and stem cell-like traits during malignant progression. The EMT program is characteristic of normal adult mammary epithelial stem/progenitor cells. Congruently, we show that the Axl receptor expressed on mammary epithelial stem/progenitor cells, and Axl signaling is necessary for mammary epithelial multipotent progenitor activity. Thus Axl receptor signaling represents a novel regulatory pathway linking normal mammary stem/progenitor cells and breast cancer stem cells. Hence, clinical Axl inhibitors represent a novel therapeutic avenue to target EMT/CSC traits of aggressive breast cancer. Citation Format: Crina Tiron, Fanny Pelissier, Katarzyna Wnuk-Lipinska, Ingunn Stefansson, Reeta Virtakoivu, Masaru Miyano, Tone Sandal, David Micklem, James Garbe, Martha Stampfer, Johanna Ivaska, Lars Akslen, Mark LaBarge, James Lorens. Axl receptor signaling in required for stem cell traits and metastasis in breast cancer. [abstract] . In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4888. doi:10.1158/1538-7445.AM2013-4888