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A phase II study of the oral selective AXL inhibitor bemcentinib with pembrolizumab in patients with advanced NSCLCKrebs, Matthew G; Helland, A.; Costa, E. C.; Aperribay, E. A.; Gomez, M. D.; Perez, J. T.; Thompson, J.; Strauss, J.; Granados, A. L. O.; Felip, E.; et al. (2021)Background: The RTK AXL is implicated in epithelial-to-mesenchymal transition, negative regulation of anti-tumour immunity and resistance to multiple therapies including immune checkpoint inhibitors. Bemcentinib (BGB324) is a first-in-class, oral, highly selective and potent AXL inhibitor which has been demonstrated to enhance anti-PD1 therapy. The combination of bemcentinib and pembrolizumab was well tolerated and showed promising efficacy in previously treated IOnaïve NSCLC patients (Cohort A, NCT03184571), particularly in those with AXL positive disease, including PD-L1 negative patients. The novel combination is now being assessed in patients refractory to anti-PD-(L)1 therapy, considering the emerging need in this population and AXL’s role as a mediator of resistance. Method: This is an open-label, single-arm, 2-stage phase II study (Cohort B, NCT03184571) to evaluate the safety and efficacy of bemcentinib (200mg/d) in combination with pembrolizumab (200mg/q3wk) in patients post anti-PD-(L)1 therapy. The primary endpoint is overall response rate (ORR), and additional endpoints include efficacy by biomarker expression, duration of response (DoR), disease control rate (DCR), progression free survival (PFS), overall survival (OS), and safety. Clinical efficacy endpoints are based on tumour imaging evaluable by RECIST v1.1. Eligible patients received a maximum of 2 prior lines of therapy, with the most recent course having included a PD-(L)1 inhibitor. To be eligible, patients must have exhibited disease control (CR/PR/SD) for at least 6 months on prior PD-(L)1 inhibitor therapy with disease progression occurring within 12 weeks since last dose. Bemcentinib will be administered as a loading dose of 400mg on days 1, 2 and 3 followed by a dose of 200mg once daily. A fixed dose of 200 mg pembrolizumab will be given by intravenous infusion over 30 minutes every 3 weeks. Bemcentinib and pembrolizumab will be given until disease progression, unacceptable dose toxicity, or for a maximum of 35 cycles. Tumour specimens will be analysed for PD-L1 expression (22C3 pharmDx), AXL by IHC, and infiltrating immune cells. The prespecified efficacy threshold for continuation into the second stage is 1 objective response among the first 13 patients, at which point up to a further 16 patients may be evaluated, for a total of 29 patients. Result: Section not applicable Conclusion: Section not applicable
A PHII study of bemcentinib, a first-in-class selective axl kinase inhibitor, in combination with pembrolizumab in pts with previously-treated advanced NSCLC: updated clinical & translational analysisSpicer, J.; Helland, A.; Carcereny, E.; Arriola, E.; Gomez, M. D.; Perez, J. M. T.; Thompson, J.; Strauss, J.; Granados, A. L. O.; Felip, E.; et al. (2020)Background AXL is implicated in resistance to immunotherapy. Bemcentinib (BGB324), a first-in-class, oral, selective and potent AXL kinase inhibitor, enhances checkpoint inhibitor (CPI) efficacy in pre-clinical models through tumor-immune mechanisms. Methods BGBC008 is a PhII single-arm, 2-stage study with bemcentinib (200 mg/d) and pembrolizumab (200 mg/q3wk) for previously-treated stage IV lung adenocarcinoma comprising 3 cohorts: chemotherapy-pretreated IO-naïve patients (Cohort-A), patients progressing on prior IO therapy (Cohort-B) or chemotherapy/pembrolizumab combination (Cohort-C). Primary endpoint was ORR according to RECIST1.1 with pre-defined criteria to proceed from the first to second stage in each cohort. Secondary endpoints included DCR, PFS, OS and safety. Exploratory endpoints include biomarker analysis and correlation with clinical endpoints, including composite (tumor and immune cell) cAXL score, PD-L1 TPS, and genome-wide mutational and transcriptome analyses. Results As of July 2020, enrollment in Cohort-A and-B (stage 1) is completed; a total of 66 NSCLC patients were dosed. Cohort-A (n=50) results were previously presented. All Cohort-B1 (n=16) patients received at least one prior line of therapy, the most recent including CPI; 4 patients had 1 and 12 had 2+ prior treatments. Of the Cohort-B1 patients, cAXL status was available for 13 patients: 8 cAXL-positive, 5 cAXL-negative. PD-L1 TPS was available for 13 patients: 5 TPS >50%, 5 TPS 1–49%, and 3 TPS <1%. Of patients who had previously undergone 1 line of CPI therapy (n=4), 75% were cAXL-positive and 25% were not evaluable for cAXL (median TPS of 20%). Patients who had previously undergone 2+ lines of therapy (n=12), 33% were cAXL-positive, 50% cAXL-negative, and 17% not evaluable for cAXL(median TPS of 50%). Of the treated pts, most common TEAEs (>25% of patients) were increased ALT (29%; 10% G3+), AST (29%; 5% G3+), and diarrhoea (29%; 1% G3+). All cases of treatment-related transaminase increase were reversible and managed with concomitant administration of steroids and treatment interruption. Of the 15 radiologically-evaluable patients in Cohort-B1, 1 PR was observed; 6/7 (86%) cAXL-positive patients (1 PR, 5 SD) achieved clinical benefit while none was observed in cAXL negative patients. mPFS was 4.7mo in cAXL-positive and 1.9mo in cAXL-negative patients. Ongoing transcriptional analysis of pre-treatment biopsies revealed a distinct gene profile correlating with clinical benefit from bemcentinib + pembrolizumab combination treatment. Conclusions Overall, bemcentinib in combination with pembrolizumab was well-tolerated and shows promising clinical activity in AXL-positive immunotherapy refractory disease. Updated survival and translation/biomarker data will be presented.