Ph I/II study of oral selective AXL inhibitor bemcentinib (BGB324) in combination with erlotinib in patients with advanced EGFRm NSCLC: End of trial update.
Authors: Byers Lauren Averett , Gold Kathryn A. , Peguero Julio Antonio , Johnson Melissa Lynne , Nieva Jorge J. , Harb Wael A. , Chiappori Alberto , Rybkin Igor I. , Strauss James Fredric , Gerber David E. 
Published: June 2021

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Background: AXL, a receptor tyrosine kinase, is over-expressed in many cancers, and has been identified as a marker of poor prognosis in NSCLC. AXL overexpression is implicated in development of resistance to EGFR inhibitors including erlotinib (Erl) and osimertinib. AXL inhibition by bemcentinib (Bem), a first-in-class, oral, selective and potent AXL kinase inhibitor, abrogates resistance to EGFR inhibitors in vivo. Bem is currently under evaluation as a monotherapy and in combination with EGFRi, CPIs and chemotherapy across several PhII trials. Methods: Phase I of this study was designed to confirm safety/tolerability of Bem in NSCLC pts as monotherapy and in combination with Erl in pts previously progressing on Erl (arm A). In Phase II, pts who had progressed on an approved EGFRi (arm B) or who were responding/stable on Erl in the 1L setting (arm C) were treated with Bem 200mg and Erl 150mg od to evaluate the safety and activity of the combination, assessing reversal or prevention of resistance to EGFR inhibition in these 2 groups, respectively. Plasma protein biomarker levels were sequentially measured using the DiscoveryMap v3.3 panel (Myriad RBM). Results: As of 7 Oct 2020, all arms have completed recruitment. Median exposure to Bem was 63d (mean: 200d, range: 2d-1175d). Treatment was generally well-tolerated. Common TRAEs (>20% pts) were diarrhea (70%; G3 20%), nausea (50%; G3 0%), QTc prolongation (35%; G3 3%), vomiting (35%; G3 0%), and fatigue (25%; G3 5%). 1 unrelated G4, 0 G5 reported. In the run-in arm (5 female, median age 61 yrs [57-76]), 2/8 pts achieved SD for ̃1 yr, including 19% tumor shrinkage in 1 pt. In arm A (5 female, median age 58 yrs [38-67]), 1/8 pts (68 F) achieved tumor shrinkage of 38%, with treatment duration of 2 yrs until progression. A further 5 pts reported SD. In arm B, 11 pts (7 female, median age 63 yrs [49-78]) had received a median of 1 (0 - 4) prior lines of chemotherapy and a median of 2 prior lines of EGFRi. One achieved a PR (51M) and one a SD (62F) on the combination (CBR of 18%); durations on treatment were 1 yr, and 6 mos, respectively. Neither had EGFR T790M. mPFS was 1.4 mos. In arm C, 13 pts (10 female, median age 66 yrs [32-80]) were enrolled. 11/13 pts were evaluable for efficacy. 1 PR (58M) was reported with 47% tumor shrinkage, duration of treatment was 315d. 9 other pts achieved SD (CBR of 91%), including 4 (3 F/1 M, age range 64-71yrs) who continued on trial for 772+ to 1008+ d. mPFS is currently 12.2 mos. Protein biomarkers predictive of pt benefit upon Bem treatment are being explored. Conclusions: Bem with Erl combination is feasible and tolerable in NSCLC pts, with benefit was seen in a subset of pts who either progressed on an EGFRi or were receiving Erl concurrently in remission in the first line. Further studies of Bem + EGFRi are warranted to explore the potential benefits of this combination. Clinical trial information: NCT02424617.