A Ph I/II Study of BGB324, a Selective AXL Inhibitor as Monotherapy and in Combination with Erlotinib in Advanced NSCLC

Transcription

1 A Ph I/II Study of BGB324, a Selective AXL Inhibitor as Monotherapy and in Combination with Erlotinib in Advanced NSCLC Don L. Gibbons, Lauren Byers, David E. Gerber 2, Julio Peguero 3, David Micklem 4, Murray Yule, James Lorens 6 MD Anderson Cancer Center, Houston, TX/United States of America, 2 UT Southwestern, Dallas, TX/United States of America, 3 Oncology Consultants, Houston/United States of America, 4 BerGenBio ASA, Bergen/Norway, BerGenBio, Bergen/Norway, 6 University of Bergen, Bergen/Norway

2 2 Speaker Disclosures Grant research support from Janssen R&D and AstraZeneca. Advisory board work for Janssen R&D and AstraZeneca. Travel expenses from BerGenBio for this presentation.

3 3 AXL overexpressed in lung cancers following epithelial-to-mesenchymal transition (EMT) and promotes EGFR TKI resistance AXL Axl IHC Baseline EGFRi Resistance BGB324 Oral selective AXL inhibitor Mesenchymal vs Epithelial NSCLC cell lines Gibbons and Byers, Cancer Discovery 204 Byers et al, CCR 203 Bivona et al., Nature Genetics 202

4 4 COMPLETED Run-in Cohort Single agent BGB324 in NSCLC pts with progression after prior therapy (n 6) ARM A (Dose Escalation) BGB324 + erlotinib Patients (n 8) with 6 wks of erlotinib 0mg daily ARM B (Erlotinib Progression) Pts with EGFR mutation, T790M-neg with progression on erlotinib Dose escalate until MTD/RP2D Minimum of 6pts at MTD/RP2D ARM C (First-line Erlotinib Combo) Pts with EGFR mutation with 4 cycles of erlotinib in first-line setting Daily BGB324 + erlotinib Daily BGB324 + erlotinib Stage (n=9), Stage 2 (n=6) Currently (n=4) Enrolling Endpoints: Safety, tolerability pharmacokinetics and preliminary efficacy Pharmacodynamics: AXL expression and mesenchymal transcriptomics Part A (Run-in): BGB324 Monotherapy Part A2 (Doseescalation): BGB324 + erlotinib n 8 8 Gender Female Male Average (range) 64 (8-77) 8 (38-68) Stage IIIB IV ECOG 0 BGBC004 Phase Ib Study design part A & A2 Demographic # pts with activating mutations Median # lines of previous treatment (range) Ethnicity African American Asian Caucasian Other (2-0) ( 3) 0 3 0

5 year Progression Free Survival in 2% of patients NSCLC Phase Ib: BGB324 monotherapy & erlotinib combination benefit Overview Monotherapy: year PFS in 2% patients Two patients treated for approximately 2 months minor response stable disease Very well tolerated, patients discontinued due to disease progression Recommended Phase II Dose Combination therapy: 0% CBR 3 SD > 4 months stable disease One patient ongoing > 20 months Very well tolerated Recommended Phase II Dose BGB324 monotherapy BGB324 + Erlotinib Weeks Weeks SD= Stable Disease according to RECIST-

6 6 Summary of Treatment-related AEs for BGB324 (Safety Population) Phase Phase 2 System Organ Class/Preferred Term[a] Nerbatim Term[bJ Run=In Arm A Arm B Arm C Overall N=8 N=8 N= N=3 N=24 N % E N % E N % E N % E N % E Number oft TEAE Gastrointestinal disorders General disorders and administration site conditions Investigations Nervous system disorders Metabolism and nutrition disorders From: IB cut off date 30 July 207 MedDRA version.- or above; Abbreviations: AE = Adverse Events Only events considered possibly/probably/definitely related to BGB324 are presented

7 7 Translational biomarkers suggest target engagement Tested biomarkers shown to correlate with AXL inhibition and lung function saxl increase correlates with exposure Angpt-2 upregulated in response to Axl knockdown () CXCL is downregulated in Axl-/- (2) Uteroglobin/Club cell protein 6 plasma levels are biomarker for lung injuries (3) () Li et al 2009 (2) Gerloff & Korshunow 202 (3) Determann et al 2008

8 8 Conclusions and Future Directions BGB324 +/- erlotinib has a tolerable side effect profile Early trial results indicate clinical activity with BGB324 (single agent) and BGB324 plus erlotinib combination in a subset of NSCLC (EGFR mutant and wildtype) Additional cohorts still enrolling AXL may play a role in immune escape and BGB324-immunotherapy combinations are being explored, including BGB324 with pembrolizumab for NSCLC (NCT03847) Byers et al, unpublished

9 Thank you