2393P - Ephrin signalling mediates resistance to programmed death ligand 1 (PD-L1) inhibition in urothelial carcinoma (UC)

Background

Ephrin ligand (EFN) and receptor (EPH) signalling is increasingly implicated in tumorigenesis. Recently, EFN-B2 and PD-L1 inhibition have demonstrated impressive synergy in metastatic UC. Using data from the ABACUS trial (NCT02662309) in muscle-invasive UC, we explore the relationship between EFN/EPH expression and response to atezolizumab.

Methods

The neoadjuvant ABACUS study design enabled transcriptomic and immunohistochemical (IHC) comparison of paired baseline and cystectomy samples. For multivariate disease-free survival (DFS) analysis, patients were grouped into high and low EFN/EPH using median expression levels. 83 patients were eligible for biomarker analysis. 64 had paired samples. 27 (33%) achieved complete pathological response and/or major pathological response and were deemed responders, and 17 (20%) relapsed.

Results

Following atezolizumab, there was reduced expression of EFN-A1 (log2FC:-0.9, p<0.05), EFN-A4 (log2FC:-0.8, p<0.05), EFN-A5 (log2FC:-0.8, p<0.05) and their cognate receptor EPH-A1 (log2FC:-1.7, p<0.05) as well as EFN-B2 (log2FC:-0.82, p<0.05) amongst responders, but not relapsed patients. Consequently, apart from EFN-B2, the post-treatment expression of these genes was significantly higher amongst relapsed patients than responders. High post-treatment EFN-A1 (HR: 11.9, 95%CI: 2.2 – 66.0, log-rank p<0.01), EFN-A4 (HR: 4.8, 95%CI: 0.9 – 25.3, log-rank p<0.01) and EFN-A5 (HR: 13.9, 95%CI: 2.9 – 67.9, log-rank p<0.05), and high baseline EFN-B2 (HR: 7.7, 95%CI: 2.1 – 27.7, log-rank p<0.01) expression was associated with reduced DFS. EFN-A1, EFN-A4 and EFN-A5 expression post-treatment, but not at baseline, correlated negatively with a cytotoxic T cell transcriptomic signature and granzyme B-positive CD8 T cells on IHC. EFN-B2 expression correlated positively with transcriptomic signatures of hypoxia and pathological angiogenesis.

Conclusions

EFN-A1, EFN-A4 and EFN-A5, likely through EPH-A1 signalling, are associated with reduced immune infiltrate and survival after atezolizumab, and represent promising biomarkers and targets. High baseline EFN-B2 expression is associated with relapse, supporting the addition of EFN-B2 inhibitors to augment response rates.

Clinical trial identification

NCT02662309.

Editorial acknowledgement

Legal entity responsible for the study

Barts Experimental Cancer Centre Clinical Trials Group.

Funding

Roche.

Disclosure

D.E. Castellano Gauna: Financial Interests, Personal, Advisory Board: Pfizer, Roche, BMS, Janssen, Astellas, MSD, Ipsen, AstraZeneca, Novartis, GSK; Financial Interests, Institutional, Local PI: Pfizer, Roche, MSD, BMS, AstraZeneca, Janssen, Astellas, Ipsen, Exelisis, Eisai, Lilly, Bayer, GSK, Clovis, QED Therapeutics; Non-Financial Interests, Personal, Other, Executive member: SOGUG (Spanish Oncology Genito-Urinary Group) Foundation. R. Banchereau: Financial Interests, Personal, Full or part-time Employment: Roche, Genentech. M. Kockx: Financial Interests, Personal, Full or part-time Employment: Histogenex; Financial Interests, Institutional, Funding: Roche. A. Rodriguez-Vida: Financial Interests, Personal, Invited Speaker: Roche, BMS, Janssen, AstraZeneca, Ipsen; Financial Interests, Personal, Advisory Board: MSD, Pfizer, Astellas, Bayer, Merck. I. Duran Martinez: Financial Interests, Personal, Advisory Board: Roche Genentech, MSD, Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker: Janssen; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Advisory Board: Ipsen; Financial Interests, Personal, Invited Speaker: Ipsen, Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Astellas; Financial Interests, Personal, Advisory Board: Immunomedics, Inc.; Financial Interests, Personal, Invited Speaker: EUSA Pharma, MSD; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Astellas; Financial Interests, Personal, Invited Speaker: Bayer; Financial Interests, Personal, Other, expenses related to EAU 2023 including registration, travel and accommodation: Bayer; Financial Interests, Personal and Institutional, Research Grant: Roche Genentech; Financial Interests, Personal, Steering Committee Member: Immunomedics, Inc.; Financial Interests, Personal and Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Coordinating PI, I am leading a study (Investigator initiated) that is funded by Gilead and sponsored by the foundation of my department (FUPOCAN): Gilead; Non-Financial Interests, Leadership Role, I am the president of an independent cooperative group of GU Oncologist from the north of Spain: GO NORTE; Non-Financial Interests, Member of Board of Directors: ASEICA; Non-Financial Interests, Member of Board of Directors: GUARD. M.S. van der Heijden: Financial Interests, Institutional, Advisory Board: AstraZeneca, BMS, Janssen, MSD, Seagen, Pfizer; Financial Interests, Institutional, Funding, Investigator-initiated trial: BMS, Roche, AstraZeneca, 4SC; Financial Interests, Institutional, Steering Committee Member, Local PI + SSC member: BMS, AstraZeneca, MSD, Seagen; Financial Interests, Institutional, Steering Committee Member, Local PI + study co-PI: Janssen; Financial Interests, Institutional, Local PI: GSK. A. Font Pous: Financial Interests, Institutional, Advisory Board: Pfizer, Bayer, Astellas. G. Gravis: Financial Interests, Institutional, Invited Speaker: AAA, Amgen, Astellas, BMS, Janssen, MSD, Pfizer, Ipsen, AstraZeneca, Alliance Merck Pfizer, Bayer, Eisai; Financial Interests, Institutional, Advisory Board: Alliance Merck-Pfizer, BMS, Janssen, Pfizer, Ipsen, Bayer, Eisai; Financial Interests, Institutional, Funding: Janssen; Financial Interests, Institutional, Coordinating PI: BMS; Non-Financial Interests, Principal Investigator: Ipsen, BMS, Merck. U. Anido Herranz: Financial Interests, Personal, Invited Speaker: Advanced Accelerator Applications, Ipsen, AstraZeneca, Merck, Pfizer, Astellas, Bayer, Eisai, BMS, Kyowa Kirin, Rovi; Financial Interests, Personal, Advisory Board: Advanced Accelerator Applications, Ipsen, AstraZeneca, Merck, Pfizer, Bayer. A. Protheroe, A. Ravaud: Financial Interests, Institutional, Funding: BMS, Roche. B.E. Szabados: Financial Interests, Personal, Other, travel funding: Roche/Genentech; Financial Interests, Personal, Invited Speaker: MSD, Pfizer; Financial Interests, Personal, Advisory Board: Ellipses, Merck kga, Ipsen. T.B. Powles: Financial Interests, Personal, Advisory Board: AstraZeneca, Bristol Myers Squibb, Exelixis, Incyte, Ipsen, Merck, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, Eisai, Roche, MSD; Financial Interests, Personal, Other, Travel/Accommodation/Expenses: Roche, Pfizer, MSD, AstraZeneca, Ipsen; Financial Interests, Personal, Other, Sponsorship for Uromigos Podcast: Mashup Ltd; Financial Interests, Institutional, Research Grant: AstraZeneca, Roche, Bristol Myers Squibb, Exelixis, Ipsen, Merck, MSD, Seattle Genetics, Novartis, Pfizer, Merck Serono, Astellas, Johnson & Johnson, Eisai. All other authors have declared no conflicts of interest.