PD-L1 as a predictor of survival in patients with metastatic urothelial carcinoma (mUC) from the phase III DANUBE trial of durvalumab (D) or durvalumab plus tremelimumab (D plus T) versus standard of care chemotherapy (SoC)

Background: DANUBE was an open-label, phase III trial in patients (pts) with previously untreated mUC. The study did not meet its co-primary endpoints; however, longer survival was observed in pts with high tumour PD-L1 expression who were treated with D or D+T compared with SoC. Further investigations were undertaken to understand PD-L1 as a predictive marker of IO benefit. Methods: Patient tumour samples stained with the VENTANA PD-L1 (SP263) assay were prospectively scored on tumour cells (TCs) and immune cells (ICs) at TC≥25%, IC≥25%, TC or IC≥25% (TC/IC25). Exploratory scoring of TC≥1%, combined positive score (CPS) ≥10, and ICs as a proportion of tumour area (ICTA) ≥5% was also performed on a subset of pts. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated by unstratified log rank test. Results: All PD-L1 algorithms (with exception of TC≥1% for D) improved the OS HR for D or D+T vs SoC compared to the all-comers population (Table). Within treatment arms, using the TC/IC25 algorithm, survival was significantly longer in pts with high vs low PD-L1 expression who received either D+T (HR=0.71, p=0.0074) or D (HR=0.77, p=0.0324) but not SoC (HR=0.98, p=0.895). Both IC and TC PD-L1 expression contributed to patient selection. Notably, the ability of PD-L1 to predict an OS benefit was impacted by subsequent therapy. Conclusions: The TC/IC25 algorithm is predictive of longer survival in pts treated with D or D+T but is not prognostic (i.e., is not associated with survival irrespective of treatment). Both IC and TC PD-L1 expression can play a role in identifying pts with mUC that benefit from IO agents and a combination of both components is likely to be optimal. [Formula presented] Clinical trial identification: NCT02516241. Editorial acknowledgement: Medical writing supportwas provided by Ward Pedersen, PhD (Parexel International, USA) and was funded by AstraZeneca. Legal entity responsible for the study: AstraZeneca. Funding: AstraZeneca. Disclosure: J. Bellmunt: Financial Interests, Personal, Advisory Role: Astellas Pharma; Financial Interests, Personal, Advisory Role: AstraZeneca/MedImmune; Financial Interests, Personal, Advisory Role: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Role: Genentech; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Pierre Fabre; Financial Interests, Institutional, Research Grant: Millennium; Financial Interests, Institutional, Research Grant: Sanofi; Non-Financial Interests, Personal, Other, Travel, Accommodations, Expenses: MSD Oncology; Non-Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Pfizer; Financial Interests, Personal, Stocks/Shares: Rainier Therapeutics. T.B. Powles: Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: Exelixis; Financial Interests, Personal, Advisory Role: Incyte; Financial Interests, Personal, Advisory Role: Ipsen; Financial Interests, Personal, Advisory Role: Merck/MSD; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Seattle Genetics; Financial Interests, Personal, Advisory Role: Merck Serono; Financial Interests, Personal, Advisory Role: Astellas; Financial Interests, Personal, Advisory Role: Johnson & Johnson; Financial Interests, Personal, Advisory Role: Eisai; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Institutional, Research Grant: Exelixis; Financial Interests, Institutional, Research Grant: Ipsen; Financial Interests, Institutional, Research Grant: Merck/MSD; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: Seattle Genetics; Financial Interests, Institutional, Research Grant: Merck Serono; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Institutional, Research Grant: Johnson & Johnson; Financial Interests, Institutional, Research Grant: Eisai; Non-Financial Interests, Personal, Other, Expenses/Travel/Accommodation: Roche; Non-Financial Interests, Personal, Other, Expenses/Travel/Accommodation: Pfizer; Non-Financial Interests, Personal, Other, Expenses/Travel/Accommodation: MSD; Non-Financial Interests, Personal, Other, Expenses/Travel/Accommodation: AstraZeneca; Non-Financial Interests, Personal, Other, Expenses/Travel/Accommodation: Ipsen. M.S. van der Heijden: Financial Interests, Personal, Advisory Role: Astellas Pharma; Financial Interests, Personal, Advisory Role: AstraZeneca/MedImmune; Financial Interests, Personal, Advisory Role: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Role: MSD Oncology; Financial Interests, Personal, Advisory Role: Roche/Genentech; Financial Interests, Personal, Advisory Role: Seattle Genetics; Financial Interests, Institutional, Research Grant: AstraZeneca/MedImmune; Financial Interests, Institutional, Research Grant: Bristol-Myers Squibb; Financial Interests, Institutional, Research Grant: Roche/Genentech; Non-Financial Interests, Personal, Other, Expenses/Travel/Accommodation: Astellas Pharma; Non-Financial Interests, Personal, Other, Expenses/Travel/Accommodation: MSD Oncology; Financial Interests, Personal, Other, Expenses/Travel/Accommodation: Novartis; Financial Interests, Personal, Other, Expenses/Travel/Accommodation: Roche. M.D. Galsky: Financial Interests, Personal, Stocks/Shares: Rappta Therapeutics; Financial Interests, Personal, Advisory Role: Aileron Therapeutics; Financial Interests, Personal, Advisory Role: Astellas Pharma; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: BioMotiv; Financial Interests, Personal, Advisory Role: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Role: Dendreon; Financial Interests, Personal, Advisory Role: Dracen; Financial Interests, Personal, Advisory Role: EMD Serono; Financial Interests, Personal, Advisory Role: Genentech; Financial Interests, Personal, Advisory Role: GlaxoSmithKline; Financial Interests, Personal, Advisory Role: Incyte; Financial Interests, Personal, Advisory Role: Inovio Pharmaceuticals; Financial Interests, Personal, Advisory Role: Janssen; Financial Interests, Personal, Advisory Role: Lilly; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: NuMab; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Seattle Genetics; Financial Interests, Institutional, Research Grant: Genentech/Roche; Financial Interests, Institutional, Research Grant: Janssen Oncology; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Bristol-Myers Squibb; Financial Interests, Institutional, Research Grant: Dendreon; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Novartis. P. He: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Full or part-time Employment: Celldex; Financial Interests, Personal, Stocks/Shares: Celldex; Financial Interests, Personal, Stocks/Shares: Sanofi; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: AstraZeneca; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Celldex. Z. Wang: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. F. Xiao: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. F. Jones: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. M. Scott: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. J. Walker: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. N. Angra: Financial Interests, Personal, Full or part-time Employment: MedImmune/AstraZeneca; Financial Interests, Personal, Stocks/Shares: MedImmune/AstraZeneca; Non-Financial Interests, Personal, Other, Travel, Accommodations, Expenses: MedImmune/AstraZeneca. A. Gupta: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Stocks/Shares: Brystol-Myers-Squibb; Financial Interests, Personal, Royalties: Bristol-Myers Squibb. A. Drakaki: Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: Exelixis; Financial Interests, Personal, Advisory Role: Janssen; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: PACT Pharma; Financial Interests, Personal, Advisory Role: Roche Genentech; Financial Interests, Personal, Advisory Role: Seattle Genetics; Financial Interests, Institutional, Principal Investigator: AstraZeneca; Financial Interests, Institutional, Principal Investigator: BMS; Financial Interests, Institutional, Principal Investigator: Infinity; Financial Interests, Institutional, Principal Investigator: KITE Pharma; Financial Interests, Institutional, Principal Investigator: Merck; Financial Interests, Institutional, Principal Investigator: Roche; Financial Interests, Institutional, Principal Investigator: Seattle Genetics. G. Kimura: Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: Ono; Financial Interests, Personal, Invited Speaker: Bayer; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Chugai; Financial Interests, Personal, Invited Speaker: Pfizer. A. Mizokami: Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Personal, Invited Speaker: Takeda Pharmaceutical; Financial Interests, Personal, Invited Speaker: Astellas Pharma; Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical; Financial Interests, Personal, Invited Speaker: FUJIFILM Toyama Chemical; Financial Interests, Personal, Invited Speaker: Janssen Pharmaceutical; Financial Interests, Personal, Invited Speaker: AstraZeneca. S. Wildsmith: Financial Interests, Personal, Full or part-time Employment: AstraZeneca.