697O - A phase III, randomized, open-label study of first-line durvalumab (D) with or without tremelimumab (T) vs standard of care chemotherapy in patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE)

Background

D is an anti–PD-L1 antibody approved in the US for patients (pts) with locally advanced or metastatic urothelial carcinoma (UC) who progressed on or after platinum-based chemotherapy (CT). DANUBE is a phase 3 study to evaluate D, with or without T (an anti–CTLA-4 agent), as a first-line treatment for metastatic UC (NCT02516241).

Methods

Eligible pts were ³18 years of age with an ECOG PS of 0 or 1 and previously untreated, unresectable, stage IV UC. Pts were randomized 1:1:1 to D (1.5 g IV q4w), D+T (D 1.5 g IV q4w + T 75 mg IV q4w for up to 4 doses, followed by D 1.5 g IV q4w), or CT (gemcitabine + cisplatin or carboplatin) for up to 6 cycles, until disease progression or unacceptable toxicity. Randomization was stratified by cisplatin eligibility, PD-L1 status (high [≥25% of tumor and/or tumor-associated immune cells staining positive] vs low [<25% of both tumor and immune cells staining positive]), and presence/absence of visceral metastases. Dual primary endpoints compared overall survival (OS) for (1) D vs CT in pts with high PD-L1 expression and (2) D+T vs CT in the ITT population. Minimum follow-up time (from the date the last pt was randomized) was 34 months.

Results

A total of 1032 pts were randomized. Median OS was not significantly different between D and CT among pts with high PD-L1 expression, nor between D+T and CT in the ITT population (Table). Treatment-related adverse events of grade 3–4 occurred in 14%, 28%, and 60% of pts in the D, D+T, and CT arms, with deaths possibly related to treatment in 0.6%, 0.6%, and 0.3% of pts, respectively. Table: 697O

Conclusions

While a trend towards improved OS was observed with D vs CT in the PD-L1 high population and with D+T vs CT in the ITT population, statistical significance was not reached. Additional analyses are ongoing to characterize D and D+T efficacy/safety in different pt subgroups.

Clinical trial identification

NCT02516241, EudraCT: 2015-001633-24.

Editorial acknowledgement

Medical writing and editorial support, which was in accordance with Good Publication Practice guidelines, were provided by Ward A. Pedersen, PhD, CMPP of PAREXEL Int. and was funded by AstraZeneca.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

T.B. Powles: Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: Merck; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: Roche/Genentech; Advisory/Consultancy: Incyte; Advisory/Consultancy: Ipsen; Advisory/Consultancy: Seattle Genetics; Travel/Accommodation/Expenses: MSD; Travel/Accommodation/Expenses: Novartis/Ipsen. M.S. van der Heijden: Advisory/Consultancy: AstraZeneca/MedImmune; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Astellas Pharma; Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Advisory/Consultancy, Travel/Accommodation/Expenses: MSD Oncology ; Advisory/Consultancy: Roche/Genentech ; Advisory/Consultancy: Seattle Genetics ; Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Novartis. D. Castellano Gauna: Advisory/Consultancy: Astellas Pharma; Advisory/Consultancy: AstraZeneca; Travel/Accommodation/Expenses: AstraZeneca Spain; Advisory/Consultancy: Bayer; Advisory/Consultancy: Boehringer Ingelheim; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Bristol-Myers Squibb; Advisory/Consultancy: Ipsen; Advisory/Consultancy: Janssen Oncology; Advisory/Consultancy: Lilly; Advisory/Consultancy: MSD Oncology; Advisory/Consultancy: Novartis; Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Roche/Genentech; Advisory/Consultancy: Sanofi; Research grant/Funding (institution): Janssen Oncology; Travel/Accommodation/Expenses: Roche. Y. Loriot: Honoraria (self), Research grant/Funding (institution): Pfizer; Honoraria (self), Research grant/Funding (institution): Sanofi; Advisory/Consultancy, Travel/Accommodation/Expenses: Astellas Pharma; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy, Research grant/Funding (institution): Clovis Oncology; Advisory/Consultancy, Research grant/Funding (institution): Incyte; Advisory/Consultancy: Janssen; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: MSD Oncology; Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy: Seattle Genetics; Research grant/Funding (institution): Boehringer Ingelheim ; Research grant/Funding (institution): CureVac; Research grant/Funding (institution): Exelixis; Research grant/Funding (institution), Travel/Accommodation/Expenses: Janssen Oncology; Research grant/Funding (institution): Medivation; Research grant/Funding (institution): Oncogenex. M.D. Galsky: Shareholder/Stockholder/Stock options: Rappta Therapeutics; Advisory/Consultancy: Aileron Therapeutics; Advisory/Consultancy: Astellas Pharma; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy: BioMotiv; Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Advisory/Consultancy, Research grant/Funding (institution): Dendreon; Advisory/Consultancy: Dracen; Advisory/Consultancy: EMD Serono; Advisory/Consultancy: Genentech; Research grant/Funding (institution): Genentech/Roche; Advisory/Consultancy: GlaxoSmithKline; Advisory/Consultancy: Incyte; Advisory/Consultancy: Inovio Pharmaceuticals; Advisory/Consultancy: Janssen; Advisory/Consultancy: Lilly; Advisory/Consultancy: Merck; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: NuMab; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Seattle Genetics; Research grant/Funding (institution): Janssen Oncology ; Research grant/Funding (institution): Merck . D.P. Petrylak: Shareholder/Stockholder/Stock options: Bellicum Pharmaceuticals; Advisory/Consultancy, Shareholder/Stockholder/Stock options: TYME; Advisory/Consultancy, Research grant/Funding (self): Astellas Pharma; Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Advisory/Consultancy, Research grant/Funding (self): Bayer; Advisory/Consultancy: Bellicum Pharmaceuticals; Advisory/Consultancy, Research grant/Funding (self): Dendreon; Advisory/Consultancy: Exelixis; Advisory/Consultancy: Ferring; Advisory/Consultancy, Research grant/Funding (self): Johnson & Johnson; Advisory/Consultancy, Research grant/Funding (self): Lilly; Advisory/Consultancy: Medivation; Advisory/Consultancy, Research grant/Funding (self): Millennium; Advisory/Consultancy, Research grant/Funding (self): Pfizer; Advisory/Consultancy, Research grant/Funding (self): Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self): Sanofi; Research grant/Funding (self): Agensys; Research grant/Funding (self): Clovis Oncology; Research grant/Funding (self): Endocyte; Research grant/Funding (self): Genentech; Research grant/Funding (self): Innocrin Pharma; Research grant/Funding (self): MedImmune; Research grant/Funding (self): Merck; Research grant/Funding (self): Novartis; Research grant/Funding (self): Progenics; Research grant/Funding (self): Seattle Genetics; Research grant/Funding (self): Sotio; Speaker Bureau/Expert testimony: Celgene.S.H. Park: Advisory/Consultancy: Lilly. A. Necchi: Advisory/Consultancy, Shareholder/Stockholder/Stock options, Full/Part-time employment: Bayer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self): Foundation Medicine; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Janssen; Honoraria (self): Merck; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Clovis Oncology; Advisory/Consultancy: Incyte; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck Sharp & Dohme; Advisory/Consultancy: Rainier Therapeutics; Advisory/Consultancy: Seattle Genetics/Astellas. J-L. Lee: Honoraria (self): Amgen Korea; Honoraria (self): Astellas Pharma; Honoraria (self), Research grant/Funding (institution): Bristol-Myers Squibb; Advisory/Consultancy: BMS Korea; Advisory/Consultancy: Eisai; Advisory/Consultancy: Pfizer Korea; Advisory/Consultancy: Sanofi Aventis Korea; Research grant/Funding (institution): AstraZeneca/MedImmune ; Research grant/Funding (institution): Janssen; Research grant/Funding (institution): MSD; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Roche/Genentech. U. De Giorgi: Advisory/Consultancy: Astellas Pharma; Advisory/Consultancy: Bayer; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Ipsen; Advisory/Consultancy: Janssen; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Sanofi. M. Bögemann: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Amgen; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Bayer; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self), Advisory/Consultancy: EUSA Pharma; Honoraria (self), Advisory/Consultancy: Ipsen; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: Janssen; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Honoraria (self), Advisory/Consultancy: Roche; Advisory/Consultancy: Advanced Biochemical Compounds. A. Bamias: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self): Bristol-Myers Squibb; Honoraria (self), Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self): AstraZeneca; Advisory/Consultancy: MSD; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy: Pierre; Advisory/Consultancy: Fabre; Research grant/Funding (self): Roche; Research grant/Funding (self): Sanofi. A.P. Fay: Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: Roche; Advisory/Consultancy: Merck Sharp & Dohme. I. Duran: Honoraria (self), Research grant/Funding (institution): Astellas Pharma; Honoraria (self), Advisory/Consultancy: Bristol-Myers Squibb; Honoraria (self): Ipsen; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Janssen Oncology; Honoraria (self), Advisory/Consultancy: MSD Oncology; Advisory/Consultancy: Bayer; Advisory/Consultancy: Novartis; Advisory/Consultancy: Pharmacyclics; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche/Genentech; Advisory/Consultancy: Seattle Genetics; Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca Spain. N. Angra: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Full/Part-time employment: MedImmune. A.K. Gupta: Advisory/Consultancy, Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca; Shareholder/Stockholder/Stock options, Licensing/Royalties: Brystol-Myers-Squibb. P. He: Travel/Accommodation/Expenses, Full/Part-time employment: AstraZeneca; Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Full/Part-time employment: Celldex; Shareholder/Stockholder/Stock options, Full/Part-time employment: Sanofi. W. Levin: Full/Part-time employment: AstraZeneca. J. Bellmunt: Advisory/Consultancy: Astellas Pharma; Advisory/Consultancy: AstraZeneca/MedImmune; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Genentech; Advisory/Consultancy: Merck; Advisory/Consultancy: Novartis; Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy: Pierre Fabre; Research grant/Funding (institution): Millennium; Research grant/Funding (institution): Sanofi; Travel/Accommodation/Expenses: MSD Oncology; Honoraria (self): UpToDate; Shareholder/Stockholder/Stock options: Rainier; Research grant/Funding (institution): Pfizer/EMD Serono; Travel/Accommodation/Expenses: Ipsen. All other authors have declared no conflicts of interest.