Background

The open-label, phase III KEYNOTE-361 study compares efficacy and safety of 1L P + C vs C for advanced UC (NCT02853305).

Methods

Eligible pts had advanced/unresectable or metastatic UC, ECOG PS 0-2, and no prior systemic therapy for advanced disease. Pts from 201 sites in 21 countries were randomized 1:1:1 to P 200 mg Q3W for ≤35 cycles, P for ≤35 cycles + C for ≤6 cycles (investigator’s choice [IC] of gemcitabine + either cisplatin or carboplatin), or IC of C for ≤6 cycles. Randomization was stratified by IC of platinum and PD-L1 combined positive score (CPS) (≥10 vs <10). Dual primary endpoints were PFS by blinded central review and OS. A sequential testing strategy was used, beginning with superiority testing of PFS and OS for P + C vs C in the total population (P-value threshold of ≤0.0019 for PFS and ≤0.0142 for OS as adjusted for α spent at interim analyses to maintain overall α=2.5% [one-sided] with 0.5% and 2.0% allocated to PFS and OS, respectively), followed by noninferiority and superiority testing of OS for P vs C in pts with CPS≥10 and total pts only if OS for P + C was statistically superior to C.

Results

1010 pts were randomized between Oct 19, 2016 and Jun 29, 2018: 351 to P + C, 307 to P, and 352 to C. As of Apr 29, 2020, median (range) time from randomization to cutoff was 31.7 (22.0-42.3) mo. Baseline characteristics were generally well-balanced across arms. Median PFS for P + C, P, and C for total pts was 8.3 mo, 3.9 mo, and 7.1 mo, respectively; median OS was 17.0 mo, 15.6 mo, and 14.3 mo, respectively. HR (95% CI) for P + C vs C was 0.78 (0.65-0.93, P = 0.0033) for PFS and 0.86 (0.72-1.02, P = 0.0407) for OS. ORR was 54.7% for P + C, 30.3% for P, and 44.9% for C. Median DOR (range) was 8.5 (2.0+-35.5+) mo, 28.2 (2.1+-36.1+) mo, and 6.2 (1.8+-36.3+) mo, respectively. 35.3%, 41.0%, and 61.1% of total pts in P+C, P, and C arms received subsequent therapy (6.6%, 4.6%, and 48.0% of total pts received anti–PD-[L]1), respectively. Grade 3-5 TRAE rate was 75.1% with P + C, 16.9% with P, and 71.6% with C; discontinuation rate of any drug due to an AE was 30.9%, 15.9%, and 18.1%, respectively.

Conclusions

PFS and OS benefit upon addition of P to C vs C did not reach statistical significance. Due to statistical design, OS noninferiority/superiority of P vs C was not tested.

Clinical trial identification

NCT02853305, August 2, 2016.

Editorial acknowledgement

Ina Nikolaeva of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Legal entity responsible for the study

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Funding

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure

A. Alva: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: MSD; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy: Pfizer; Advisory/Consultancy: EMD Serono; Research grant/Funding (institution): Clovis Oncology; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Progenics; Research grant/Funding (institution): Janssen; Research grant/Funding (institution): Genentech; Research grant/Funding (institution): Esanik; Research grant/Funding (institution): Ionis; Research grant/Funding (institution): Argus Biosciences; Research grant/Funding (institution): Prometheus; Full/Part-time employment: University of Michigan. T. Csőszi: Research grant/Funding (institution): Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. M. Ozguroglu: Honoraria (self): Roche; Honoraria (self), Advisory/Consultancy: Sanofi; Honoraria (self), Advisory/Consultancy: Astellas; Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: Janssen; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: AstraZeneca; Travel/Accommodation/Expenses: BMS; Research grant/Funding (institution): Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. N. Matsubara: Advisory/Consultancy, Research grant/Funding (institution): Janssen; Advisory/Consultancy, Research grant/Funding (institution): MSD, a subsidiary of Merck & Co., Inc.; Advisory/Consultancy, Research grant/Funding (institution): Chugai; Research grant/Funding (institution): Astellas; Research grant/Funding (institution): Eli Lilly; Research grant/Funding (institution): Taiho; Research grant/Funding (institution): Pfizer; Advisory/Consultancy: Chigai; Advisory/Consultancy: Sanofi. L. Geczi: Research grant/Funding (institution): Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. S.Y-S. Cheng: Advisory/Consultancy, Research grant/Funding (institution): Merck & Co., Inc.; Advisory/Consultancy: BMS; Advisory/Consultancy: AstraZeneca. Y. Fradet: Advisory/Consultancy: Merck & Co., Inc.; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy, Travel/Accommodation/Expenses: Sanofi; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Tersera; Research grant/Funding (institution): Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.; Research grant/Funding (institution): Janssen; Research grant/Funding (institution): Astellas. S. Oudard: Honoraria (self), Research grant/Funding (self), Travel/Accommodation/Expenses: BMS; Honoraria (self), Travel/Accommodation/Expenses: Merck & Co., Inc.; Honoraria (self), Research grant/Funding (self), Travel/Accommodation/Expenses: Sanofi; Honoraria (self), Research grant/Funding (self), Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Research grant/Funding (self), Travel/Accommodation/Expenses: Novartis; Honoraria (self), Travel/Accommodation/Expenses: Janssen; Honoraria (self), Travel/Accommodation/Expenses: Astellas; Honoraria (self), Research grant/Funding (self), Travel/Accommodation/Expenses: Bayer; Honoraria (self), Research grant/Funding (self): Ipsen; Research grant/Funding (institution): Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. C. Vulsteke: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.; Honoraria (self): Janssen; Honoraria (institution), Travel/Accommodation/Expenses: Roche; Honoraria (institution): Leo Pharma; Advisory/Consultancy: Ipsen; Advisory/Consultancy: Astellas; Travel/Accommodation/Expenses: Novartis. R. Morales Barrera: Honoraria (self), Advisory/Consultancy: Sanofi Aventis; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: MSD, a subsidiary of Merck & Co., Inc.; Advisory/Consultancy, Travel/Accommodation/Expenses: Bayer; Advisory/Consultancy, Travel/Accommodation/Expenses: Janssen; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Asofarma; Travel/Accommodation/Expenses: Pharmacyclics; Travel/Accommodation/Expenses: Clovis; Travel/Accommodation/Expenses: Lilly. A. Fléchon: Honoraria (self), Travel/Accommodation/Expenses: Astellas; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.; Honoraria (self), Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Travel/Accommodation/Expenses: Roche; Honoraria (self), Travel/Accommodation/Expenses: AstraZeneca. S. Gunduz: Travel/Accommodation/Expenses: Roche; Research grant/Funding (institution): Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. Y. Loriot: Honoraria (self), Travel/Accommodation/Expenses: Roche; Honoraria (self): Astellas; Honoraria (self), Honoraria (institution), Research grant/Funding (institution), Travel/Accommodation/Expenses: Janssen; Honoraria (self): Seattle Genetics; Honoraria (self), Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self): BMS; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.; Honoraria (self), Honoraria (institution): Pfizer; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Sanofi; Honoraria (self): Ipsen. A. Rodriguez-Vida: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Astellas; Honoraria (self), Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Bayer; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: BMS; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Janssen; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck Sharp & Dohme, a subsidiary of Merck & Co., Inc.; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Ipsen; Honoraria (self), Travel/Accommodation/Expenses: Sanofi-Aventis; Advisory/Consultancy: Clovis; Research grant/Funding (institution): Takeda. R. Mamtani: Honoraria (self): Med Learning Group; Advisory/Consultancy: Flatiron Health; Advisory/Consultancy: Roche/Genetech; Advisory/Consultancy: Seattle Genetics/Astellas; Research grant/Funding (institution): Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. E.Y. Yu: Advisory/Consultancy: AbbVie; Advisory/Consultancy: Advanced Accelerator Applications; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy: Clovis; Advisory/Consultancy: Janssen; Advisory/Consultancy, Research grant/Funding (institution): Merck Sharp & Dohme, a subsidiary of Merck & Co., Inc.; Advisory/Consultancy: Sanofi; Research grant/Funding (institution): Blue Earth; Research grant/Funding (institution): Daiichi-Sankyo; Research grant/Funding (institution): Dendreon; Research grant/Funding (institution): Pharmacyclics; Research grant/Funding (institution): Seattle Genetics; Research grant/Funding (institution): Taiho. K. Nam: Full/Part-time employment: Merck & Co., Inc. K. Imai: Full/Part-time employment: Merck & C., Inc. B.H. Moreno: Full/Part-time employment: Merck & Co., Inc. T.B. Powles: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Honoraria (institution), Advisory/Consultancy: BMS; Honoraria (institution), Advisory/Consultancy: Seattle Genetics; Honoraria (institution), Advisory/Consultancy: Ipsen; Honoraria (institution), Advisory/Consultancy: MSD, a subsidiary of Merck & Co., Inc.; Honoraria (institution), Advisory/Consultancy: Novartis; Honoraria (institution), Advisory/Consultancy: Pfizer; Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche.

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.

Background

Patients with mUC have limited options after progression on PLT/ CPI. SG is an antibody-drug conjugate composed of a humanized IgG1 kappa anti–Trop-2 monoclonal antibody coupled to SN-38 via a unique hydrolyzable linker. TROPHY-U-01 cohort 1 interim results (n=35) reported a 29% objective response rate (ORR). FDA has granted fast track designation for SG (TRODELVY™) in mUC.

Methods

TROPHY-U-01 (NCT03547973) is a multicohort, global, open-label, phase 2 study evaluating SG clinical activity (10 mg/kg, days 1 and 8 of 21-day cycles) in patients with unresectable locally advanced or mUC with measurable disease, ECOG PS 0–1, and creatinine clearance ≥30 mL/min. Cohort 1 includes patients progressing after PLT and CPI, with unlimited prior lines of therapy. Primary objective was ORR evaluated by RECIST v1.1 via central review; secondary objectives were progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. This cohort had a Simon two-stage design with 90% power to reject the null hypothesis of ORR ≤12%.

Results

113 patients (78% male; median age 66 y; 72% ECOG PS 1; Bellmunt score 0 [12%],1 [54%], 2 [27%],3 [6%]; 62% with visceral metastases) received a median of 3 prior therapies. Central review confirmed an ORR of 27% (31/113; 95% CI 19–37) with 6 complete responses, 25 partial responses and 25% (95% CI 11.5–43.4) ORR in patients with liver metastases. Median DOR was 5.9 mo (95% CI 4.7–8.6) and clinical benefit rate was 37% (42/113). Median PFS and OS were 5.4 mo (95 %CI 3.5- 6.9) and 10.5 mo (95 %CI 8.2–12.3), respectively. Key grade ≥3 treatment-related adverse events were neutropenia (35%), anemia (14%), febrile neutropenia (10%), and diarrhea (10%). There was no treatment-related grade >2 ocular toxicity, neuropathy or interstitial lung disease. There was 1 treatment-related death (neutropenic sepsis).

Conclusions

SG demonstrated meaningful efficacy with manageable toxicity. These results confirm interim findings, suggest that SG may be a treatment option for mUC, and support a randomized phase III trial.

Clinical trial identification

NCT03547973.

Legal entity responsible for the study

Immunomedics, Inc.

Funding

Immunomedics, Inc.

Disclosure

Y. Loriot: Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Astellas; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Janssen; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Seattle Genetics; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Astrazeneca; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): BMS; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): MSD; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Sanofi; Honoraria (self), Advisory/Consultancy: Ipsen; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Astellas; Research grant/Funding (institution): Clovis; Research grant/Funding (institution): Incyte. A.V. Balar: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Genentech; Honoraria (self), Advisory/Consultancy: Incyte; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Merck; Honoraria (self), Advisory/Consultancy: Janssen; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): AstraZeneca/MedImmune; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Nektar; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Seattle Genetics; Research grant/Funding (institution): Immunomedics. D.P. Petrylak: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Advanced Accelerator Applications; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Astellas; Honoraria (self), Advisory/Consultancy: Amgen; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Bayer; Honoraria (self), Advisory/Consultancy: Bicycle Therapeutics; Honoraria (self), Advisory/Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Bristol Myer Squibb; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Clovis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Eli Lilly; Honoraria (self), Advisory/Consultancy: Exelixis; Honoraria (self), Advisory/Consultancy: Incyte; Honoraria (self), Advisory/Consultancy: Janssen; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Honoraria (self), Advisory/Consultancy: Pharmacyclics; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Roche Laboratories; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Seattle Genetics; Honoraria (self), Advisory/Consultancy: Urogen; Research grant/Funding (institution): Endocyte; Research grant/Funding (institution): Genentech; Research grant/Funding (institution): Innocrin; Research grant/Funding (institution): MedImmune; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Progenics; Research grant/Funding (institution): Sanofi Aventis; Shareholder/Stockholder/Stock options: Bellicum; Shareholder/Stockholder/Stock options: Tyme. S.T. Tagawa: Honoraria (self), Research grant/Funding (institution): Immunomedics. A. Rezazadeh: Shareholder/Stockholder/Stock options: ECOM Medical; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Exelixis; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Bayer; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy, Travel/Accommodation/Expenses: Genentech; Advisory/Consultancy: BMS; Advisory/Consultancy: EMD Serono; Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Janssen; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Astellas Medivation; Speaker Bureau/Expert testimony: Sanofi; Speaker Bureau/Expert testimony: Genentech/Roche; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Eisai; Speaker Bureau/Expert testimony, Research grant/Funding (institution): BMS; Speaker Bureau/Expert testimony: Amgen; Speaker Bureau/Expert testimony: EMD Serono; Speaker Bureau/Expert testimony: Merck; Speaker Bureau/Expert testimony: Seattle Genetics/Astellas; Research grant/Funding (institution): Genentech; Research grant/Funding (institution): Eisai; Research grant/Funding (institution): Macrogenics; Research grant/Funding (institution): Astellas Pharma; Research grant/Funding (institution): Beyond Spring; Research grant/Funding (institution): BioClin Therapeutics; Research grant/Funding (institution): Clovis Oncology; Research grant/Funding (institution): Bavarian Nordic; Research grant/Funding (institution): Seattle Genetics; Research grant/Funding (institution): Immunomedics, Epizy; Travel/Accommodation/Expenses: Prometheus Laboratories. A. Fléchon: Honoraria (self): MSD; Honoraria (self): Roche; Honoraria (self): AstraZeneca; Honoraria (self): Astellas. R. Jain: Honoraria (self), Speaker Bureau/Expert testimony: Astellas; Honoraria (self), Speaker Bureau/Expert testimony: Pfizer. N. Agarwal: Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Exelixis; Advisory/Consultancy: Argos; Advisory/Consultancy: EMD Serono; Advisory/Consultancy, Research grant/Funding (institution): Eisai; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution): Genentech; Advisory/Consultancy, Research grant/Funding (institution): BMS; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): Medivation; Advisory/Consultancy: Clovis; Advisory/Consultancy: Foundation One, Seattle Genetics; Advisory/Consultancy: Astellas; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy: Nektar; Research grant/Funding (institution): Active Biotech; Research grant/Funding (institution): Bavarian Nordic; Research grant/Funding (institution): Calithera; Research grant/Funding (institution): Celldex; Research grant/Funding (institution): GlaxoSmithKline; Research grant/Funding (institution): Immunomedics; Research grant/Funding (institution): Janssen; Research grant/Funding (institution): Merck; Research grant/Funding (institution): New Link Genetics; Research grant/Funding (institution): Prometheus; Research grant/Funding (institution): Rexahn; Research grant/Funding (institution): Sanofi; Research grant/Funding (institution): Takeda; Research grant/Funding (institution): Tracon. M. Bupathi: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: BMS; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Exelixis; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: AstraZeneca; Honoraria (self), Speaker Bureau/Expert testimony: Pfizer; Honoraria (self), Speaker Bureau/Expert testimony: Astellas. P. Barthélémy: Advisory/Consultancy, Travel/Accommodation/Expenses: BMS; Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy: Novartis; Advisory/Consultancy, Travel/Accommodation/Expenses: Ipsen; Advisory/Consultancy: MSD; Advisory/Consultancy: EUSAPharma; Advisory/Consultancy, Travel/Accommodation/Expenses: Janssen-Cilag; Honoraria (self): Astellas; Advisory/Consultancy, Travel/Accommodation/Expenses: Sanofi. P.L. Palmbos: Research grant/Funding (institution): Immunomedics. D. Pouessel: Honoraria (self), Research grant/Funding (institution), Non-remunerated activity/ies: AstraZeneca; Honoraria (self): Sanofi; Honoraria (self): Merck; Honoraria (self): Astellas; Honoraria (self): Janssen; Research grant/Funding (institution): MSD; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Incyte; Research grant/Funding (institution), Non-remunerated activity/ies: Janssen; Honoraria (self), Research grant/Funding (institution): BMS; Honoraria (self): Ipsen; Honoraria (self), Non-remunerated activity/ies: Pfizer. C.N. Sternberg: Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: Merck; Honoraria (self), Advisory/Consultancy: Incyte; Honoraria (self), Advisory/Consultancy: BMS; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy: UroToday. Q. Hong: Leadership role, Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Full/Part-time employment: Immunomedics. T. Goswami: Leadership role, Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Full/Part-time employment: Immunomedics. L.M. Itri: Advisory/Consultancy, Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment: Immunomedics; Advisory/Consultancy, Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment: The Medicines Company; Shareholder/Stockholder/Stock options, Immediate Family Member: MSKCC. P. Grivas: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Genentech; Honoraria (self), Research grant/Funding (institution): Bayer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Merck; Honoraria (self), Research grant/Funding (institution): Mirati Therapeutics; Research grant/Funding (institution): Oncogenex; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): BMS; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Non-remunerated activity/ies: AstraZeneca; Honoraria (self), Advisory/Consultancy: Biocept; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): ClovisOncology; Honoraria (self), Advisory/Consultancy: EMD Serono; Honoraria (self), Advisory/Consultancy: Seattle Genetics; Honoraria (self), Advisory/Consultancy: Foundation Medicine; Honoraria (self), Advisory/Consultancy: Driver Inc.; Honoraria (self), Advisory/Consultancy: QED Therapeutics; Honoraria (self), Advisory/Consultancy: Heron Therapeutics; Honoraria (self), Advisory/Consultancy: Janssen; Research grant/Funding (institution), Non-remunerated activity/ies: Bavarian Nordic; Research grant/Funding (institution), Non-remunerated activity/ies: Immunomedics; Research grant/Funding (institution), Non-remunerated activity/ies: Debiopharm; Honoraria (self), Advisory/Consultancy: GlaxoSmithKline; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Genzyme; Honoraria (self), Advisory/Consultancy: Exelixis. All other authors have declared no conflicts of interest.

Background

IMvigor130 met its co-primary endpoint of PFS (HR, 0.82 [95% CI: 0.70, 0.96]) for Arm A (atezo + PBC) vs C (PBO + PBC; Grande ESMO 2019; Galsky Lancet 2020). Atezo + PBC was well tolerated. Here we present PROs (Arm A vs C) to better evaluate the overall treatment (tx) benefit of adding atezo to PBC.

Methods

1213 eligible patients (pts) were randomized to Arm A, B (atezo monotherapy) or C. Atezo or PBO was given 1200 mg IV on day (D) 1 of each 3-wk tx cycle; PBC included gemcitabine 1000 mg/m² IV on D1 and 8 + carboplatin AUC 4.5 or cisplatin 70 mg/m² IV on D1. EORTC QLQ-C30 was completed q3w during tx, at tx discontinuation and ≈ q3 mo during survival follow-up. Descriptive analyses of scale scores (range, 0-100) included change from baseline (BL) summaries and time to deterioration (TTD) in all-comers in Arm A (n = 451) and C (n = 400).

Results

Completion rates were 86% at BL and > 70% until wk 66 in both arms; BL PRO scores were comparable. TTD was similar for most function/quality of life (QOL; Table) and symptom scales. HRs for symptom scales (nausea/vomiting, insomnia, appetite loss, diarrhoea, pain, constipation, fatigue, dyspnoea) ranged from 0.74 (95% CI: 0.57, 0.96; nausea/vomiting) to 1.16 (95% CI: 0.89, 1.51; dyspnoea). 12-mo deterioration-free rates favoured Arm A for nausea/vomiting, appetite loss, role function and social function. Change from BL summaries suggested similar changes (stable or marginal improvement) for both arms in most symptom, function and QOL domains through wk 51 (23% pts eligible for PRO assessments). Arm A pts sustained improved QOL above BL until wk 117 (wk 69 in Arm C). Table: 698O

IMvigor130 Arms A vs C TTD

Conclusions

Atezo + PBC improved PFS vs PBO + PBC without compromising pt function or QOL. Collectively, prolonged PFS, a satisfactory safety profile and these PROs reinforce atezo + PBC as an important new 1L mUC tx option.

Clinical trial identification

NCT02807636.

Editorial acknowledgement

Medical writing support for this abstract was provided by Madhubrata Ghosh, PhD, of Health Interactions, and funded by F. Hoffmann-La Roche, Ltd.

Legal entity responsible for the study

F. Hoffmann-La Roche, Ltd.

Funding

F. Hoffmann-La Roche, Ltd.

Disclosure

A. Bamias: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Roche; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): BMS; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Honoraria (self): Debiopharm; Research grant/Funding (self): Pfizer; Research grant/Funding (self): Novartis; Research grant/Funding (institution): Pierre-Fabre; Research grant/Funding (institution): GSK. M. De Santis: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Astellas Pharma; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Bayer; Honoraria (self): Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Pierre Fabre; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche/Genentech; Advisory/Consultancy: Amgen; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Basilea; Advisory/Consultancy: BioClin Therapeutics; Advisory/Consultancy: BioSyn Healthy Pharma Co; Advisory/Consultancy, Travel/Accommodation/Expenses: Bristol-Myers Squibb; Advisory/Consultancy: Ferring; Advisory/Consultancy: GlaxoSmithKline; Advisory/Consultancy, Travel/Accommodation/Expenses: Ipsen; Advisory/Consultancy, Travel/Accommodation/Expenses: Janssen; Advisory/Consultancy: Merck Sharp & Dohme; Advisory/Consultancy: Sandoz-Novartis; Advisory/Consultancy, Travel/Accommodation/Expenses: Sanofi; Advisory/Consultancy: Seattle Genetics; Advisory/Consultancy: Synthon; Advisory/Consultancy: Takeda. J.Á. Arranz: Honoraria (self), Advisory/Consultancy: Astellas Pharma; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: EUSA Pharma; Honoraria (self), Travel/Accommodation/Expenses: Ipsen; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Janssen-Cilag; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: MSD Oncology; Honoraria (self): Roche Pharma AG; Honoraria (self): Sanofi; Advisory/Consultancy: Amgen; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Bayer; Advisory/Consultancy: Eisai; Advisory/Consultancy: Merck; Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Research grant/Funding (institution): Pierre Fabre; Travel/Accommodation/Expenses: Roche. E. Grande: Honoraria (self): Adacap; Honoraria (self): Astellas Pharma; Honoraria (self), Travel/Accommodation/Expenses: Bristol-Myers Squibb; Honoraria (self): Celgene; Honoraria (self): Eisai; Honoraria (self): Eusa Pharma; Honoraria (self): Genzyme; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Ipsen; Honoraria (self), Travel/Accommodation/Expenses: Janssen-Cilag; Honoraria (self): Lexicon; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self): Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Honoraria (self): Pierre Fabre; Honoraria (self), Research grant/Funding (institution): Roche; Research grant/Funding (institution): Molecular Templates; Research grant/Funding (institution): AstraZeneca ; Travel/Accommodation/Expenses: Roche/Genentech. 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, Research grant/Funding (institution): Genentech/Roche; Advisory/Consultancy: GlaxoSmithKline; Advisory/Consultancy: Incyte; Advisory/Consultancy: Inovio Pharmaceuticals; Advisory/Consultancy, Research grant/Funding (institution): Janssen; Advisory/Consultancy: Lilly; Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Seattle Genetics; Licensing/Royalties: Methods and compositions for treating cancer and related methods. Mount sinai school of medicine July 2012 Application number: 20120322792. E. Kikuchi: Honoraria (self), Research grant/Funding (institution): Astellas; Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self): Bristol; Honoraria (self), Research grant/Funding (institution): Chugai; Honoraria (self): Fuso; Honoraria (self): Janssen; Research grant/Funding (institution): Kissei; Honoraria (self), Research grant/Funding (institution): Kyorin; Honoraria (self), Research grant/Funding (institution): MSD; Honoraria (self), Research grant/Funding (institution): Nippon Kayaku; Research grant/Funding (institution): Nippon Shinyaku; Honoraria (self), Research grant/Funding (institution): Novartis; Honoraria (self), Research grant/Funding (institution): Ono; Honoraria (self), Research grant/Funding (institution): Pfizer; Honoraria (self), Research grant/Funding (institution): Sanofi; Research grant/Funding (institution): Taiho; Honoraria (self), Research grant/Funding (institution): Takeda. S.H. Park: Honoraria (self): Merck Sharp & Dohme; Honoraria (self): Sanofi/Aventis; Advisory/Consultancy: Janssen Oncology; Advisory/Consultancy: Lilly; Research grant/Funding (institution): Kura Oncology, Inc; Research grant/Funding (institution): Ono Pharmaceutical. U. De Giorgi: Advisory/Consultancy: Astellas Pharma; Advisory/Consultancy: Bayer; Advisory/Consultancy, Travel/Accommodation/Expenses: Bristol-Myers Squibb; Advisory/Consultancy, Travel/Accommodation/Expenses: Ipsen; Advisory/Consultancy, Travel/Accommodation/Expenses: Janssen; Advisory/Consultancy: Merck; Advisory/Consultancy: MSD; Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Sanofi; Research grant/Funding (institution): AstraZeneca ; Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche. X. Garcia del Muro: Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Bristol-Myers Squibb; Advisory/Consultancy: Eusa Pharma; Advisory/Consultancy, Speaker Bureau/Expert testimony: Ipsen; Advisory/Consultancy: Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Speaker Bureau/Expert testimony: PharmaMar; Advisory/Consultancy: Roche; Research grant/Funding (institution): AstraZeneca. M. Mencinger: Honoraria (self): Roche; Honoraria (self): Swiss Pharma; Advisory/Consultancy: MSD; Advisory/Consultancy, Travel/Accommodation/Expenses: Sanofi; Travel/Accommodation/Expenses: Astellas Pharma; Travel/Accommodation/Expenses: Pfizer. B. Alekseev: Speaker Bureau/Expert testimony: Astellas; Speaker Bureau/Expert testimony: AstraZeneca; Speaker Bureau/Expert testimony: Bayer; Speaker Bureau/Expert testimony: BMS; Speaker Bureau/Expert testimony: Eisai; Speaker Bureau/Expert testimony: Ferring; Speaker Bureau/Expert testimony: Janssen; Speaker Bureau/Expert testimony: Ipsen; Speaker Bureau/Expert testimony: MSD; Speaker Bureau/Expert testimony: Pfizer; Speaker Bureau/Expert testimony: Roche; Speaker Bureau/Expert testimony: Sanofi. J. Puente: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Astellas Pharma; Honoraria (self): AstraZeneca; Honoraria (self), Advisory/Consultancy: Bayer; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self): EUSA Pharma; Honoraria (self), Advisory/Consultancy: Ipsen; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Janssen-Cilag; Honoraria (self), Travel/Accommodation/Expenses: MSD Oncology; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Honoraria (self): Pierre Fabre; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy: Sanofi; Advisory/Consultancy: Clovis Oncology; Advisory/Consultancy: Merck Sharp & Dohme. K. Izumi: Research grant/Funding (institution): Chugai Pharmaceutical. M. Gumus: Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Honoraria (institution): Novartis; Honoraria (institution): BMS; Honoraria (institution): MSD; Honoraria (institution): Amgen; Honoraria (institution), Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy: Gen İlac; Advisory/Consultancy: Astellas. B. Mellado Gonzalez: Speaker Bureau/Expert testimony, Research grant/Funding (institution): Astellas Pharma; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Bayer; Speaker Bureau/Expert testimony: Bristol-Myers Squibb; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Ipsen; Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Janssen; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Pfizer; Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Sanofi. J-R. Li: Honoraria (self): Amgen; Honoraria (self): Astellas Pharma; Honoraria (self): AstraZeneca; Honoraria (self): Bayer ; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Ipsen; Honoraria (self): Johnson & Johnson; Honoraria (self): MSD; Honoraria (self): Ono Pharmaceutical; Honoraria (self): Pfizer; Honoraria (self): Roche. C. Quach: Shareholder/Stockholder/Stock options, Full/Part-time employment: Genentech. B. Ding: Shareholder/Stockholder/Stock options, Full/Part-time employment: Roche/Genentech. S. Bernhard: Full/Part-time employment: Roche. I.D. Davis: Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Astellas Pharma; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Bristol-Myers Squibb; Research grant/Funding (institution): Eisai; Research grant/Funding (institution): Janssen Oncology; Research grant/Funding (institution): MSD Oncology; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Roche/Genentech; Licensing/Royalties: International Patent Application No: PCT /US2004/032147 (NY-ESO-1) through Ludwig Institute for Cancer Research.

Background

In the phase 3 JAVELIN Bladder 100 trial (NCT02603432), avelumab (anti–PD-L1 IgG1 antibody) 1L maintenance + BSC significantly prolonged overall survival (OS) vs BSC alone in patients (pts) with advanced UC without disease progression with 1L induction chemotherapy in all randomized pts and pts with PD-L1+ tumors. We report exploratory biomarker analyses.

Methods

Tumor biopsies were collected prior to randomization. Tumor analyses included PD-L1 (Ventana SP263 assay) and CD8 immunohistochemistry, whole-exome sequencing (including FCGR2A and FCGR3A genotypes), whole-transcriptome sequencing, and T-cell receptor (TCR) sequencing. Analyses of peripheral blood included baseline C-reactive protein (CRP) level and neutrophil:lymphocyte ratio (NLR) as well as TCR sequencing before and on treatment. Associations between OS or progression-free survival and biomarkers were evaluated using the Cox proportional hazards model. Hazard ratios and nominal p values were reported, and no multiplicity adjustments were made (5% level for statistical significance).

Results

Increased OS benefit with avelumab 1L maintenance + BSC vs BSC alone was positively associated with CD8⁺ T cells in the invasive margin or tumor center, high tumor mutation burden, and tumor gene expression signatures of innate and adaptive immune response. Increased OS benefit was also positively associated with the number of FCGR2A/FCGR3A alleles encoding high-affinity Fcγ receptors for IgG1. OS benefit with avelumab was negatively associated with tumor epithelial cell gene signatures, mutations affecting fibroblast growth factor receptor signaling, CRP, and NLR. In pts with elevated immune gene expression signatures, lower TGFb expression was associated with greater OS benefit with avelumab. Further analyses will be presented, including outcomes by exploratory PD-L1 cutoffs in tumor vs immune cells.

Conclusions

OS benefits of avelumab 1L maintenance in pts with advanced UC are positively associated with biomarkers of immune activity and negatively associated with biomarkers of tumor homeostasis and chronic inflammation.

Clinical trial identification

NCT02603432.

Editorial acknowledgement

Medical writing support was provided by Abhijith Thippeswamy of ClinicalThinking (Hamilton, NJ, USA) and funded by Pfizer and Merck KGaA, Darmstadt, Germany.

Legal entity responsible for the study

Pfizer.

Funding

This study was sponsored by Pfizer, and is part of an alliance between Pfizer and Merck KGaA, Darmstadt, Germany.

Disclosure

T.B. Powles: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Genetech/Roche; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: Merck; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy, Travel/Accommodation/Expenses: Ipsen; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy: Incyte; Honoraria (self), Advisory/Consultancy: Seattle Genetics; Travel/Accommodation/Expenses: MSD; Travel/Accommodation/Expenses: Research to Practice; Honoraria (self), Travel/Accommodation/Expenses: Ferring; Honoraria (self): Gerson Lehrman Group; Honoraria (self): Janssen Research & Development. Y. Loriot: Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Janssen; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Astellas; Honoraria (self): Sanofi; Honoraria (self), Research grant/Funding (self): Roche; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: MSD; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: BMS; Advisory/Consultancy, Travel/Accommodation/Expenses: Seattle Genetics. J. Bellmunt: Advisory/Consultancy: Pfizer; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Genetech; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Merck. C.N. Sternberg: Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy: MSD; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Roche; Advisory/Consultancy, Research grant/Funding (institution): Incyte; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): Sanofi; Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy: Medscape; Advisory/Consultancy: UroToday; Advisory/Consultancy: Astellas Pharma; Research grant/Funding (institution): Janssen; Research grant/Funding (institution): Medivation; Research grant/Funding (institution): Exelixis; Research grant/Funding (institution): Genzyme; Research grant/Funding (institution): Aragon Pharmaceuticals; Research grant/Funding (institution): Array BioPharma; Research grant/Funding (institution): Aveo; Research grant/Funding (institution): Bristol-Myers Squibb; Research grant/Funding (institution): Boehringer Ingelhein; Research grant/Funding (institution): Clovis Oncology; Research grant/Funding (institution): Eisai; Research grant/Funding (institution): GlaxoSmithKline; Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Millenium; Research grant/Funding (institution): Myovant Sciences; Research grant/Funding (institution): Nektar. S. Sridhar: Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Merck; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: Janssen; Honoraria (self), Advisory/Consultancy: Astellas. D.P. Petrylak: Advisory/Consultancy, Research grant/Funding (institution): Ada Cap (Advanced Accelerator Applications); Advisory/Consultancy: Amgen; Advisory/Consultancy, Research grant/Funding (institution): Astellas; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy: Bicycle Therapeutics; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Advisory/Consultancy, Research grant/Funding (institution): Clovis; Advisory/Consultancy, Research grant/Funding (institution): Eli Lilly; Advisory/Consultancy: Exelixis; Research grant/Funding (institution): Endocyte; Advisory/Consultancy: Incyte; Advisory/Consultancy: Janssen; Research grant/Funding (institution): Genetech; Research grant/Funding (institution): Innocrin; Research grant/Funding (institution): MedImmune; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy: Pharmacyclics; Research grant/Funding (institution): Progenies; Advisory/Consultancy, Research grant/Funding (institution): Roche Laboratories; Advisory/Consultancy, Research grant/Funding (institution): Seattle Genetics; Research grant/Funding (institution): Sanofi Aventis; Advisory/Consultancy: Urogen; Shareholder/Stockholder/Stock options, Ownership Interest/Investment: Bellicum; Shareholder/Stockholder/Stock options, Ownership Interest/Investment (Sold 10/2019): Tyme. L.M. Dourthe: Honoraria (self), Advisory/Consultancy: Astellas ; Honoraria (self), Advisory/Consultancy: Bayer; Travel/Accommodation/Expenses: Janssen; Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer. C. Alvarez-Fernandez: Advisory/Consultancy: Ipsen; Advisory/Consultancy: Boehringer Ingelheim; Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Pfizer; Travel/Accommodation/Expenses: Astellas. X.J. Mu: Research grant/Funding (self), Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. K.A. Ching: Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Licensing/Royalties, Full/Part-time employment: Pfizer. J. Pu: Travel/Accommodation/Expenses, Full/Part-time employment: Roche; Full/Part-time employment: Pfizer. S. Roychoudhury: Full/Part-time employment: Pfizer. C.B. Davis: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. A. di Pietro: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. P. Grivas: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Bayer; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Biocept; Research grant/Funding (institution): Bavarian Nordic; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses, Educational unbranded activity with Bristol-Myers Squibb (2017): Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Clovis Oncology; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Driver; Research grant/Funding (institution): Debiopharm; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: EMD Serono; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Exelixis; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Foundation Medicine; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Genentech; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: GlaxoSmithKline; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Heron Therapeutics; Research grant/Funding (institution): Immunomedics; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Janssen; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Mirati Therapeutics; Research grant/Funding (institution): Oncogenex; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Seattle Genetics; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: QED Therapeutics; Honoraria (institution): KureIT; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Genzyme. All other authors have declared no conflicts of interest.