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The treatment landscape for advanced urothelial cancer has changed dramatically owing to the US Food and Drug Administration approval and introduction of antibody-drug conjugates (ADCs), including enfortumab vedotin and sacituzumab govitecan. Efforts have begun to use these therapies in earlier disease states, specifically bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC). We assessed gene expression associated with these newly approved therapies in a novel cohort of treatment-naïve NMIBC tumors before and after BCG therapy. Multiple genes, including Nectin-4, Trop-2, and Her-2, exhibited increased expression after BCG therapy compared to baseline. However, few of the tumors with increased expression of ADC targets also exhibited increased PD-L1/PD-1 expression. Taken together, these data demonstrate the heterogeneous genomic landscape of BCG-exposed NMIBC, and provide evidence supporting the evaluation of ADCs in NMIBC. PATIENT SUMMARY: We evaluated the potential role of targeted therapies that have been approved in the USA for advanced non-muscle-invasive bladder cancer (NMIBC) that has recurred after treatment with bacillus Calmette-Guérin (BCG). By assessing levels of specific genes and proteins linked to the targeted therapies, we demonstrate that there is rationale for further evaluation of these therapies in NMIBC.

Enfortumab vedotin (EV) was FDA approved in December 2019 for platinum- and checkpoint-refractory urothelial cancer based on an exceptional 44% response rate, and is currently approved for use after platinum and checkpoint inhibitor therapy. Enfortumab is an antibody-drug conjugate that targets Nectin-4, which is widely expressed in urothelial cancer. Despite this ample target, clinical benefit is not achieved by all patients, and mechanisms of treatment resistance are undescribed. Herein we summarize what is known to date regarding coorelative findings and subgroup analysis and EV response, including novel biopsy data in patients with tumor progression post EV.

Background Locally advanced or metastatic urothelial carcinoma (la/mUC) is an aggressive cancer with low survival rates. Anti-PD-(L)1 antibodies are current treatment options for patients who progressed during or after platinum-based chemotherapy. While some of these patients achieve durable responses with anti-PD-(L)1 therapy, response rates are ≤21%; as such, novel therapies are needed for patients after treatment with platinum and anti-PD-(L)1 therapies. Enfortumab vedotin (EV) is an investigational humanized monoclonal antibody that delivers the microtubule-disrupting agent monomethyl auristatin E to tumors expressing Nectin-4, which is highly expressed in la/mUC. In a multicohort phase 2 study of EV (EV-201; NCT03219333), which included sites in Japan and Korea, single-agent EV 1.25 mg/kg was generally well tolerated. In Cohort 1 of EV-201 (closed to enrollment), EV demonstrated a confirmed ORR of 44% and a median DoR of 7.6 months as assessed by independent central review in patients with la/mUC with prior platinum chemotherapy and antiPD(L)1. Trial design EV-301 (NCT03474107) is a global, multicenter, open-label, phase 3 trial being conducted in the USA, Europe, and Asia, including sites in Japan, Korea, and Taiwan. Adult patients with la/mUC and an ECOG score ≤1, who have received a prior platinum-containing chemotherapy, and have experienced disease progression during or following treatment with anti-PD-(L)1 are eligible; these patients are consistent with the population in Cohort 1 of EV-201. Approximately 550 patients will be randomized (1:1) to receive EV (1.25 mg/kg) by IV on Days 1, 8, and 15 of each 28-day cycle (Arm A), or investigator’s choice of IV docetaxel, paclitaxel, or vinflunine (where approved) on Day 1 of each 21day cycle (Arm B). Treatment with EV will continue until radiological disease progression, intolerance, or other discontinuation criterion is met. Radiological assessments of tumor response status will be performed at baseline and every 8 weeks. The primary endpoint is overall survival; secondary endpoints include PFS, DoR, ORR, and assessment of safety/tolerability and quality-of-life parameters. Clinical trial identification NCT03474107. Legal entity responsible for the study Astellas Pharma US, Inc. Funding Astellas Pharma US, Inc. Disclosure D.P. Petrylak: Research grant / Funding (institution): Astellas ; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution), Shareholder / Stockholder / Stock options: Bellicum; Advisory / Consultancy, Research grant / Funding (institution): Dendreon; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Ferring; Advisory / Consultancy, Research grant / Funding (institution): Johnson and Johnson; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy, Research grant / Funding (institution): Medivation; Advisory / Consultancy, Research grant / Funding (institution): Millineum; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Roche Laboratories; Advisory / Consultancy, Research grant / Funding (institution): Sanofi Aventis; Research grant / Funding (institution): Agensys; Research grant / Funding (institution): Clovis; Shareholder / Stockholder / Stock options: Tyme; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Endocyte; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Innocrin. J.E. Rosenberg: Advisory / Consultancy, Research grant / Funding (institution): Astellas; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Seattle Genetics; Advisory / Consultancy: Merck; Advisory / Consultancy: BMS; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy: Lilly; Advisory / Consultancy: Sanofi; Advisory / Consultancy: EMD Serono. J. Lee: Advisory / Consultancy, Research grant / Funding (institution): Pfizer Korea; Advisory / Consultancy, Research grant / Funding (institution): Ipsen Korea; Advisory / Consultancy: Janssen; Advisory / Consultancy: Sanofi Aventis; Advisory / Consultancy: Novartis Korea; Advisory / Consultancy: Astellas Korea; Advisory / Consultancy: BMS Korea. I. Duran: Advisory / Consultancy: Seattle Genetics. Y. Loriot: Advisory / Consultancy: Astellas; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche. G. Sonpavde: Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Onyx-Amgen; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Genentech; Advisory / Consultancy: Novartis; Advisory / Consultancy: Argos; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Agensys; Advisory / Consultancy: Astellas; Speaker Bureau / Expert testimony: Clinical Care Options; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Uptodate; Advisory / Consultancy: Biotheranostics; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Bristol-Myers-Squibb; Advisory / Consultancy: Janssen; Advisory / Consultancy: Amgen; Advisory / Consultancy: Eisai; Advisory / Consultancy: NCCN. C. Wu: Full / Part-time employment: Astellas. E.M. Gartner: Full / Part-time employment: Seattle Genetics, Inc. A. Melhem-Bertrandt: Full / Part-time employment: Astellas. T. Powles: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Roche; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): Merck; Honoraria (self): BMS. All other authors have declared no conflicts of interest.

Background Platinum-based chemotherapy remains the standard of care for patients (pts) with locally advanced or metastatic urothelial carcinoma (la/mUC). Despite the use of first-line (1L) PD-1/PD-1L inhibitors, 71–76% of pts who are cisplatin-ineligible do not respond. EV is an antibody-drug conjugate targeting Nectin-4, which is highly expressed in mUC. EV monotherapy data are encouraging; combination therapy may provide additional benefit. Here, we report initial data on a cohort of cis-ineligible pts receiving 1L EV + pembrolizumab. Methods This phase 1b study (NCT03288545) evaluated the safety/activity of EV + pembrolizumab. In the dose-escalation cohort, 1L or 2L pts received 1.0 or 1.25mg/kg EV+200mg pembrolizumab. Cohort A pts received the recommended dose of 1.25mg/kg EV + pembrolizumab as 1L therapy. In each 21-day cycle, EV was administered on Days 1 and 8 and pembrolizumab on Day 1. The primary endpoint was safety/tolerability; key secondary objectives: recommended EV dose, antitumor activity, DCR, DOR, PFS, and OS. Results As of 20 Feb 2019, 29 la/mUC pts (median 68 [51–90] y; 31% liver metastasis, 17% ECOG 2) have been treated with EV (1.25mg/kg) + pembrolizumab in the 1L setting and completed at least 2 post-baseline scans or discontinued treatment. The most common treatment-emergent adverse events (AE) were fatigue (66%, 14% ≥Grade 3), decreased appetite (52%, 0% ≥Grade 3), alopecia (45%), and diarrhea (41%, 3% ≥Grade 3). Among AE of clinical interest, rash of any type occurred in 45% of pts (14% ≥Grade 3), peripheral neuropathy of any type in 52% (3% ≥Grade 3), and 17% experienced immune-mediated events that required systemic steroid treatment (10% ≥Grade 3). Overall, 2 pts (7%) discontinued treatment with EV + pembrolizumab due to AE (lipase increase,multi-organ failure). Preliminary confirmed ORR per RECIST 1.1 was 62% by investigators, including a 14% CR rate. The DCR was 90%. Conclusions In 1L cis-ineligible pts with la/mUC, EV + pembrolizumab demonstrates encouraging efficacy with a tolerable and manageable safety profile. Further evaluation of this combination is warranted. Updated data, including responses pending confirmation, will be available at the meeting. Clinical trial identification NCT03288545. Editorial acknowledgement Heather Brignull, PhD of Seattle Genetics. Legal entity responsible for the study Seattle Genetics, Inc. Funding Seattle Genetics, Inc. Astellas Pharma, Inc, and Merck. Disclosure C.J. Hoimes: Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy: Eisai; Advisory / Consultancy: Foundation Medicine; Advisory / Consultancy, Speaker Bureau / Expert testimony: Genentech; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: Prometheus Labs; Honoraria (self), Advisory / Consultancy: Seattle Genetics. J.E. Rosenberg: Advisory / Consultancy: Adicet Bio; Advisory / Consultancy, Research grant / Funding (institution): Agensys; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy: BioClin Therapeutics; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Fortress Biotech; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Genentech; Advisory / Consultancy: Inovio Pharma; Honoraria (self): Eli Lilly; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Merck; Advisory / Consultancy: Pharmacyclics; Advisory / Consultancy: QED Therapeutics; Advisory / Consultancy: Sanofi; Advisory / Consultancy, Research grant / Funding (institution): Seattle Genetics; Advisory / Consultancy: Sensei Biotherapeutics; Advisory / Consultancy: Western Oncolytics; Shareholder / Stockholder / Stock options: Illumina; Honoraria (self): Chugai Pharma. S. Srinivas: Advisory / Consultancy: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Seattle Genetics. D.P. Petrylak: Advisory / Consultancy, Research grant / Funding (institution): Astellas; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Bellicum Pharm; Advisory / Consultancy, Research grant / Funding (institution): Dendreon; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Ferring; Advisory / Consultancy, Research grant / Funding (institution): Johnson & Johnson; Advisory / Consultancy, Research grant / Funding (self): Eli Lilly; Advisory / Consultancy, Research grant / Funding (institution): Millennium; Advisory / Consultancy: Medivation; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Sanofi; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Tyme; Advisory / Consultancy, Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Agensys; Speaker Bureau / Expert testimony: Celgene; Research grant / Funding (institution): Clovis Oncology; Research grant / Funding (institution): Genentech. M. Milowsky: Research grant / Funding (institution): Mirati Therapeutics; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Cerulean Pharm; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Acerta Pharma; Research grant / Funding (institution): BioClin Therapeutics; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): X4 Pharma; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Innocrin Pharma; Research grant / Funding (institution): Inovio Pharmaceuticals. J.R. Merchan: Research grant / Funding (institution): Seattle Genetics; Advisory / Consultancy: Exelixis; Research grant / Funding (institution): Rexahn; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Tocagen; Research grant / Funding (institution): Agensys; Research grant / Funding (institution): Tracon. M.A. Bilen: Advisory / Consultancy: Exelixis; Advisory / Consultancy, Research grant / Funding (institution): Nektar; Advisory / Consultancy: Genomic Health; Advisory / Consultancy, Research grant / Funding (institution): Seattle Genetics; Advisory / Consultancy: Sanofi; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Tricon Pharmaceuticals; Research grant / Funding (institution): Peleton; Research grant / Funding (institution): Pfizer. S. Gupta: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Genentech; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Innocrin Pharma; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Merck. A. Carret: Honoraria (self), Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Seattle Genetics. N. Yuan: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Seattle Genetics. A. Melhem-Bertrandt: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Astellas. T. Flaig: Advisory / Consultancy: GTX; Leadership role, Shareholder / Stockholder / Stock options, Officer / Board of Directors: Aurora Oncology; Honoraria (self): BN ImmunoTherapeutics; Research grant / Funding (institution): Agensys; Research grant / Funding (institution): Aragon Pharma; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Bavarian Nordic; Research grant / Funding (institution): Dendreon; Research grant / Funding (institution): Exelisix; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): GTx; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): La Roche-Posay; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Pfizer.