4844 - EV-103: Initial results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma.

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 1.25 mg/kg EV + 200 mg pembrolizumab. Cohort A pts received the recommended dose of 1.25 mg/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 (1.25 mg/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.