ESMO 2019: EV-103 Enfortumab Vedotin plus Pembrolizumab for Urothelial Carcinoma

Barcelona, Spain ( Recently, we’ve seen some major advances for patients with locally advanced and metastatic urothelial carcinoma.  For instance, pembrolizumab, an anti-PD-1 antibody has received regulatory approval for both cisplatin ineligible patients in the first-line setting and also in the post-platinum treated population.1, 2  Enfortumab vedotin is a novel antibody drug conjugate, targeting Nectin-4, with 44% overall response rates and 12% complete response rates in the patients previously treated with platinum chemotherapy and anti-PD-(L)1 therapy.3  The United States Food and Drug Administration will consider accelerated approval of enfortumab vedotin for this patient population.  Additionally, novel combinations of enfortumab vedotin with other active agents have ensued.

At the 2019 European Society of Medical Oncology (ESMO) Congress, the initial results from EV-103 trial was presented by Dr. Christopher Hoimes.  
ESMO 2019 EV103 studydesign

Although the trial is designed with multiple cohorts with various combinations of enfortumab vedotin in first and second line, the ESMO presentation focused on Cohort A, which was comprised of first-line treated, cisplatin-ineligible patients with combination enfortumab vedotin with pembrolizumab.  Enfortumab vedotin was dosed at 1.25 mg/kg on days 1 and 8 of 3-week cycles while pembrolizumab was administered at 200 mg on day 1 of 3-week cycles.  A 5-patient dose escalation cohort led into an additional 40 patient expansion.  The primary endpoint of adverse events revealed 7 (16%) patients with treatment-related serious adverse events.  There were 4 (9%) patients who discontinued study treatment due to adverse events, with peripheral neuropathy being the cause for 2 of those patients.  Peripheral neuropathy occurred in 22 (49%) patients with 2 (4%) having a grade 3 or greater event.  Rash occurred in 21 (47%) patients with 5 (11%) have a grade 3 or greater event.  There was 1 treatment-related death due to multiorgan dysfunction.

ESMO 2019 EV103 objective response rate
Most impressive was the fact that 32 (71%) patients have a confirmed objective response rate, and 6 (13%) experienced a complete response.  Responses occurred in PD-L1 high and low patients defined with the cutoff of CPS of 10 as the delineating factor.  All but 3 patients on trial had some degree of tumor shrinkage, translating into 93% of patients with some level of tumor reduction on trial.  Responses were rapid and durable, with 91% of responses occurring at the first assessment at 9 weeks.
ESMO percentchange

In summary, Enfortumab vedotin with pembrolizumab has significant antitumor activity in cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma with an acceptable safety profile.  Further exploration of this synergistic-appearing combination should be considered not only in the advanced disease setting but also in earlier disease states where the potential for improving upon curative treatment outcomes should not be ignored.
ESMO2019 EV103 percent

Presented by: Christopher J. Hoimes, DO,  Assistant Professor, Department of Medicine Division of Hematology and Oncology, School of Medicine Member, GU Malignancies Program, Case Comprehensive Cancer Center, Case Western Reserve University/University Hospitals, Cleveland, Ohio

Written by: Evan Yu, MD Professor, Department of Medicine, Division of Oncology, University of Washington School of Medicine  at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept - 1 Oct 2019 in Barcelona, Spain


  1. Bellmunt J et al.  Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med 2017; 376:1015-26.
  2. Balar AV et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol 2017; 18:1483-92.
  3. Rosenberg JE et al. Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy. J Clin Oncol 2019:JCO1901140 [Epub ahead of print].