Barcelona, Spain (UroToday.com) Platinum-based chemotherapy is the standard of care in patients with locally advanced or metastatic urothelial carcinoma, but this therapy is often toxic with overall response rates of 50% or less. These tumors highly and consistently express the type I transmembrane cellular adhesion protein, Nectin-4. Enfortumab vedotin (EV) is an antibody-drug conjugate against Nectin-4 with a chemotherapy payload of monomethyl auristatin E (MMAE) that has shown promising phase 1 and phase 2 results as monotherapy in cisplatin-ineligible patients who have received prior immunotherapy. In preclinical models, MMAE has been shown to induce immunogenic cell death, suggesting a hypothesis of potential synergy between MMAE and immune checkpoint blockade therapies. To evaluate this hypothesis as well as the efficacy of EV-combinations in the first-line therapy setting, Dr. Christopher J. Hoimes presented initial data from a phase Ib trial (NCT03288545) looking at first-line EV in combination with pembrolizumab. 

This study enrolled 45 cisplatin-ineligible locally advanced or metastatic urothelial cancer patients (40 in cohort A, 5 patients from the dose-escalation cohort who received the final recommended EV dose) to receive 1.25 mg/kg of EV (days 1, 8 of 21 day cycle) and 200 mg of pembrolizumab (day 1 of 21 day cycle). Primary endpoints were adverse events and lab abnormalities, and key secondary endpoints were dose-limiting toxicities, overall response rate, and overall survival. The patients enrolled were predominantly male (80%), had a median age of 69 (range 51-90), predominantly lower tract disease (69%), had visceral metastatic disease (91%, 33% with liver metastatic disease), and 29% had PDL1 status score 10 by 22C3 PharmDX assay.

At the time of data cut-off, median follow-up was 7.7 months. The median duration of treatment was 6 months, with a median of 7 treatment cycles administered. A total of 21 patients (47%) were off treatment at this point, with 12 discontinuing because of progressive disease and 5 because of adverse events. Of the treatment discontinuations due to adverse effects, 3 were for neuropathy and 1 was for acute renal failure. One patient died while on therapy soon after receiving cycle 1 therapy due to multi-organ dysfunction. 

The confirmed overall objective response rate was 71% (95% CI 55.7-83.6), with 13% complete response rate. In total, 93% of patients exhibited some degree of tumor shrinkage on therapy, regardless of PD-L1 status. Median time to response was 2 months. To date, 22 of 32 responders remain on treatment. The most common side effects noted were fatigue, alopecia, decreased appetite and diarrhea. The most common grade 3/ 4 side effects noted were fatigue (9%), peripheral sensory neuropathy (4%), rash (7%) and lipase elevation (13%, no clinically significant cases). 5% of patients experienced grade 3 or 4 immune-mediated events requiring steroids, including pneumonitis, bullous dermatitis and myasthenia gravis. 

Overall, this data point to an encouraging response rate for the combination of enfortumab vedotin and pembrolizumab, regardless of PD-L1 status. The toxicity profile noted was similar to EV monotherapy. This combination warrants further evaluation to determine its role as a potential first line therapeutic option in cisplatin-ineligible locally advanced or metastatic urothelial carcinoma patients. 

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: Alok Tewari, MD, PhD, Medical Oncology Fellow at the Dana-Farber Cancer Institute, at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept – 1 Oct 2019 in Barcelona, Spain

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