It may be possible to use a platinum-free combination as first-line treatment for advanced or metastatic urothelial carcinoma in cisplatin-ineligible patients, if the results of the phase Ib/II EV-103 trial hold up. The combination of the newly approved antibody-drug conjugate (enfortumab vedotin) and a checkpoint inhibitor (pembrolizumab) as first-line therapy led to an objective response rate of 73% in previously untreated patients with locally advanced or metastatic urothelial cancer who were ineligible for cisplatin-based chemotherapy, according to updated results of the EV-103 trial, which were presented by Jonathan E. Rosenberg, MD, at the 2020 Genitourinary Cancers Symposium.1
The combination yielded a progression-free survival of 12.3 months, as well as tumor shrinkage in 93% of patients enrolled in the phase Ib portion of the trial. The median duration of response was not yet reached at the time of the presentation, and more than half of the responses lasted 1 year or longer.
Jonathan E. Rosenberg, MD
“Cisplatin-based chemotherapy is the standard treatment for first-line advanced urothelial cancer; however, it isn’t an option for many patients,” said Dr. Rosenberg, who is Chief of the Genitourinary Medical Oncology Service at Memorial Sloan Kettering Cancer Center, New York. “I’m encouraged by these interim results, including a median progression-free survival of 1 year, for patients who received the platinum-free combination of enfortumab vedotin and pembrolizumab in the first-line setting.”
Dr. Rosenberg continued: “Based on these results, further investigation of enfortumab vedotin plus pembrolizumab as a platinum-free option is warranted in patients with untreated locally advanced and metastatic urothelial cancer.”
A phase III trial is planned to evaluate the combination of enfortumab vedotin plus pembrolizumab, with or without chemotherapy, compared with gemcitabine/platinum chemotherapy in patients with locally advanced or metastatic disease in the first-line setting.
The first results of this trial were presented at the European Society for Medical Oncology (ESMO) Congress 2019. At that time, the objective response rate was 71%, including a complete response rate of 13%. An additional 22 patients had stable disease, for a disease control rate of 93%.2
“Based on these results, further investigation of enfortumab vedotin plus pembrolizumab as a platinum-free option is warranted in patients with untreated locally advanced and metastatic urothelial cancer.”— Jonathan E. Rosenberg, MD
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At the 2020 Genitourinary Cancers Symposium, Dr. Rosenberg presented the first data on the key secondary endpoints of durability of response, progression-free survival, and overall survival in the dose-expansion phase of cohort A from the ongoing, multicohort, open-label, multicenter phase (Ib) of the trial. Patients included in this cohort (n = 45) had locally advanced or metastatic urothelial carcinoma and were ineligible for cisplatin-based chemotherapy.
In cohort A, patients received enfortumab vedotin intravenously on days 1 and 8 and pembrolizumab on day 1 in a 21-day cycle. At the time of the initial analysis, 45 patients (dose-escalation, n = 5; dose-expansion, n = 40) with locally advanced and/or metastatic urothelial cancer received enfortumab vedotin at 1.25 mg/kg plus pembrolizumab as front-line therapy.
The median age of patients was 69 years, and 80% (n = 36) were men.
The primary tumor site was in the lower tract in 69% (n = 31). A total of 4 patients had positive lymph nodes, and the remaining 41 patients had visceral metastases. PD-L1 expression status by combined composite score was up to 10 in 19 patients, at least 10 in 13 patients, and not evaluable in 13 patients.
At a median follow-up of 11.5 months (range = 0.7–19.2 months), the objective response rate was 73%, including a 15.6% complete response rate and a 57.8% partial response rate. The median duration of response had not yet been reached but ranged from 1.2 to 12.9 months.
Data for the duration of response, progression-free survival, and overall survival remain immature. More than half of all responses (55%) were ongoing at the time of the analysis, with 83.9% of responses lasting at least 6 months and 53.7% of responses lasting at least 12 months, according to Kaplan-Meier estimates. The median progression-free survival was 12.3 months, and the median overall survival had not been reached. The 1-year overall survival rate was 81.6%.
Among 45 evaluable patients, 26 (57.8%) had grade 3 or higher treatment-related adverse events. The most common treatment-related adverse events of any grade included fatigue, alopecia, and sensory neuropathy (49% each), diarrhea (44%), decreased appetite (38%), dysgeusia (33%), maculopapular rash (31%), nausea and pruritus (29% each), anemia and weight loss (20% each), and increased lipase (18%). The most common treatment-related adverse events of grade 3 or higher were increased lipase (18%), fatigue and maculopapular rash (9% each), and diarrhea and anemia (7% each).
Additional urothelial cancer cohorts of EV-103 will evaluate enfortumab vedotin: alone or in combination with pembrolizumab or a platinum-based chemotherapy in the first-line setting for patients with metastatic disease; with pembrolizumab and carboplatin or cisplatin in the first-line setting for patients with metastatic disease; alone or in combination with pembrolizumab in muscle-invasive disease; in combination with pembrolizumab in the second-line setting for patients with metastatic disease; and with gemcitabine in the first- or second-line setting for patients with metastatic disease.
A phase II trial of enfortumab vedotin as a single agent has been published. This trial included patients with metastatic urothelial cancer who were previously treated with platinum and anti–PD-1/PD-L1 therapies.3
In December 2019, the U.S. Food and Drug Administration granted accelerated approval to enfortumab vedotin in the treatment of adult patients with locally advanced or metastatic urothelial cancer who have received prior treatment with a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy.
During the discussion period after Dr. Rosenberg’s presentation, he addressed the issue of cost. “This is going to be a shockingly expensive combination. I do think that, as time goes on, we need to prove it is in fact better [than other options]. To have patients on enfortumab and pembrolizumab for several years may not be financially reasonable for many health systems, even if these results are very good.”
DISCLOSURE: The study was supported by Astellas and Seattle Genetics. Dr. Rosenberg owns stock or other ownership interests in Illumina; has received honoraria from AstraZeneca, Bristol Myers Squibb, Chugai Pharma, Clinical Care Options, Clinical Mind, Intellisphere, Medscape, PeerView, Research to Practice, UpToDate, and Vindico; has served as a consultant or advisor to Adicet Bio, Agensys, Astellas Pharma, AstraZeneca/MedImmune, Bayer, BioClin Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, EMD Serono, Fortress Biotech, GlaxoSmithKline, Inovio Pharmaceuticals, Janssen Oncology, Lilly, Merck, Pharmacyclics, QED Therapeutics, Roche/Genentech, Seattle Genetics, Sensei Biotherapeutics, and Western Oncolytics; has received institutional research funding from Astellas Pharma, AstraZeneca, Bayer, Genentech/Roche, Incyte, Jounce Therapeutics, Mirati Therapeutics, Novartis, QED Therapeutics, Seattle Genetics, and Viralytics; holds institutional intellectual property for a “predictor of platinum sensitivity”; and has been reimbursed for travel, accommodations, or other expenses by Bristol Myers Squibb and Genentech/Roche.
1. Rosenberg JE, Flaig TW, Friedlander TW, et al: Study EV-103: Preliminary durability results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma. 2020 Genitourinary Cancers Symposium. Abstract 441.
2. Hoimes CJ, Rosenberg JE, Srinivas S, et al: EV-103: Initial results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma. European Society for Medical Oncology Congress 2019. Abstract 901O.
3. Rosenberg JE, O’Donnell PH, Balar AV, 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 37:2592-2600, 2019.
Philip J. Saylor, MD, Attending Physician at Massachusetts General Hospital and Assistant Professor at Harvard Medical School, Boston, commented on this study.
“The results presented are clearly exciting and cause us to look forward to a likely phase III study of this strategy. The high response...