In the phase II EV-201 trial, reported in the Journal of Clinical Oncology, Jonathan E. Rosenberg, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues found high activity of the antibody-drug conjugate enfortumab vedotin in patients with metastatic urothelial carcinoma who had previously received platinum-based therapy and anti–programmed cell death protein 1 or ligand 1 (PD-1/L1) therapy.¹ According to the investigators, enfortumab vedotin is the first antibody-drug conjugate targeting Nectin-4 in clinical development. Nectin-4 is highly expressed in urothelial carcinoma.

Jonathan E. Rosenberg, MD

As related by the investigators, Nectin-4 is a transmembrane protein in the Nectin family of cell-adhesion molecules involved in cellular processes associated with oncogenesis. It is highly expressed in a number of solid tumors, including breast, gastric, and lung carcinomas, in addition to urothelial carcinomas; it is weakly to moderately expressed in normal skin.

Study Details

The current report provides findings from cohort 1 of the trial; enrollment is ongoing in cohort 2, which includes patients with just prior anti–PD-1/L1 therapy.

In the study, 125 evaluable patients with metastatic disease from 51 sites in the United States (n = 117) and Japan (n = 8) were enrolled between October 2017 and July 2018; they were treated with intravenous enfortumab vedotin at 1.25 mg/kg on days 1, 8, and 15 of 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or investigator decision. The primary endpoint was objective response rate based on Response Evaluation Criteria in Solid Tumors v1.1 on blinded independent central review.

Among the 125 patients, the median age was 69 years (27% ≥ 75 years); the Eastern Cooperative Oncology Group (ECOG) performance status was 0 for 32% and 1 for 68%; histology was urothelial carcinoma alone in 67%, with squamous differentiation in 12% and other variants in 21%; the sites of metastasis were lymph nodes alone in 10% and visceral in 90%, including in the bone in 41%, liver in 40%, and lungs in 42%.

Patients had received a median of three systemic therapies (range = 1–6; ≥ 3 in 50%) for locally advanced or metastatic disease. Prior anti–PD-1/L1 treatment produced a response in 20% of patients and no response in 80%. PD-L1 expression status using Combined Positive Score (CPS) was less than 10 in 65% and at least 10 in 35%. All 120 patients with adequate tissue for testing had tumor biopsies positive for Nectin-4 expression.

Response Rates

The median follow-up was 10.2 months. An objective response was observed in 55 patients (44%), with a complete response in 15 (12%). An additional 35 patients (28%) had stable disease. Target lesions were reduced in 92 of 110 evaluable patients (84%). The median time to response was 1.84 months (range = 1.2–9.2 months), with most responses being identified at first disease assessment. The median duration of response was 7.6 months (range = 0.9–11.3 months); at the time of analysis, 44% of responders had ongoing responses.

Response rates by subgroups included the following data: 47% and 35% in patients aged < 75 and ≥ 75 years; 60% and 36% in patients with an ECOG performance status of 0 and 1; 51% and 33% in those with a Bellmunt risk score of 0 to 1 and ≥ 2; 38% and 48% in those with and without liver metastases; 47% and 41% in those with one to two and at least three prior therapies in the metastatic setting; 39% and 47% in those with upper tract and bladder/other primary tumor site; 56% and 41% in those with and without a response to prior anti–PD-1/L1 treatment; and 47% and 36% in those with PD-L1 expression of CPS < 10 and CPS ≥ 10.

The estimated median progression-free survival was 5.8 months (95% confidence interval [CI] = 4.9–7.5 months). The estimated median overall survival was 11.7 months (95% CI = 9.1 months to not reached).

Adverse Events

The most common treatment-related adverse events of any grade were fatigue (50%), peripheral neuropathy (50%), alopecia (49%), rash (48%), decreased appetite (44%), and dysgeusia (40%). Treatment-related grade ≥ 3 adverse events occurred in 54% of patients, with the most common being neutropenia (8%), anemia (7%), fatigue (6%), and rash/maculopapular (4%). Treatment-related serious adverse events occurred in 19% of patients, with the most common being febrile neutropenia (4%). Treatment-related adverse events led to discontinuation of treatment in 12%, with the most common cause being peripheral sensory neuropathy (6%).

The investigators observed: “[T]he objective response rate of enfortumab vedotin monotherapy in this study is similar to that of gemcitabine and carboplatin in the first-line setting, which suggests that treatment earlier in the disease course should be explored in clinical trials.”

They concluded: “[E]nfortumab vedotin is the first antibody-drug conjugate targeting Nectin-4 in clinical development, and the antitumor activity observed in EV-201 validates Nectin-4 as a therapeutic target in urothelial carcinoma. In cohort 1 patients who previously received platinum and anti–PD-1/L1 therapies, enfortumab vedotin has a 44% objective response rate and a 12% complete response rate. Data reported here demonstrate that enfortumab vedotin has the potential to change the treatment landscape of metastatic urothelial carcinoma.” ■

DISCLOSURE: The study was supported by Seattle Genetics and Astellas Pharma. Dr. Rosenberg owns stock or other ownership interests in Illumina; has received honoraria from UpToDate, Bristol-Myers Squibb, AstraZeneca, Medscape, Vindico, Peerview, Chugai Pharma, Research To Practice, Intellisphere, Clinical Care Options, and Clinical Mind; has had a consultant/advisory role for Lilly, Merck, Agensys, Roche/Genentech, AstraZeneca/MedImmune, Bristol-Myers Squibb, EMD Serono, Seattle Genetics, Bayer, Inovio Pharmaceuticals, BioClin Therapeutics, QED Therapeutics, Adicet Bio, Sensei Biotherapeutics, Fortress Biotech, Pharmacyclics, Western Oncolytics, GlaxoSmithKline, Janssen Oncology, and Astellas Pharma; has received research funding from Mirati Therapeutics, Novartis, Viralytics, Genentech/Roche, Incyte, Seattle Genetics, Bayer, AstraZeneca, QED Therapeutics, Astellas Pharma, and Jounce Therapeutics; has received institutional patents/royalties fora predictor of platinum sensitivity; has received travel/accommodation expenses from Genentech/Roche and Bristol-Myers Squibb. For full disclosures of the study authors, visit jco.ascopubs.org.

REFERENCE

1. 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.