Enfortumab vedotin offers hope to poor-prognosis patients with advanced urothelial cancer

Drilling down on treatment-related adverse events

As might be expected for cisplatin-ineligible patients, adverse events were higher for patients in cohort 2 than for cohort 1 and led to treatment discontinuation in 16% of patients overall.

TRAEs over grade 3 occurred in 55% of patients. TRAEs of special interest included rash (61% overall; 17% ≥ grade 3), peripheral neuropathy (54% overall; 8% ≥ grade 3), and hyperglycemia (10% overall; 6% ≥ grade 3). Dose reductions, interruptions, and physical therapy were helpful.

Twenty percent of patients with TRAE hyperglycemia had hyperglycemia at baseline, and 30% of TRAEs were in patients with high body mass index (BMI).

There were four treatment-related deaths, all in patients 75 years or older with multiple comorbidities. Three of the four deaths occurred within 30 days of first EV dose in patients with BMI of 30 or greater (acute kidney injury, metabolic acidosis, and multiple organ dysfunction syndrome). The remaining death occurred more than 30 days after the last dose (pneumonitis).
 

Context and caution

The authors concluded that EV produced durable responses in platinum-ineligible patients with la/mUC, including 20% complete responses. Safety was felt to be as expected, given the known toxicities of the agent and the compromised medical condition of the patients studied.

The study discussant, Arlene O. Siefker-Radtke, MD, of the University of Texas MD Anderson Cancer Center, Houston, agreed that EV fills an unmet need, showing impressive responses in patients with visceral, liver, and bone metastases. She agreed that EV should be investigated across the spectrum of urothelial cancer.

Dr. Siefker-Radtke reminded attendees that the FDA package insert for EV described a 48% increase in the area under the concentration-time curve concentration of the MMAE active moiety in patients with mild hepatic impairment and that EV use should be avoided entirely in patients with moderate to severe liver disease.

She speculated whether augmented toxicity in patients with a high BMI could be attributable to clinically occult impaired hepatic function from fatty liver infiltration.

She indicated that clinicians should monitor closely patients with higher BMI and grade 3-4 hyperglycemia or elevated hemoglobin A1c levels and advised holding EV in patients who develop:

• Glucose levels above 250 mg/dL
• Peeling skin or bullous skin lesions. These lesions can be heralded by a diffuse erythematous or papillary rash in the preceding weeks.
• Grade 3 diarrhea or mucosal membrane toxicity of other types.

Notwithstanding concerns about toxicity and the need for monitoring, EV merits continued study in combination with other agents and in additional settings in the clinical spectrum of urothelial cancer. It is an important new option for oncologists caring for patients with urothelial cancer.

The EV-201 study was funded by Seagen. Dr. Balar and Dr. Siefker-Radtke disclosed relationships with Seagen and many other companies.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.