Treatment of Locally Advanced or Metastatic Urothelial Cancer

Standard Administration Protocol

The National Comprehensive Cancer Network recommends that Keytruda (pembrolizumab) and Padcev (enfortumab vedotin) be administered together as a combination regimen, not sequentially, for the treatment of locally advanced or metastatic urothelial cancer, with a median overall survival of 31.5 months and a median progression-free survival of 12.5 months 1
The combination regimen has a complete response rate of 29.1% compared to 12.5% with chemotherapy, and is designated as Category 1 (highest level of evidence and consensus) by the NCCN panel 1

The phase III EV-302 trial established the combination of enfortumab vedotin and pembrolizumab as the preferred first-line regimen for locally advanced or metastatic urothelial cancer, with a hazard ratio of 0.47 for overall survival and 0.45 for progression-free survival compared to chemotherapy 1

The American Society of Clinical Oncology recommends evaluating pre-existing neuropathy severity before initiating treatment, as this is a risk factor for worsening chemotherapy-induced peripheral neuropathy (CIPN) 2
The National Comprehensive Cancer Network recommends assessing for other treatable causes of neuropathy, such as vitamin B12 deficiency and hypothyroidism, and documenting baseline neuropathy symptoms using a numeric scale (0-10) and functional impact 3
Duloxetine is the only evidence-based treatment for painful CIPN, and should be started at 20 mg daily for one week, then increased to 40 mg daily 4

The National Comprehensive Cancer Network recommends alternative first-line options, including cisplatin-based or carboplatin-based chemotherapy, gemcitabine/cisplatin plus nivolumab, and pembrolizumab monotherapy, if the patient cannot tolerate the enfortumab vedotin plus pembrolizumab combination due to severe pre-existing neuropathy or other contraindications 1

The European Society for Medical Oncology (ESMO) and National Comprehensive Cancer Network (NCCN) recommend enfortumabe vedotin + pembrolizumabe as a preferred first-line regimen, regardless of cisplatin eligibility, with a Level of Evidence I, Grade A recommendation 5, 6
Patients with pre-existing peripheral neuropathy should be evaluated for baseline severity before initiating treatment, and those with incapacitating neuropathy should consider alternative regimens 7
Patients with a history of severe immune-mediated reactions, such as pneumonitis or interstitial lung disease, should have their treatment delayed until resolution 7

Peripheral neuropathy occurs in 56.4% of patients (grade 3 in 6.8%), with discontinuation in 15-20% of cases, and requires careful monitoring and management 7
Skin reactions occur in 68-71% of patients (grade 3 in 15-21%), and are a common cause of discontinuation after neuropathy 7
Hyperglycemia (grade 3) occurs in 6.1-14% of patients, and requires baseline screening and management with metformin or insulin 7

Patients with uncontrolled diabetes should have their condition managed before initiating treatment, but it is not an absolute contraindication 7
Patients with a history of myasthenia gravis or recent onset should be evaluated with extreme caution 6
Patients with a history of muscular disease should have their baseline muscle enzymes monitored 6

The benefit of survival (median OS 31.5 vs 16.1 months) outweighs the risks in carefully selected patients with compromised renal function 6
Permanent discontinuation occurs in 35-36% of patients, but reflects adequate management of toxicities rather than treatment failure 8