On April 3, 2023, enfortumab vedotin-ejfv with pembrolizumab was granted accelerated approval for patients with locally advanced or metastatic urothelial carcinoma ineligible for cisplatin-con­taining chemotherapy.^1,2 Enfortu­mab ­vedotin-ejfv is an antibody-drug conjugate targeting nectin 4.

Supporting Efficacy Data

Approval was based on findings from the EV-103/KEYNOTE-869 study (ClinicalTrials.gov identifier NCT03288545), in which 121 patients with no prior systemic therapy for locally advanced or metastatic disease received enfortumab vedotin at 1.25 mg/kg on days 1 and 8 of a 21-day cycle, followed at approximately 30 minutes by pembrolizumab at 200 mg on day 1. Patients receiving the combination were from single-arm cohorts (dose-escalation, n = 5; cohort A, n = 40) or cohort K (n = 76), which compared the combination with enfortumab vedotin.

An objective response on blinded independent central review was observed in 68% patients (95% confidence interval [CI] = 59%–76%), with a complete response in 12%. Median duration of response was 22 months (range = 1+ to 46+ months) in the dose-escalation cohort and cohort A; it was not reached (range = 1 to 24+ months) in cohort K.

How It Is Used

The recommended enfortumab vedotin dose is 1.25 mg/kg (up to a maximum of 125 mg for patients ≥ 100 kg) on days 1 and 8 of a 21-day cycle until disease progression or unacceptable toxicity.

The recommended pembrolizumab dose, administered after enfortumab vedotin when given on the same day, is 200 mg every 3 weeks or 400 mg every 6 weeks until disease progression, unacceptable toxicity, or up to 24 months.

Safety Profile

Among the 121 patients in the EV-103/KEYNOTE-869 trial, the most common adverse events of any grade were rash (71%), peripheral neuropathy (65%), fatigue (60%), alopecia (52%), decreased weight (48%), diarrhea (45%), and pruritus (40%). The most common grade 3 or 4 adverse events included rash (21%), urinary tract infection (12%), and fatigue (11%). The most common grade 3 or 4 laboratory abnormalities were increased lipase (32%), hyponatremia (19%), and lymphopenia (17%).

Serious adverse events were reported in 50% of patients, most commonly acute kidney injury (7%), urinary tract infection (7%), urosepsis (5%), hematuria (3.3%), pneumonia (3.3%), pneumonitis (3.3%), and sepsis (3.3%). Adverse events led to discontinuation of enfortumab vedotin in 36% of patients, most commonly because of peripheral neuropathy (20%) and rash (6%) and to discontinuation of pembrolizumab in 32%, most commonly on account of pneumonitis (5%) and peripheral neuropathy (5%). Fatal adverse events occurred in 5%, including sepsis (1.6%), bullous dermatitis (0.8%), myasthenia gravis (0.8%), and pneumonitis (0.8%).

Enfortumab vedotin has a boxed warning for severe and fatal cutaneous adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. It has warnings/precautions for hyperglycemia, pneumonitis/interstitial lung disease, peripheral neuropathy, ocular disorders, infusion-site extravasation, and embryofetal toxicity.

Pembrolizumab has warnings/precautions for immune-mediated adverse reactions, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis with renal dysfunction, dermatologic reactions, and solid organ transplantation rejection; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation; and embryofetal toxicity. 

REFERENCES

1. Padcev (enfortumab vedotin-ejfv) for injection for intravenous use prescribing information, Agensys, Inc, and Seagen Inc, April 2023. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761137s018.pdf. Accessed April 10, 2023.

2. Keytruda (pembrolizumab) injection for intravenous use prescribing information, Merck & Co, Inc, April 2023. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/125514s136.pdf. Accessed April 10, 2023.