General Information

Padcev (enfortumab vedotin-ejfv) is a Nectin-4-directed antibody and microtubule inhibitor conjugate. Keytruda (pembrolizumab) is an anti-programmed death receptor-1 (PD-1) therapy.

The combination is specifically indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma.

When given in combination with pembrolizumab, the recommended dose of Padcev is 1.25 mg/kg (up to a maximum of 125 mg for patients ≥100 kg) administered as an intravenous infusion over 30 minutes on Days 1 and 8 of a 21-day cycle until disease progression or unacceptable toxicity. 

The recommended dose of Keytruda is 200 mg every 3 weeks or 400 mg every 6 weeks.

Mechanism of Action

Padcev (enfortumab vedotin-ejfv) is an antibody-drug conjugate (ADC). The antibody is a human IgG1 directed against Nectin-4, an adhesion protein located on the surface of cells. The small molecule, MMAE, is a microtubule-disrupting agent, attached to the antibody via a protease-cleavable linker. Nonclinical data suggest that the anticancer activity of enfortumab vedotin-ejfv is due to the binding of the ADC to Nectin-4-expressing cells, followed by internalization of the ADC-Nectin-4 complex, and the release of MMAE via proteolytic cleavage. Release of MMAE disrupts the microtubule network within the cell, subsequently inducing cell cycle arrest and apoptosis. The combination of enfortumab vedotin-ejfv with a PD-1 blocking antibody resulted in up-regulation of immune function and increased anti-tumor activity in syngeneic mouse tumor models expressing Nectin-4.

Keytruda is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. Keytruda is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Side Effects

Adverse effects associated with the use of Keytruda in combination with Padcev may include, but are not limited to, the following:

• rash
• peripheral neuropathy
• fatigue
• alopecia
• weight loss
• diarrhea
• pruritus
• decreased appetite
• nausea
• dysgeusia
• urinary tract infection
• constipation
• peripheral edema
• dry eye
• dizziness
• arthralgia
• dry skin

Clinical Trial Results

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

The approval is based on data from the KEYNOTE-869 (also known as EV-103) open-label, multi-cohort (dose escalation cohort, Cohort A, Cohort K) study in patients with la/mUC who were ineligible for cisplatin-containing chemotherapy and received no prior systemic therapy for locally advanced or metastatic disease. 

Patients in the dose escalation cohort (n=5), Cohort A (n=40), and Cohort K (n=76) received enfortumab vedotin 1.25 mg/kg as an intravenous (IV) infusion over 30 minutes on Days 1 and 8 of a 21-day cycle followed by Keytruda 200 mg as an IV infusion on Day 1 of a 21-day cycle approximately 30 minutes after enfortumab vedotin. Patients were treated until disease progression or unacceptable toxicity.

The median follow-up time for the dose escalation cohort + Cohort A was 44.7 months (range, 0.7 to 52.4 months) and for Cohort K was 14.8 months (range, 0.6 to 26.2 months). In the combined efficacy analysis of the dose escalation cohort, Cohort A and Cohort K (n=121), Keytruda in combination with enfortumab vedotin demonstrated an objective response rate (ORR) of 68%, with complete and partial response rates of 12% and 55%, respectively. The median duration of response (DOR) for the dose escalation cohort + Cohort A was 22.1 months (range, 1.0+ to 46.3+ months) and for Cohort K was not reached (range, 1.2 to 24.1+ months).

Approval was also based on data from the Phase 3 KEYNOTE-A39 trial in 886 patients with locally advanced or metastatic urothelial cancer. Keytruda plus enfortumab vedotin demonstrated a statistically significant improvement in the trial’s major efficacy endpoints of overall survival (OS) and progression-free survival (PFS) versus platinum-based chemotherapy (gemcitabine plus cisplatin or carboplatin). Keytruda plus enfortumab vedotin reduced the risk of death by 53% versus platinum-based chemotherapy. Median OS was 31.5 months for Keytruda plus enfortumab vedotin versus 16.1 months for platinum-based chemotherapy. Keytruda plus enfortumab vedotin reduced the risk of disease progression or death by 55% versus platinum-based chemotherapy. Median PFS was 12.5 months for Keytruda plus enfortumab vedotin versus 6.3 months for platinum-based chemotherapy.

The trial also demonstrated a statistically significant improvement in objective response rate (ORR) in patients randomized to receive Keytruda plus enfortumab vedotin compared with patients randomized to receive platinum-based chemotherapy. The ORR was 68% for Keytruda plus enfortumab vedotin versus 44% for platinum-based chemotherapy. For Keytruda plus enfortumab vedotin, the complete response (CR) rate was 29% and the partial response (PR) rate was 39%, and for platinum-based chemotherapy, the CR rate was 12% and the PR rate was 32%. Efficacy results (OS, PFS and ORR) were consistent across all stratified patient subgroups.