The U.S. Food and Drug Administration (FDA) has granted Padcev ( Enfortumab vedotin-ejfv; Enfortumab vedotin ) with Pembrolizumab ( Keyrtruda ) accelerated approval in the U.S. as a combination therapy for the treatment of adult patients with locally advanced or metastatic urothelial cancer ( la/mUC ) who are not eligible to receive Cisplatin-containing chemotherapy.
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication is contingent upon verification and description of clinical benefit in the EV-302 confirmatory trial.
The U.S. Prescribing Information for Padcev includes Boxed Warning for serious skin reactions as well as the following Warnings and Precautions: hyperglycemia, pneumonitis/interstitial lung disease, peripheral neuropathy, ocular disorders, infusion site extravasation, and embryo-fetal toxicity.
The approval is based on objective response rates ( ORR ) and median duration of response ( DOR ) in combined Dose Escalation / Cohort A and Cohort K of the phase 1b/2 EV-103 trial ( also known as KEYNOTE-869 ).
In these EV-103 cohorts, patients treated with Enfortumab vedotin in combination with Pembrolizumab ( n=121 ) obtained a 68% confirmed ORR ( 95% CI: 58.7 to 76.0 ) per RECIST v1.1 by blinded independent central review ( BICR ), with 12% of patients experiencing a complete response and 55% of patients experiencing a partial response.
The median DOR per BICR for Dose Escalation/Cohort A was 22.1 months ( range: 1.0+ to 46.3+ ) and was not reached ( range: 1.2 to 24.1+ ) for Cohort K.1
The median number of treatment cycles ( per 21-day treatment cycle ) was nine in Dose Escalation / Cohort A and 11 in Cohort K.
The most common adverse reactions ( 20% or more ), including laboratory abnormalities, in patients treated with Enfortumab vedotin in combination with Pembrolizumab were glucose increased ( 74% ), aspartate aminotransferase increased ( 73%) , rash ( 71% ), hemoglobin decreased ( 69% ), creatinine increased ( 69% ), peripheral neuropathy ( 65% ), lymphocytes decreased ( 64% ), fatigue ( 60% ), alanine aminotransferase increased ( 60% ), sodium decreased ( 60% ), lipase increased ( 59% ), albumin decreased ( 59% ), alopecia ( 52% ), phosphate decreased ( 51% ), decreased weight ( 48% ), diarrhea ( 45% ), pruritus ( 40% ), decreased appetite ( 38% ), nausea ( 36% ), dysgeusia ( 35% ), potassium decreased ( 35% ), neutrophils decreased ( 32% ), urinary tract infection ( 30% ), constipation ( 27% ), potassium increased ( 27% ), calcium increased ( 27% ), peripheral edema ( 26% ), dry eye ( 25% ), dizziness ( 23% ), arthralgia ( 23% ), and dry skin ( 21% ).
Enfortumab vedotin is a first-in-class antibody-drug conjugate ( ADC ) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer.
Nonclinical data suggest the anticancer activity of Enfortumab vedotin is due to its binding to Nectin-4-expressing cells, followed by the internalization and release of the anti-tumor agent monomethyl auristatin E ( MMAE ) into the cell, which result in the cell not reproducing ( cell cycle arrest ) and in programmed cell death ( apoptosis ).
It is estimated that approximately 82,290 people in the U.S. will be diagnosed with bladder cancer in 2023.
Urothelial cancer accounts for 90% of all bladder cancers and can also be found in the renal pelvis, ureter and urethra.
Approximately 12% of cases are locally advanced or metastatic urothelial cancer at diagnosis.6
Globally, approximately 573,000 new cases of bladder cancer and 212,000 deaths are reported annually. ( Xagena )
Source: Astellas & Seagen, 2023