Padcev Keytruda Combo Garners Breakthrough Therapy Designation for Urothelial Cancer
By Ruchi Jhonsa, Ph.D.
Jointly developed by Seattle Genetics, Inc. and Astellas Pharma Inc., PADCEV in combination with Merck’s KEYTRUDA received a breakthrough therapy designation from the FDA to expedite its development for treating life-threatening locally advanced or metastatic urothelial cancer. Looking at the unmet need, the FDA had already granted accelerated approval to PADCEV in December last year.
Platinum containing chemotherapy is a standard therapy for treating urothelial cancer, which accounts for more than 90% of bladder cancers today. However, it is not suitable for all patients. This new combo therapy gives hope to patients who cannot be treated with this prevailing chemo regimen. PADCEV in combination with KEYTRUDA is advised for patients whose tumor has grown too big to be surgically removed (locally advanced) or has spread into other parts of the body (metastatic) and are unable to receive cisplatin-based chemotherapy because of kidney impairment.
“This is an important step in our investigation of PADCEV in combination with pembrolizumab as first-line therapy for patients with advanced urothelial cancer who are unable to receive cisplatin-based chemotherapy,” said Roger Dansey, M.D., Chief Medical Officer, Seattle Genetics. “Based on encouraging early clinical activity, we recently initiated a phase 3 trial of this platinum-free combination and look forward to potentially addressing an unmet need for patients.”
PADCEV: A Unique Drug
Urothelial cancer begins in the cells that line the urethra, bladder, uterus and renal pelvis. Approximately, 549000 people were diagnosed with bladder cancer in 2018 globally and there were approximately 200,000 deaths worldwide.
PADCEV is a first-in-class antibody drug conjugate that binds to Nectin-4, which is highly expressed in urothelial cancer. This microtubule inhibitor conjugate binds to Nectin-4 protein expressed on the cell surface and kills the cancer cells possibly by cell cycle arrest and apoptosis following internalization of the antibody drug conjugate that releases anti-tumor agent monomethyl auristatin E (MMAE) into the cell.
Successful Clinical Trial Data
The EV-103 trial is an ongoing, multi-cohort, open-label, multicenter phase 1b/2 trial that evaluates safety, tolerability and efficacy of PADCEV alone or in combination with pembrolizumab (Keytruda) in muscle-invasive, locally advanced and first-and second-line metastatic urothelial cancer. The Breakthrough Therapy designation was an outcome of encouraging results from the dose-escalation cohort and expansion cohort-A of the phase 1b/2 trial EV-103 of PADCEV alone or in combination with pembrolizumab.
Last year, PADCEV alone received accelerated approval and breakthrough designation based on the EV-201 trial, a phase II, multicenter trial involving 125 patients with locally advanced or metastatic urothelial cancer who received prior treatment with a PD-1 or PD-L1 inhibitor and platinum-based chemotherapy. The Objective Response Rate (ORR), one of the intended primary endpoints, was assessed to be 44%. Interestingly, at the time of assessment, no signs of cancer were observed in 12% of patients. A reduction in tumor size or extent of cancer was observed in 32% of total patients. However, these gains were accompanied by some adverse side effects like peripheral neuropathy, sepsis, acute kidney injury, alopecia, and urinary tract infection.
“The FDA’s breakthrough therapy designation reflects the encouraging preliminary evidence for the combination of PADCEV and pembrolizumab in previously untreated advanced urothelial cancer to benefit patients who are in need of effective treatment options,” said Andrew Krivoshik, M.D., Ph.D., Senior Vice President, and Oncology Therapeutic Area Head, Astellas. “We look forward to continuing our work with the FDA as we progress our clinical development program as quickly as possible.”
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