On November 13, the U.S. Food and Drug Administration (FDA) approved the PD-L1 inhibitor durvalumab (Imfinzi) in combination with the antibody-drug conjugate enfortumab vedotin-ejfv as neoadjuvant treatment, followed by single-agent durvalumab as adjuvant treatment after radical cystectomy, for the treatment of adult patients with muscle-invasive bladder cancer (MIBC) who are ineligible for or who have refused cisplatin-based chemotherapy.
VOLGA
Efficacy was evaluated in VOLGA (ClinicalTrials.gov identifier NCT04960709), a randomized, open-label trial. The trial randomly assigned 695 patients with MIBC who were candidates for radical cystectomy and who were ineligible for or who refused cisplatin-based chemotherapy 1:1:1 to receive either neoadjuvant durvalumab and enfortumab vedotin prior to surgery followed by adjuvant durvalumab, radical cystectomy alone, or an additional investigational combination regimen.
The major efficacy outcome measure was event-free survival by blinded independent central review assessment. Overall survival was an additional efficacy outcome measure.
The trial demonstrated statistically significant improvements in both event-free and overall survival for durvalumab/enfortumab vedotin compared to radical cystectomy alone. Median event-free survival was not reached (95% confidence interval [CI] = 33.2 months to not reached) in the durvalumab/enfortumab vedotin arm and was 12.1 months (95% CI = 7.6–27.0 months) in the radical cystectomy alone arm (hazard ratio [HR] = 0.51, 95% CI = 0.38–0.67; two-sided P < .0001). Median overall survival was not reached in either the durvalumab/enfortumab vedotin arm or the radical cystectomy alone arm (HR = 0.58, 95% CI = 0.40–0.83; two-sided P = .0027).
The durvalumab prescribing information includes warnings and precautions for immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryo-fetal toxicities.
The most common adverse reactions occurring in > 20% of patients, including laboratory abnormalities, for durvalumab in combination with enfortumab vedotin were increased AST, increased ALT, decreased hemoglobin, rash, increased creatinine, pruritus, decreased calcium, increased lipase, increased potassium, urinary tract infection, increased amylase, fatigue, decreased sodium, decreased lymphocytes, diarrhea, decreased leukocytes, constipation, decreased appetite, increased alkaline phosphatase, dysgeusia, nausea, peripheral neuropathy, musculoskeletal pain, and alopecia.
Recommended Dosage
The recommended durvalumab dose for patients with a body weight of ≥ 30 kg is 1,500 mg every 3 weeks in combination with neoadjuvant enfortumab vedotin 1.25 mg/kg (on days 1 and 8 of each cycle) for three cycles prior to surgery, followed by durvalumab at 1,500 mg as a single agent every 4 weeks for up to nine cycles after surgery. The recommended durvalumab dose for patients with a body weight < 30 kg is 20 mg/kg every 3 weeks in combination with neoadjuvant enfortumab vedotin 1.25 mg/kg (on days 1 and 8 of each cycle) for three cycles prior to surgery, followed by durvalumab at 20 mg/kg every 4 weeks as a single agent for up to nine cycles after surgery. Treatment should continue until disease progression that precludes definitive surgery, recurrence, or unacceptable toxicity, or a maximum of nine cycles after surgery.
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence which provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, the FDA collaborated with the Australian Therapeutic Goods Administration, the Brazilian Health Regulatory Agency, Health Canada, Israel’s Ministry of Health, Singapore’s Health Sciences Authority, and the United Kingdon’s Medicines and Healthcare products Regulatory Agency. The applications may be undergoing the submission process or still be under review at the other regulatory agencies.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. The FDA approved this application 6 weeks ahead of the FDA goal date.
This application was granted Priority Review.
