Durvalumab Approval Withdrawn for Urothelial Carcinoma

High-grade urothelial carcinoma.

Today, AstraZeneca voluntarily withdrew the indication of durvalumab (Imfinzi®, AstraZeneca) for patients with previously treated locally advanced or metastatic urothelial carcinoma based on results of the phase 3 DANUBE trial (NCT02516241), which did not meet its primary end points. The withdrawal does not affect durvalumab’s indications for non-small cell lung cancer or for extensive stage small-cell lung cancer.

Durvalumab, a human monoclonal antibody that binds to programmed death ligand 1 (PD-L1), was granted accelerated approval for the treatment of patients with urothelial carcinoma in May 2017 based on results of Study 1108 (NCT01693562), a single-arm phase 1/2 trial. Continued approval was contingent on efficacy data from DANUBE, which randomized 1,032 patients with locally advanced or metastatic urothelial carcinoma to receive 1,500 mg durvalumab once every four weeks; 1,500 mg durvalumab plus 75 mg tremelimumab every four weeks followed by durvalumab maintenance every four weeks; or standard-of-care chemotherapy consisting of gemcitabine in combination with cisplatin or carboplatin for up to six cycles. The primary end points were overall survival in patients with high programmed death ligand 1 (PD-L1) expression in patients receiving durvalumab alone and in patients receiving durvalumab/tremelimumab regardless of programmed death ligand 1 (PD-L1) status.

In patients with high PD-L1 expression, durvalumab produced a median overall survival of 14.4 months compared with 12.1 months for chemotherapy, a difference which was not statistically significant (hazard ratio 0.89, 95% confidence interval 0.71–1.11). In the intention-to-treat population, the median overall survival was 15.1 months with durvalumab/tremelimumab compared with 12.1 months with chemotherapy, a difference which was also not statistically significant (hazard ratio 0.85, 95% confidence interval 0.72–1.02). Grade 3/4 adverse events occurred in 14% of patients receiving durvalumab alone, 27% of those receiving durvalumab/tremelimumab, and 60% of those receiving chemotherapy. Serious treatment-related adverse events were experienced by 9% of patients receiving durvalumab, 23% of those receiving durvalumab/tremelimumab, and 16% of those receiving chemotherapy.

“This study did not meet either of its coprimary end points,” concluded the investigators, led by Thomas Powles, MD, MBBS, MRCP, Director of Barts Cancer Institute of Queen Mary University of London, in their September 2020 publication of the trial’s results in Lancet Oncology. “Further research to identify the patients with previously untreated metastatic urothelial carcinoma who benefit from treatment with immune checkpoint inhibitors, either alone or in combination regimens, is warranted.”

For More Information

Powles T, van der Heijden MS, Castellano D, et al (2020). Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol, 21(12):1574-1588. DOI:10.1016/S1470-2045(20)30541-6

Powles T, O’Donnell PH, Massard C, et al (2017). Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study. JAMA Oncol, 3(9):e172411. DOI:10.1001/jamaoncol.2017.2411

AstraZeneca (2021). Voluntary withdrawal of Imfinzi indication in advanced bladder cancer in the US. Available at: https://www.astrazeneca.com/media-centre/press-releases/2021/voluntary-withdrawal-imfinzi-us-bladder-indication.html

Image credit: TexasPathologistMSW. Licensed under CC BY-SA 4.0

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