Durvalumab in Bladder Cancer Indication Voluntarily Withdrawn from US Market

The durvalumab indication as a treatment for previously treated adult patients with locally advanced or metastatic bladder cancer has been voluntarily withdrawn in the United States by AstraZeneca, the developer of the PD-L1 inhibitor, the company announced in a press release.

The durvalumab (Imfinzi) indication as a treatment for previously treated adult patients with locally advanced or metastatic bladder cancer has been voluntarily withdrawn in the United States by AstraZeneca, the developer of the PD-L1 inhibitor, the company announced in a press release.1 The decision for withdrawal was made in consultation with the FDA.

“The science of immunotherapy has moved swiftly over the past few years, bringing new options to patients at an unprecedented pace. While the withdrawal in previously treated metastatic bladder cancer is disappointing, we respect the principles FDA set out when the accelerated approval pathway was founded and remain committed to bringing new and innovative options to patients. In the last 3 years, Imfinzi has become an important standard of care in multiple lung cancer settings, an area of considerable focus for AstraZeneca,” David Fredrickson, executive vice president, Oncology Business Unit, AstraZeneca, said in a statement.

The indication of durvalumab was granted in May 2017 as an accelerated approval by the FDA based on findings from the phase 1/2 Study 1108 (NCT01693562). Continued approval was contingent upon results from a confirmatory trial, which was the phase 3 DANUBE trial (NCT02516241). However, the trial did not meet its primary end points.

Withdrawal was aligned with the FDA guidance for evaluating indications with accelerated approvals that did not confirm benefit as part of their post-marketing requirements. The withdrawal, however, does not impact other indications for durvalumab within or outside of the United States as well as for this indication outside of the United States.

Study 1108 was an open-label study that explored the safety and efficacy of durvalumab in patients with advanced solid tumors. In a group of 191 patients with locally advanced or metastatic urothelial carcinoma who received 10 mg/kg intravenous durvalumab every 2 weeks for up to a year or until disease progression or unacceptable toxicity.2

Patients had a median age of 67.0 years and stage IV disease; 99.5% of patients were previously treated, with 95.3% receiving prior platinum therapy.

The primary end points were safety and confirmed objective response rate (ORR) by blinded independent central review per RECIST 1.1 criteria.

After a median follow-up of 5.78 months (range, 0.4-25.9), the ORR was 17.8% (95% CI, 12.7%-24.0%), which included complete responses in 7 patients. Patients with high PD-L1 expression had an ORR of 27.6% (95% CI, 19.0%-37.5%), and those treated in the second line or beyond after platinum had an ORR of 17.6% (95% CI, 12.3%-23.9%).

The median progression-free survival (PFS) was 1.5 months (95% CI, 1.4-1.9) and the median overall survival (OS) was 18.2 months (95% CI, 8.1 – not estimable). At 1 year, the PFS rate was 16% (95% CI, 10%-23%) and the OS rate was 55% (95% CI, 44%-65%).

Treatment-related adverse events (TRAEs) were reported in 60.7% of patients, with the most common events being fatigue (19.4%), decreased appetite (9.4%), diarrhea (8.4%), and rash (7.3%). Grade 3/4 TRAEs were observed in 6.8% of patients. TRAEs led to death in 2 patients due to autoimmune hepatitis in one patient and pneumonitis in another.

DANUBE is an open-label, multicenter, randomized, controlled trial of patients with previously untreated, unresectable, locally advanced, or metastatic urothelial carcinoma. The trial randomized patients equally between 3 treatment arms: durvalumab monotherapy at 1500 mg intravenously every 4 weeks, durvalumab 1500 mg plus tremelimumab 75 mg intravenously every 4 weeks for up to 4 doses then followed by durvalumab maintenance 1500 mg every 4 weeks, or standard-of-care chemotherapy for up to 6 cycles. Standard-of-care chemotherapy consisted of gemcitabine plus cisplatin or gemcitabine plus carboplatin, depending on cisplatin eligibility.3

The primary end points were OS of durvalumab monotherapy versus chemotherapy in patients with high PD-L1 expression (≥25% of tumor or immune cells; n = 621) as well as OS of durvalumab and tremelimumab versus chemotherapy in the intention to treat (ITT) population.

A total of 1032 patients were randomized between the 3 arms and followed for a median of 41.2 months (range, 37.9-43.2).

Among patients with high PD-L1 expression, the median OS was 14.4 months (95% CI, 10.4-17.3) in the durvalumab monotherapy arm versus 12.1 months (95% CI, 10.4-15.0) in the chemotherapy arm (HR, 0.89; 95% CI, 0.71-1.11; 2-sided P = .30). Although not included in the primary analysis, the median OS was 17.9 months (95% CI, 14.8-24.2) for patients with high PD-L1 expression in the combination arm (HR vs chemotherapy, 0.74; 95% CI, 0.59-0.93).

In the ITT population, the median OS was 15.1 months (95% CI, 13.1-18.0) in the durvalumab/tremelimumab arm versus 12.1 months (95% CI, 10.9-14.0) in the chemotherapy arm (HR, 0.85; 95% CI, 0.72-1.02; 2-sided P = .075). Although not included in the primary analysis, in the ITT group patients in the durvalumab monotherapy arm had a median OS of 13.2 months (95% CI, 10.3-15.0) (HR vs chemotherapy, 0.99; 95% CI, 0.83-1.17).

The study authors noted that the proportional hazards assumption was found to be violated for both coprimary end points.

Grade 3/4 TRAEs were reported in 14% of patients treated with durvalumab monotherapy, 27% of patients treated with the combination, and in 60% of patients treated with chemotherapy. Increased lipase was the most common grade 3/4 TRAE in the monotherapy arm (2%) as well as the combination arm (5%). Serious TRAEs were observed in 9% of patients in the monotherapy arm, 23% in the doublet arm, and 16% of the chemotherapy arm. Two patients in the durvalumab arm died from toxicities of the study drug as well as 2 patients in the combination arm and 1 in the chemotherapy arm.

Durvalumab is continuing to be investigated in other bladder cancer settings, including in patients with muscle-invasive disease in the phase 3 NIAGARA trial and in non–muscle invasive disease in the phase 3 POTOMAC trial.

AstraZeneca recommended that patients with metastatic bladder cancer currently being treated with durvalumab should consult with their healthcare provider.


Voluntary withdrawal of Imfinzi indication in advanced bladder cancer in the US. News release. AstraZeneca. February 22, 2021. Accessed February 22, 2021. https://bit.ly/3dPZimL

Powles T, O’Donnell PH, Massard C, et al. Efficacy and Safety of Durvalumab in Locally Advanced or Metastatic Urothelial Carcinoma: Updated Results From a Phase 1/2 Open-label Study. JAMA Oncol. 2017;3(9):e172411. doi:10.1001/jamaoncol.2017.2411

Powles T, van der Heijden MS, Castellano D, et al; DANUBE study investigators. 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. 2020;21(12):1574-1588. doi:10.1016/S1470-2045(20)30541-6