AstraZeneca Withdraws Durvalumab Advanced Bladder Cancer Indication From US Market


AstraZeneca has voluntarily withdrawn durvalumab from the US market for the treatment of adult patients with locally advanced or metastatic bladder cancer.

Dave Frederickson, executive vice president of the Oncology Business Unit at AstraZeneca

Dave Frederickson

AstraZeneca has voluntarily withdrawn durvalumab (Imfinzi) from the US market for the treatment of adult patients with locally advanced or metastatic bladder cancer.1

The PD-L1 inhibitor was granted an accelerated approval from the FDA in May 2017 for use in patients with locally advanced or metastatic urothelial carcinoma who have experienced disease progression during or after platinum-containing chemotherapy or who had disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

The regulatory decision had been based on data from the single-arm, phase 1/2 Study 1108, where durvalumab elicited an objective response rate (ORR) of 17.0% (95% CI, 11.9-23.3) per blinded independent central review in a total of 182 patients.2 Moreover, the median duration of response (DOR) had not been reached at the time of the data cutoff (range, 0.9+ to 19.9+ months).

Moreover, the ORR with durvalumab was even higher, at 26.3% (95% CI, 17.8-36.4) among 95 patients with a high PD-L1 expression. In 73 patients with low or no PD-L1 expression, the ORR was just 4.1% (95% CI, 0.9-11.5)

Continued approval for durvalumab was contingent on data from the phase 3 DANUBE trial, which examined frontline durvalumab with or without tremelimumab compared with standard-of-care chemotherapy in patients with unresectable, locally advanced or metastatic urothelial carcinoma. However, neither single-agent durvalumab or durvalumab/tremelimumab met the co-primary end points of overall survival compared with chemotherapy in this population.3

Following a consultation with the FDA, the pharmaceutical company decided to withdraw the bladder cancer indication from the US market. This action was done in accordance with the regulatory agency’s standard procedures for evaluating accelerated approvals that have not satisfied their post-marketing requirements, as part of a larger industry-wide assessment.

“The science of immunotherapy has moved swiftly over the past few years, bringing new options to patients at an unprecedented pace,” Dave Frederickson, executive vice president of the Oncology Business Unit at AstraZeneca, stated in a press release “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, [durvalumab] has become an important standard of care in multiple lung cancer settings, an area of considerable focus for AstraZeneca.”

In Study 1108, the median age of participants was 67 years, 64% were white, 72% were male, and two-thirds had visceral metastases in the bone, liver, or lung; 34% of patients had liver metastases. Moreover, just under half, or 41%, had a baseline creatinine clearance of less than 60 mL/min and 66% had an ECOG performance status of 1. Thirty-five percent of participants had previously received at least 2 lines of systemic treatment. Seventy percent of patients had previously received cisplatin, while 35% had prior carboplatin. Twenty percent of patients had experienced disease progression following treatment with platinum-containing neoadjuvant or adjuvant chemotherapy as their only previous line of therapy.

If they had a history of immunodeficiency, conditions that required systemin immunosuppression, a history of severe autoimmune disease, untreated central nervous system metastases, human immunodeficiency virus, active tuberculosis, or hepatitis B or C infection, they were excluded.

Participants received intravenous (IV) durvalumab at a dose of 10 mg/kg every 2 weeks for up to 1 year or until progressive disease or intolerable toxicity. Tumors were evaluated at weeks 6, 12, and 16; then, they were examined every 8 weeks for the first year and every 12 weeks thereafter.

At a median follow-up of 5.6 months, 31 patients experienced a response to treatment; this comprised 5 complete responses (CRs) and 26 partial responses (PRs). Of those who had high PD-L1 expression, 25 patients responded to durvalumab; 3 patients had CRs, while 22 had PRs. In the PD-L1–low or none cohort, only 3 patients experienced a response to the PD-L1 inhibitor; this included 1 CR and 2 PRs. Three of the patients whose PD-L1 status was not evaluable experienced a response to treatment, with 1 CR and 2 PRs.

All-grade toxicities that were experienced by 15% or more of participants comprised fatigue (39%), musculoskeletal pain (24%), constipation (21%), reduced appetite (19%), nausea (16%), peripheral edema (15%), and urinary tract infection (15%). Forty-three percent of patients experienced toxicities that were grade 3 or higher in severity and these included fatigue, urinary tract infection, musculoskeletal pain, abdominal pain, dehydration, and general physical health deterioration.

Approximately 3% of patients experienced adverse effects that resulted in treatment discontinuation. Eight patients died because of cardiorespiratory arrest, general physical health deterioration, sepsis, ileus, pneumonitis, or immune-mediated hepatitis.

The confirmatory DANUBE trial enrolled a total of 1032 patients with untreated, unresectable, locally advanced, or metastatic urothelial carcinoma. Here, participants were randomized 1:1:1 to receive IV durvalumab at 1500 mg once monthly until disease progression (n = 346); IV durvalumab at 1500 mg once monthly until progression in combination with tremelimumab at 75 mg, once monthly for up to 4 doses (n = 342); and a standard-of-care chemotherapy regimen comprised of gemcitabine plus cisplatin or carboplatin up to 6 cycles (n = 344).

Patients were stratified based on cisplatin eligibility, PD-L1 status, and presence or absence of liver and/or lung metastases.

The co-primary end points of the trial comprised overall survival (OS) for durvalumab versus chemotherapy in patients with high PD-L1 expression and OS for durvalumab/tremelimumab versus chemotherapy in the intention-to-treat (ITT) population.

Data presented during the 2020 ESMO Virtual Congress showed that the median OS for patients in the durvalumab monotherapy arm was 14.4 months compared with 12.1 months in the chemotherapy arm (HR, 0.89; 95% CI, 0.71-1.11). In the durvalumab/tremelimumab arm, the median OS was 15.1 months (HR, 0.85; 95% CI, 0.72-1.02).

The median DOR in the ITT population was 9.3 months in the single-agent durvalumab arm, 11.1 months in the durvalumab/tremelimumab arm, and 5.7 months in the chemotherapy arm. In the PD-L1–high group, the median DORs with durvalumab monotherapy, durvalumab/tremelimumab, and chemotherapy were 18.5 months, 10.0 months, and 5.8 months, respectively.

Fifty-six percent of patients experienced treatment-related toxicities in the durvalumab monotherapy arm versus 75% of those in the durvalumab/tremelimumab arm and 90% of those in the chemotherapy arm. Both single-agent durvalumab and durvalumab/tremelimumab were determined to have acceptable toxicity profiles, with no new safety signals observed.

The withdrawal does not impact the indication outside of the United States, nor does it impact other approved durvalumab indications within or outside of the United States.


  1. Voluntary withdrawal of Imfinzi indication in advanced bladder cancer in the US. News release. AstraZeneca. February 22, 2021. Accessed February 22, 2021.
  2. Durvalumab (Imfinzi). News release. FDA. May 1, 2017. Accessed February 22, 2021.
  3. Powles TB, van der Heijden MS, Gauna DC, et al. A phase III, randomized, open-label study of first-line durvalumab (D) with or without tremelimumab (T) vs standard of care chemotherapy in patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE). Ann Oncol. 2020;31(suppl 4):S550-S551. doi:10.1016/j.annonc.2020.08.769
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