AstraZeneca Voluntarily Withdraws Imfinzi's U.S. Indication for Previously Treated Locally Advanced or Metastatic Bladder Cancer

On February 22, AstraZeneca announced the voluntary withdrawal in the United States of the indication for Imfinzi (durvalumab) in adult patients with previously treated locally advanced or metastatic bladder cancer. This decision was reached following discussions with the U.S. Food and Drug Administration (FDA), as Imfinzi failed to meet the FDA’s post-approval confirmatory requirements for accelerated approval in this second-line bladder cancer setting. However, this action does not affect the approval status of this indication outside the United States, nor does it impact the global approval status of Imfinzi for other indications.

On May 1, 2017, the FDA granted accelerated approval for Imfinzi based on response rate and duration of response data from the Phase I/II Study 1108 (which evaluated the efficacy and safety of Imfinzi in solid tumors). The approval was for the treatment of locally advanced or metastatic urothelial carcinoma in patients who experienced disease progression during or after platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. The FDA required post-marketing Phase III studies to verify the clinical benefit and safety of Imfinzi. Subsequently, Imfinzi received FDA approval in February 2018 for the treatment of Stage III non-small cell lung cancer (NSCLC), and in March 2020, it was approved in combination with carboplatin or cisplatin plus etoposide as first-line treatment for extensive-stage small cell lung cancer (ES-SCLC).

In March 2020, the results of the confirmatory Phase III DANUBE study were published, showing that neither Imfinzi nor Imfinzi plus tremelimumab as first-line treatment for unresectable, Stage IV (metastatic) bladder cancer demonstrated a significant improvement in overall survival (OS) compared with standard therapy. At that time, analyses suggested that the FDA might re-evaluate the prior accelerated approval of Imfinzi for the second-line indication in bladder cancer.

Dave Fredrickson, Executive Vice President of AstraZeneca’s Oncology Business Unit, stated: “Significant scientific advances in cancer immunotherapy over the past few years have provided patients with numerous treatment options. Although we are disappointed by the withdrawal of the indication for Imfinzi as a second-line treatment for bladder cancer, we respect the FDA’s regulations regarding accelerated approval. We remain committed to developing more treatment options for patients. Over the past three years, Imfinzi has also become the standard of care for patients with lung cancer. For some patients with metastatic bladder cancer currently receiving Imfinzi, it is recommended that they consult their healthcare providers to determine the next steps in their treatment plan.”

Imfinzi was previously approved in 18 countries for second-line treatment of bladder cancer, achieving global sales of $2.042 billion in 2020, a year-on-year increase of 39%, primarily driven by its lung cancer indications. Imfinzi has been approved in 67 countries, including the United States, Japan, China, and Europe, for the treatment of stage III non-small cell lung cancer (NSCLC), and in 51 countries, including the United States, Japan, and Europe, for the treatment of extensive-stage small cell lung cancer (ES-SCLC).

Prior to this, a total of seven PD-1/PD-L1 inhibitors sequentially obtained marketing approval for the indication of bladder cancer: atezolizumab (Roche, May 18, 2016), nivolumab (BMS, February 2, 2017), avelumab (Merck/Pfizer, May 9, 2017), durvalumab (AstraZeneca, May 1, 2017), pembrolizumab (MSD, May 18, 2017), and tislelizumab (BeiGene, April 10, 2020).

Imfinzi has carved out its niche in the PD-1/PD-L1 landscape by excelling in phase III NSCLC sub-indications. The withdrawal of its bladder cancer indication has had a relatively limited impact on its sales revenue. In contrast, Opdivo’s revenue is primarily concentrated in lung cancer, renal cell carcinoma, and melanoma, while more than 50% of Keytruda’s revenue comes from lung cancer. Therefore, bladder cancer has remained the primary battleground for Roche’s PD-L1 inhibitor. Tecentriq was the first to be approved as a first-line treatment in April 2017, achieving global sales of CHF 2.738 billion in 2020. However, avelumab met the primary endpoint of improving overall survival (OS) in the phase III JAVELIN Bladder 100 study for first-line treatment of bladder cancer, becoming the first first-line immunotherapy to successfully improve overall survival in patients with advanced urothelial carcinoma. Approved in June 2020, it is poised to compete with Roche.