In a setback for Astrazeneca plc's plans to tackle previously untreated cases of advanced bladder cancer, neither its immune checkpoint inhibitor, Imfinzi (durvalumab), nor a pairing of it with the investigational drug tremelimumab beat standard-of-care (SOC) chemotherapy in improving overall survival (OS) during a phase III trial evaluating the treatments as first-line (1L) care for patients with advanced disease.

Astrazeneca, which owns both drugs, has already gained approval for using Imfinzi to treat advanced bladder cancer after SOC. But the combination of it with tremelimumab was expected to yield even greater antitumor activity than either drug could deliver alone.

Bladder cancer has always been expected to represent a relatively small fraction of Imfinzi's revenues. But SVB Leerink analyst Andrew Berens said that its failure to demonstrate an OS benefit in front-line care for the indication "could diminish Imfinzi's position" in that market "and hamper the clinical development to move to earlier line of therapy."

Just two agents, Merck & Co. Inc.'s Keytruda (pembrolizumab) and Roche Holding AG’s Tecentriq (atezolizumab), are already approved for 1L bladder cancer care, but only for certain patients ineligible for cisplatin-containing chemo. However, they've been challenged by trials showing lower survival in some patients with low levels of PD-L1, leading the EMA to recommend restricting their use only to patients with high levels of the cancer protein.

Still, PD-L1, the target of Imfinzi, is widely expressed in bladder tumor cells. And CTLA4, the target of tremelimumab, acts as a brake on T-cell attacks. Since combining those mechanisms has been shown to offer survival advantages over single-agent immunotherapies – e.g. Bristol Myers Squibb Co.'s Opdivo (nivolumab) plus Yervoy (ipilimumab) for melanoma – it's unsurprising that Astrazeneca has sought to combine Imfinzi and tremelimumab to fight a broad swath of cancers.

In doing so, it designed Danube, a randomized, open-label phase III trial in the 1L treatment of both cisplatin eligible and ineligible patients with unresectable, stage IV urothelial cancer (UC). Started in November 2015 to address a post-approval commitment to the FDA, the trial compared Imfinzi monotherapy or Imfinzi plus tremelimumab vs. cisplatin and gemcitabine or carboplatin and gemcitabine chemotherapy. The 1,126 participants who ultimately enrolled included those with transitional cell carcinoma of the urothelium, including renal pelvis, ureters, urinary bladder and urethra.

Neither patients whose tumors and/or immune cells showed high PD-L1 expression nor any patients, regardless of their PD-L1 expression saw better OS than those on SOC chemotherapy in the trial, according to top-line results reported March 6 by Astrazeneca.

What's to blame for the miss is unclear. Astrazeneca declined to provide an interview on Friday with anyone who might have provided insight into the failure.

Another of Astrazeneca's phase III studies in 1L metastatic bladder cancer continues to test the Imfinzi plus tremelimumab combo. Called Nile, it’s testing Imfinzi with or without tremelimumab with SOC chemotherapy followed by Imfinzi monotherapy vs. SOC alone. Further testing of Imfinzi plus tremelimumab is underway in head and neck cancer, 1L hepatocellular carcinoma and non-small-cell lung cancer.

But the medical need for new options remains great. UC, the most common form of bladder cancer and the target of both Astrazeneca's study and a Keytruda combo trial, is the 10th most common cancer worldwide. It was responsible for about 200,000 deaths globally in 2018, according to the International Agency for Research on Cancer and will be diagnosed in about 81,000 people in the U.S. this year, according to the American Cancer Society.

Merck, Roche and Astrazeneca have all sought to extend their reach to the broader first-line patient populations across numerous cancer types and to supplant first-line chemo. Now, without the specter of immediate competition from Astrazeneca in 1L bladder cancer, Merck is proceeding with a phase III trial testing Keytruda plus Padcev (enfortumab vedotinb, Seattle Genetics Inc. and Astellas Pharma Inc.). The trial, which includes patients with previously untreated locally advanced or metastatic urothelial cancer, recently received an FDA breakthrough therapy designation.

Astrazeneca's American depository shares (NYSE:AZN) fell 1.8% to $47.52 on Friday.

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