AstraZeneca's Imfinzi, tremelimumab fail to improve OS versus chemotherapy in bladder cancer study

AstraZeneca announced Friday that a Phase III study investigating the PD-L1 inhibitor Imfinzi (durvalumab), both as monotherapy and in combination with the anti-CTLA4 antibody tremelimumab, as a first-line treatment for patients with unresectable, stage IV bladder cancer failed to meet the primary endpoints of improving overall survival (OS) versus standard-of-care chemotherapy.

Specifically, the company noted that in the DANUBE trial, Imfinzi monotherapy did not improve OS in patients whose tumour cells and/or tumour-infiltrating immune cells express high levels of PD-L1, while the combination of Imfinzi and tremelimumab failed to improve OS in patients regardless of their PD-L1 expression. José Baselga, executive vice president of oncology R&D, said the results "will inform our comprehensive Phase III development programme in bladder cancer."

The DANUBE study included both cisplatin-eligible and -ineligible patients with unresectable, stage IV urothelial cancer, including those with transitional cell carcinoma of the urothelium lining the renal pelvis, ureters, urinary bladder and urethra. Subjects were randomised to receive Imfinzi monotherapy or Imfinzi plus tremelimumab, versus cisplatin and gemcitabine or carboplatin and gemcitabine chemotherapy.

AstraZeneca noted that the trial was conducted as a post-approval commitment after the FDA granted accelerated approval to Imfinzi in 2017 for use in previously treated patients with advanced bladder cancer. Further data from the study will be presented at a future medical meeting.

Commenting on the results, analysts at Liberum said "this is disappointing and makes [Imfinzi] ever more reliant on the early-stage lung cancer indication where it has shown a very clear benefit." AstraZeneca recently reported that sales of Imfinzi in the fourth quarter of 2019 grew 62% year-over-year to $424 million, with the drug expected to generate revenue of $2 billion this year, rising to $4 billion by 2024.

Imfinzi is also being investigated in patients with unresectable, locally advanced or metastatic bladder cancer in the Phase III NILE trial, either in combination with chemotherapy or with chemotherapy and tremelimumab. In addition, Imfinzi is being tested in earlier stages of bladder cancer in the late-stage NIAGARA study in combination with chemotherapy, and in the Phase III POTOMAC trial in combination with standard-of-care Bacillus Calmette-Guérin immunotherapy.

In October last year, AstraZeneca reported that in the Phase III POSEIDON study, the addition of Imfinzi to chemotherapy significantly improved progression-free survival (PFS) in patients with previously-untreated stage IV non-small-cell lung cancer (NSCLC) versus chemotherapy alone. Moreover, the triple combination of Imfinzi plus tremelimumab and chemotherapy was also associated with significantly extended PFS over chemotherapy alone.

However, the combination of Imfinzi and tremelimumab previously failed to significantly improve either PFS or OS in patients with EGFR and ALK wild-type, locally-advanced or metastatic NSCLC who express PD-L1 on at least 25% of their cancer cells in the Phase III MYSTIC trial. Further, Imfinzi plus tremelimumab also failed to hit the main OS goal in the Phase III NEPTUNE study, which compared the combination against standard chemotherapy in previously untreated patients with stage IV NSCLC.

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