AstraZeneca’s aspirations that Imfinzi could join the ranks of checkpoint inhibitors used in previously-untreated bladder cancer have been dealt a setback with the failure of the phase 3 DANUBE trial.
PD-L1 inhibitor Imfinzi (durvalumab) – given on its own and in combination with experimental CTLA4 inhibitor tremelimumab – wasn’t able to improve overall survival in patients with advanced (stage IV) bladder cancer that has spread to other parts of the body compared to standard chemotherapy.
In the trial, Imfinzi monotherapy was tested in patients whose tumours had elevated expression of the PD-L1 biomarker, while the combination with tremelimumab was trialled in ‘all-comer’ patients regardless of their PD-L1 status.
The failed study sets back AZ’s plans to expand Imfinzi into the first-line bladder cancer category, although it has already been granted an accelerated approval in the US for second-line use in previously-treated patients.
It also delays further competition to Roche’s rival PD-L1 inhibitor Tecentriq (atezolizumab), which became the first checkpoint inhibitor to be approved for first-line bladder cancer therapy in patients unable to receive first-line chemotherapy three years ago.
Last year, Roche also showed that Tecentriq given alongside chemotherapy was more effective than chemo alone in previously-untreated patients enrolled in the IMvigor130 trial, setting up regulatory filings that would consolidate its lead in this type of tumour.
Previously-untreated bladder cancer is split roughly 50:50 between patients who can and cannot be treated with chemotherapy, and the DANUBE trial enrolled subjects in both categories.
At the moment, Tecentriq’s only direct competitor in the frontline setting is Merck & Co’s PD-1 inhibitor Keytruda (pembrolizumab), which is also approved for first-line use in chemo-refractory bladder cancer patients.
Merck’s attempts expand the use of its drug in bladder cancer have so far also resulted in failure however, as Keytruda seemed to perform worse than chemo in the head-to-head KEYNOTE-361 trial.
DANUBE’s outcome means that for now Imfinzi will still have to jostle for position in the increasingly congested second-line bladder cancer immunotherapy category, along with other PD-1/L1 inhibitors including Bristol-Myers Squibb’s Opdivo (nivolumab) and Merck KGaA/Pfizer’s Bavencio (avelumab).
Bavencio is closing on a first-line approval however, thanks to positive results in the JAVELIN trial earlier this year which could form the basis for regulatory filings.
For tremelimumab, the trial adds another failed trial to the tally for the CTLA4 inhibitor, which remains in testing in a number of studies across different tumour types but is looking increasingly like a hopeless candidate.
AZ’s head of oncology José Baselga said that Imfinzi is still in a “comprehensive” phase 3 programme in bladder cancer.
Ongoing trials are the NILE study of the drug either in combination with chemo or chemo plus tremelimumab in advanced bladder cancer, the NIAGARA study of Imfinzi plus chemo in neoadjuvant (pre-surgery) bladder cancer treatment, and the POTOMAC study, which include subjects with non-muscle invasive bladder cancer (NMIBC) and will pair Imfinzi with MCG immunotherapy.
Keytruda became the first checkpoint inhibitor to get a green light in NMIBC earlier this year, getting FDA approval for use in BCG non-responder patients.