AstraZeneca’s combination of Imfinzi (durvalumab) and tremelimumab has faced multiple late-stage failures within the last couple of weeks. On March 5, the combination failed to achieve its primary endpoint in the Phase III DANUBE trial (NCT02516241), and then also failed to achieve its co-primary endpoint in the Phase III CASPIAN trial (NCT03043872) on March 17, as was reported by the company. In both trials, the combination did not demonstrate statistical significance in overall survival (OS) when compared to the respective standard of care (SOC) regimens.

The DANUBE trial evaluated Imfinzi in combination with tremelimumab versus SOC in the frontline locally advanced and metastatic bladder cancer setting for patients who are ineligible for cisplatin. Early results for overall response rate (ORR) in patients with high and low/negative programmed death-ligand 1 (PD-L1) expression levels were reported to be 27.6%, and 5.1%, respectively. The median time to response was 1.41 months. Upon further analysis, the trial was not successful in showing significant difference with OS, progression free survival (PFS), and median time to response when compared to the SOC. Similarly, the CASPIAN trial evaluated the combination in frontline therapy for patients with extensive stage small cell lung cancer (ES-SCLC), where it again failed to show any improvement in OS data when compared to the platinum-based regimen for patients with ES-SCLC.

GlobalData forecasts that two consecutive failures for this combination might have a negative impact on Imfinzi‘s use as monotherapy in bladder cancer and small cell lung cancer. PD-L1 in combination with CTLA-4 has a theoretical advantage, but did not generate much excitement regarding clinical usage from key opinion leaders interviewed by GlobalData. These failures are expected to be perceived by physicians and payers as being similar to previous failures in PD-1 and IDO-1 combinations, and may raise questions regarding other combination PD-L1 and CTLA-4 agents being evaluated in late-stage clinical trials for other solid tumors.

GlobalData expects Imfinzi to be approved as a monotherapy in the frontline setting for patients with ES-SCLC in Q1–Q2 2020, as per the Prescription Drug User Fee Act (PDUFA) data issued by the FDA last year. Imfinzi is also expected to continue to be used in the locally advanced and metastatic bladder cancer settings, among other immune checkpoint inhibitors approved in bladder cancer. Furthermore, Imfinzi will continue to be evaluated in other late-stage clinical trials in combination with chemotherapies and immunotherapies. For example, Imfinzi is being studied in combination with SOC chemotherapy in the NILE trial for locally advanced metastatic bladder cancer, and with the Bacillus Calmette-Guerin vaccine in the POTOMAC trial for non-muscle invasive bladder cancer.