I’m presenting a phase II study of gemcitabine cisplatin and ipilimumab in patients with metastatic urothelial cancer.

What was the background to this study?

For years immune therapies have been used for the treatment of urothelial cancer, predominantly for the treatment of non-muscle invasive disease and there has been a sense that immune therapies might have a role in the treatment of more advanced disease but that had been under-explored. We initiated this study several years ago before the current wave of interest in PD-1 and PD-L1 blockade but based on some interesting data suggesting that in patients with localised bladder cancer CTLA4 blockade with ipilimumab caused pharmacodynamic effects and resulted in infiltration of T cells within the tumour specimen. So we reasoned that if we gave chemotherapy first we might be able to cause destruction of some cancer cells, release of tumour antigen which can then be exploited by the administration of CTLA4 blockade.

What was your method?

We used a phased treatment schedule in this study where patients received two cycles of chemotherapy along with gemcitabine and cisplatin, those were given in standard doses and schedules, and that was followed by four cycles of the combination of gemcitabine, cisplatin plus ipilimumab. Ipilimumab was given at a dose of 10mg/kg, that’s a higher dose than the dose approved for the treatment of metastatic melanoma but it was a dose that in a prior window of opportunity study where ipilimumab was given prior to cystectomy showed more marked pharmacodynamic effects. So patients received four cycles of gem cis plus ipilimumab and then after completion of that sequence of six cycles of treatment if they had at least stable disease they could go on to receive maintenance ipilimumab once every three months.

What did you find?

We enrolled 36 patients on the study and the primary endpoint was the one year overall survival rate. We chose that endpoint based on the phased treatment schedule employed and also based on data at the time that we were designing the study suggesting that immune checkpoint blockade, particularly CTLA4 blockade, might have a bigger impact on survival as compared to response or progression. So the primary endpoint was one year overall survival rate and we were seeking a one year overall survival rate of 80% as compared to historical controls with gemcitabine and cisplatin alone demonstrating one year overall survival rate of about 60%. The study design called for the regimen to be fit for further evaluation if the lower bound of the 90% confidence interval exceeded 60%.

So we enrolled 36 patients and the one year overall survival rate on the study was 59% with the lower bound of the 90% confidence interval at 41% suggesting that the study didn’t reach that primary endpoint.

What are the implications of what you’ve found?

This was actually the first study initiated to explore immune checkpoint blockade in urothelial cancer, although not the first study reported it was the first study initiated. It’s the first study reported combining chemotherapy with immune checkpoint blockade in urothelial cancer. What we found was that although this did not improve outcomes compared to historical controls, we did immune monitoring of peripheral blood both after chemotherapy alone and after the combination of chemotherapy and ipilimumab and were able to demonstrate that after chemotherapy alone we did not see any particularly detrimental effects on the circulating immunocytes, however after the addition of ipilimumab we did see an expansion of peripheral blood CD4 and CD8 cells, suggesting pharmacodynamic effects of immune checkpoint blockade even when given concurrently with chemotherapy.  While the results of this study don’t suggest that this regimen in an overall population of patients improves outcomes, this does potentially bode well for future combinations combining chemotherapy with PD-1 and PD-L1 blockade which we know has single agent activity in urothelial cancer.

What could this lead to?

The potential combinations, the logical combinations in these studies, are already being initiated, would be to combine standard chemotherapy with PD-1 and PD-L1 blockade either in a phased schedule like we did in this study or using a switch maintenance schedule where the chemotherapy is given first and after chemotherapy as long as patients aren’t progressing they go right on to receive the PD-1 or PD-L1 blockade.