The Bladder JAVELIN 100 trial is a randomised trial which we’ve performed in bladder or urothelial cancer. Bladder cancer is the sixth most common cancer in the US and accounts for 200,000 deaths annually. First line standard treatment is platinum-based chemotherapy; the problem with that is that although most patients respond, relapse and resistance occurs and actually survival is pretty short. Second line therapy doesn’t work that well. Second line therapy is based around immune checkpoint inhibitors and immune checkpoint inhibitors at that late stage are not as effective as we’d like them to be. What the maintenance bladder trial does is it brings that second line therapy all the way forward and sequences it directly after frontline chemotherapy. So instead of waiting for the cancer to come back and treating second line, you get frontline chemotherapy and as soon as you finish the chemotherapy instead of waiting for a relapse to occur you then give the avelumab at that point.
So that was the hypothesis, that earlier intervention directly after the chemotherapy, well firstly the chemotherapy gets control of the disease which means it gives more time for the immunotherapy to work. Secondly, you’re not waiting for the cancer to come back in which case it’s probably too late for many patients. So it’s a Goldilocks effect of not too early and not too late, that’s the principle of what we did.
It’s a 700 patient randomised phase III study, metastatic urothelial cancer patients. They either have stable disease or responded to that frontline standard chemotherapy and then they are randomised to either avelumab plus best supportive care or best supportive care alone. The primary endpoint was split between overall survival in the PD-L1 positive population and overall survival in the all comer population. After a median follow-up of 19 months we showed a hazard ratio in the all comer population of 0.69 with a median overall survival of 21 months for avelumab and 14 months for best supportive care. We also showed in the PD-L1 positive population a hazard ratio, survival favouring avelumab, of 0.56. Again a landmark analysis showed a really great result.
So at that point we then looked at other factors, so subgroup analysis, forest plot analysis, and we showed it didn’t really seem to matter which type of chemotherapy you got or whether you had visceral metastasis or other factors, all seemed to benefit the avelumab arm. Progression free survival benefitted the avelumab arm. The toxicity signal was very much in line with what one would expect for the drug.
We also looked at how many patients got on to get subsequent therapy and we showed that the majority of patients in the best supportive care, 61% of patients in best supportive care, after progression went on to get subsequent therapy, which is a high proportion looking at historical controls in this environment. The majority of patients, indeed, on best supportive care who progressed ended up getting immune checkpoint inhibitors.
So, overall, the study hit its primary endpoint, delaying progression free survival in both the ITT and the PD-L1 positive population, working across broad subgroups of patients and well tolerated. So therefore we think it’s a practice changing approach which will be adopted to large groups of patients.