At ESMO 2020, I had the honor of presenting the final results for KEYNOTE-361, which was an open-label, randomized, 3-armed trial in first-line untreated-previously metastatic urothelial carcinoma. The three arms were cytotoxic chemotherapy-- both cisplatin and carboplatin-based, but treatment-investigator's choice. And the two interventional arms are pembrolizumab alone, and there was a combination arm of cytotoxic chemotherapy plus pembrolizumab.
Now, the background for this trial was that we have known, through multiple already-published and standard-of-care studies that immune checkpoint inhibitors, like pembrolizumab, which is an anto-PD-1 antibody, have value and efficacy in urothelial cancer. So for example, KEYNOTE-045 proved that it was better than cytotoxic chemotherapy in the second-line setting and is now standard of care.
Similarly, we have been using pembrolizumab and other immune checkpoint inhibitors in the cisplatin-ineligible patients whose tumors express PD-L1. So we have known that immune checkpoint inhibitors do have value in urothelial cancer. And this KEYNOTE-361 trial was an attempt to check if the combination of chemotherapy plus pembrolizumab would have value in the first-line setting in a different context.
And the reason for that, in urothelial cancer, particularly, where patients have multiple comorbidities and there is frailty in patients, often elderly, there is significant drop-off in a number of patients going on to subsequent lines of therapy between first-line and second-line, for example. 50% of the patients may not receive second-line therapy. Either their disease overwhelms them or the comorbidities overwhelm them. So getting effective therapies upfront, frontline, is of value if achievable, and if efficacious. So KEYNOTE-361 was one of many trials designed with that endpoint.
So the study was designed as a 3M trial, as I mentioned, with dual primary endpoint of overall survival. And PFS is just Progression-Free Survival as assessed by blinded central review comparing the cytotoxic chemotherapy plus pembrolizumab arm versus the standard-of-care chemotherapy-only arm. Unfortunately, in this study, which enrolled 1,010 patients, did not meet either of the dual primary endpoints. And therefore, it will not change practice.
So my bottom-line take-home message from this study and similar studies in this same context is that the magnitude of benefit of adding immune checkpoint inhibitors to cytotoxic chemotherapy is not large enough. Perhaps we were overambitious in assessing the treatment effect in these trials. And there is clearly a role for immune checkpoint inhibitors that will be there even after this and other negative trials in this context. But perhaps we need to be more strategic.
And one approach that has proven already to be successful is to use cytotoxic chemotherapy upfront, where its lack of selectivity maybe is because of advantage and cyto-reduce the tumor, and then put them on immunotherapy for the long-term durable remissions and durable sponsors that we know occur with these agents. So perhaps the solution is not to add them together concurrently, but rather stagger them-- chemotherapy first and then immune checkpoint inhibitors.
And this approach was successful, as presented in ASCO 2020 with the JAVELIN study, and has become the standard of care now. And therefore, I think adding them concurrently, at least at this point, because of the lack of good markers, like CPS, Combined Positive Score, was used in KEYNOTE-361, unfortunately did not discriminate between patients who would benefit from the combination versus those who do not. And therefore, our lack of good quality biomarkers in this combination approach is a significant drawback.
So for now, the standard of care has evolved into chemotherapy followed by switch maintenance, with, avelumab, for example, and another immune checkpoint inhibitor in anti-PD-L1. Until we get better biomarkers and plan for studies with smaller treatment effects, we will not be able to, for the planned time, combine them together at the same time.
Pembrolizumab and immune checkpoint inhibitors do, overall, in general, have a better safety profile than cytotoxic chemotherapy. We are all agreed on that. And the pembrolizumab-monotherapy arm was an attempt to perhaps, identify patients who could award the cytotoxic chemotherapy toxicities if we could identify them well and benefit them.
Unfortunately, at the current time, chemotherapy is still the first-line therapy of choice. There is one narrow sliver of patients who are not platin-eligible at all, either cisplatin or carboplatin. And for them, there is FDA guidance on using one on the immune checkpoint inhibitors-- pembrolizumab, for example, as the treatment first line. But other than those patients, in general, chemotherapy, whether it's cisplatin-based or carboplatin-based, followed by switch maintenance, is currently-- with the immune checkpoint inhibitor-- is the standard of care. But obviously, immune checkpoint inhibitors are associated with fewer toxicities and therefore, will have a role going forward.