The phase II KEYNOTE-057 study was a multi-cohort study evaluating pembrolizumab monotherapy in patients with high-risk non-muscle invasive disease unresponsive to BCG. Cohort 1 of the study was focussed on patients with a carcinoma in situ component with or without papillary high-risk disease. Results provided a CR rate, a complete response rate, at three months approximating 40% with a median duration of response of 16 months. About one-third of the responders maintained a response long term and these results provided the label of pembrolizumab by the US FDA for the treatment of BCG unresponsive CIS patients.
Cohort B of the study, which was the focus of the present abstract, was including patients without a CIS presenting with BTa or BT1 papillary disease without CIS after centralised review who were unresponsive, again, to BCG treatment. The treatment for these patients is still a matter of huge debate. The design of the study was the same as for Cohort A, so pembrolizumab monotherapy every three weeks according to standard schedule for up to two years of treatment. Disease assessments were done at the 12 week interval and 24 weeks and thereafter up to five years in patients who continued treatment without the evidence of high-grade recurrence.
The primary endpoint for Cohort B of the study was the 12-month disease-free survival for high-risk disease. Secondary endpoints included disease-free survival for any grade disease and progression free survival, overall survival and, of course, safety and quality of life outcomes. The primary endpoint of the study, the 12-month disease-free survival for high-risk disease, was provided as a 43% rate which was compelling also because the vast majority of the patients who developed an event in the progression-free survival analysis and the overall survival analysis, actually this event was represented by death from any cause and not by disease progression. So very few disease progression or recurrence events have been recorded after a median follow-up approximating 45 months. So a pretty decent long-term follow-up.
The safety outcomes were also quite good and confirmed the safety profile of pembrolizumab which has been already provided in several disease settings, including Cohort A of the same study. Quality of life outcomes measured by the Functional Assessment of Cancer Therapy scores provided the evidence that the rates and the scores measured at the 40-week interval and compared to baseline levels revealed a stability or a slight improvement over time in the vast majority of the patients. The results, the mean values, the mean scores, for the FACT bladder score were stable over time in patients who continued treatment without evidence of recurrence.
So, overall, the study provided quite compelling outcomes in a disease for which we do not have a solid benchmark for intravesical therapy and confirmed to be good and reliable in providing improved or stable quality of life outcomes without compromising the quality of life of these patients.
How could this affect the future treatment of bladder cancer?
It may revitalise the discussion around the treatment of papillary high-risk disease, BCG unresponsive disease, because there is a well-established path for drug registration by the FDA and drug approval by the FDA in CIS refractory disease. There are a lot of trials ongoing including patients with CIS high-risk disease BCG unresponsive but quite a few studies and quite a few evidence from the literature regarding patients without CIS with a papillary component for which we do have the suggestion and the guidance by the FDA to provide a randomised study but the problem is to identify the right benchmark towards which randomising any new drug in this disease setting. So we may re-discuss the options for therapy and the rationale, the trial design, to set new standard therapies in the near future for this patient population. It may mean expanding the indication, the current indication, for CIS or pembrolizumab.