We are talking about the CREST trial and CREST is a trial which is running in the non-muscle invasive bladder carcinoma, the NMIBC, space. We know that patients have organ-confined disease in the mucosa and the submucosa but not invading the muscle, the detrusor muscle. So there are different risk categories in the NMIBC stage and the high-risk category, the high-risk stage, defined as pT1 tumours high-grade or Ta tumours high-grade plus/minus CIS was the target group of the CREST trial. Usually these patients are treated with BCG which is some kind of immunotherapy with an induction and then a maintenance period of at least two years.
The idea behind CREST was to use the subcutaneous PD-1 antibody in combination with BCG compared to BCG alone. Actually, the trial had three arms, so arm A was BCG induction maintenance plus sasanlimab, the subQ PD-1 antibody, compared to BCG induction and maintenance in arm C. The primary data release of the primary endpoint of the event free survival was significantly improved by the addition of sasanlimab as the PD-1 antibody plus BCG compared to BCG alone.
The importance of this trial is that it’s the first trial in this NMIBC space proving the additional benefit of a checkpoint inhibitor, adding that to the conventional classical scheme of BCG induction and maintenance.
What was the methodology and what were the findings?
The methodology was the intravesical application of BCG in the standard scheme. So induction is an induction period of weekly dosages over six weeks and then followed by three- and then later on six-monthly maintenance courses of three-weekly intravesical installation of BCG. Sasanlimab was given subcutaneously every four weeks for the methodology and for the application.
It's a totally new routine to go for subQ injection. We all know that the checkpoint inhibitors are usually given by the IV administration route. So I think subQ is much easier in the clinical setting, faster, more convenient for the patient of course.
The primary endpoint was event free survival and, as mentioned earlier, the event free survival was significantly improved. Event free survival was recurrence, progression, progression to cystectomy or the development of metastatic disease, significantly improved by BCG induction, maintenance plus sasanlimab.
What are the clinical implications of these findings?
The clinical implications are that we have a new kind of therapy in this specific setting of NMIBC. We learned from the trial a lot about BCG alone and saw and observed that BCG has a good efficacy in this high-risk population of NMIBC patients as an intravesical agent. But we also learned that this efficacy, in terms of increasing the rate of event free survival, by local increasing or having less local recurrences by the addition of sasanlimab further improves the good result of BCG. So we are going from good to better with this trial.
We also observed the side effects, the side effect of classical BCG side effects, and the sasanlimab proved to have the classical PD-1 side effect profile which was observed in this setting.
At this ASCO meeting we also had a more detailed subgroup analysis splitting the T1 high-grade patients, the CIS patients, and observed that specifically in patients having a CIS in combination with T1 plus/minus T1 high-grade tumours, had a more pronounced benefit of the addition of sasanlimab.
We also asked the question, and the data was presented here at the ASCO meeting, does this regimen impact the quality of life. We showed for the pro analysis by the EORTC QLQ-C30 questionnaire and also by the NMIBC24 questionnaire that there is no significant difference, not even a significant difference, between BCG and BCG plus sasanlimab. Both treatments, either BCG alone or BCG plus sasanlimab, did not have a clinically meaningful impact on the quality of life over the time but also in a more detailed analysis of a mixed effect model.
Is there anything else you would like to add?
We are moving into the next step. We also know that the second trial, the POTOMAC trial is positive, there was a press release on that. It’s in the same setting as the CREST trial. I think it’s a good signal for the whole space here, high-risk NMIBC BCG plus checkpoint, that if you have two positive trials that they are moving in the right direction.
On the other hand, we also learned that they have a side effect profile by the PD-1 inhibitors that adds on to the BCG side effect profile. It’s a question about which patient will need this therapy? Is it just CIS patients in combination with T1 high-grade, is it the T1 high-grade population? I think there will be a patient selection for these patients in this new indication.
Let’s summarise that: the field has moved forward with the checkpoint inhibitors now also to the NMIBC space.
