When we think about bladder cancer, the majority of bladder cancer is urothelial carcinoma and there has been a tremendous number of advances in the treatment of urothelial carcinoma, now with multiple positive studies. We have antibody-drug conjugates, immunotherapy. But when you look at the variant histology – squamous cell, adeno, small cell – a lot of the data, the best data now, comes from studies from over 15 years ago. It really represents an unmet need.

So we’re trying to look at how do we treat these different patients and overall see in the WHO 2022 consultation, this is a wide variety of tumours. Each tumour is quite different – when we think about, ‘Oh, it’s just a variant histology,’ well, small cell carcinoma of the bladder is nowhere similar to what we see with adenocarcinoma. So it’s important when we think about this how we approach this overall. 

The first step is small cell carcinoma of the bladder is really a unique entity which needs systemic therapy, regardless of what stage you’re at, with a platinum etoposide, even for the smallest amount, with aggressive local control. 

A lot of the other histologies, if they arise in the setting of predominant urothelial carcinoma studies have shown even in the neoadjuvant setting with the VESPER trial if there’s predominant urothelial, some minority variant, that those patients do just as well as with pure urothelial. But those with pure variant histology it’s much more challenging. Really, in the localised setting pure variant histology, specifically squamous cell, adenocarcinoma, the standard of care is to go right to surgery.

When we start getting into the metastatic setting, that’s where clinical trials are very important to figure out what the best approach is. A lot of the data is based on cytotoxic chemotherapy, looking at carboplatin and taxane, [inaudible], based on a study of less than 20 patients which is still quoted to this day. 

So at Dana Farber we actually took an initiative to say, ‘Hey, can we do something more for these patients?’ We looked at the combination of nivolumab and ipilimumab in variant histologies. It was a wide trial, 60 patients were enrolled across different rare tumours. What this trial showed is we were able to enrol 60 patients with really rare tumours in less than 18 months. We saw some activity in the bladder cohort and now we’re expanding the bladder cohort. We saw some activity in the small cell and we’re expanding it. So it’s a model for these rare tumours to say, ‘Hey, we can study these. We can, we just need to work together.’ There’s really preliminary exciting data looking at the NECTIN4 and TROP2 and some of the variant histologies and it shows that it’s there. 

So as we look at these new advances in traditional urothelial carcinoma, akin to what we saw with immunotherapy, we can take that data and hopefully do similar trials, look at these variant histologies with these new agents.

With these tumours we really don’t know what is the best treatment. We saw data with nivolumab ipilimumab, a 37% objective response rate which is amazing. 50% in those patients with small cell and a lot of those were durable. We saw responses across histologies but we can do better. So, without a doubt, genomic sequencing is important. When we look at adenocarcinoma [inaudible] they do the genomic sequencing it’s far more akin to colorectal carcinoma than it is to urothelial carcinoma. So sometimes finding that germline sequencing may lead to a target that can be used and specifically a trial like the NCI-MATCH or other trials using that targeted therapy may be the approach. I think it’s always a question if we find this target does it work in that tumour, but in this area where we really are exploring new options, genomic sequencing is incredibly important as we look to try and find new targets in this situation.

So overall the treatment of variant histologies in bladder tract carcinoma really is an unmet need. As a group we can certainly work together to do more. What we showed with our trial where we were able to enrol 60 patients of rare tumours in under 18 months from four sites, that the patients are there, patients are excited to do this. So if we can work together and come up with smart designs I think it’s important. Obviously the best, the purest, approach would be, ‘We’re going to do a study in squamous cell,’ or adeno, that’s fantastic but that can take some time. So sometimes these trials including all these histologies and then looking for a signal and expanding can really be the way to move forward.