FGFR Inhibition: A Novel Therapeutic Strategy - Episode 3

Treating Advanced Bladder Cancer

June 21, 2019

Sumanta Pal, MD:Bladder cancer tends to have a male to female gender distribution similar to kidney cancer, it tends to be about 3:1 male to female. It tends to be a disease of older age. We don’t often think of it that way, but typically folks are around the age of 60 to 70 when they develop bladder cancer. And outcomes, unfortunately, have been very poor for advanced disease, but there’s a whole spectrum that ranges from non-muscle invasive, which is a disease one can live with for years, to muscle invasive, which is a scenario that requires surgical intervention, to advanced where systemic therapy is really the mainstay of treatment.

The FGFR [fibroblast growth factor receptor] inhibition in bladder cancer I feel is a very potentially potent strategy in the sense that we do have about 20% of patients who demonstrate FGFR mutations and/or fusions. In that subpopulation of patients, I’m quite convinced that FGFR is a major driver of pathogenesis of the disease. I’ll take that one step further and say that for upper tract bladder cancer, which is a less common but very aggressive subset, that rate of FGFR alteration actually jumps to somewhere in the ballpark of 50% to 70%.

For nonmuscle invasive bladder cancer, recurrence is exquisitely common. I would tell you that for nonmuscle invasive bladder cancer patients, the initial treatment is BCG [Bacillus Calmette-Guerin] intravesically, but they tend to have repeat surgeries to clear tumor, repeat administrations of BCG chronically. And it can be a very costly and troubling state for the patient.

The muscle invasive bladder cancer really straddles the line between a modality that’s treated by the urologist versus the medical oncologist. I’d say both can play equal roles in muscle invasive disease. For muscle-invasive bladder cancer, the paradigm that’s been established to date is the use of neoadjuvant chemotherapy. There have been multiple studies done using cisplatin-based chemotherapy. And if you look across these studies, it seems as though there’s about a 5% survival advantage that’s ascribed to this. That may not be meaningful in an octogenarian or a nonagenarian, but in the vast majority of patients, I think it’s actually a fairly compelling result. So typically we’ll do 4 to 6 cycles of neoadjuvant chemotherapy with a cisplatin-based regimen, if a patient can tolerate cisplatin, and then take that patient to surgery.

If I were to use the standard paradigm of neoadjuvant cisplatin-based chemotherapy followed by surgery, I would typically expect an outcome of 3-year disease-free survival, something in the ballpark of around 50%, which unfortunately implies that a lot of these patients recur. I will say that there’s a disease setting that I get even more concerned about and that’s upper tract bladder cancer. In the context of upper tract bladder cancer, recurrence rates are far higher, perhaps in the order of 50% at the 1-year mark. That, in my mind, really represents a true unmet need.

When we think about muscle-invasive bladder cancer, I had mentioned this paradigm where folks get chemotherapy followed by surgery; unfortunately we’re going to have patients who progress beyond that. I think there’s a real opportunity to explore other therapies in this setting because frankly, the standards that we have right now aren’t that great. The 2 options that one considers, if somebody recurs fairly quickly after this neoadjuvant window of treatment for muscle-invasive bladder cancer, would be further chemotherapy, the effects of that aren’t particularly desirable, or we now have FDA approved immune checkpoint inhibitors. In that setting, I think that they represent a huge treatment advance, but we’re still looking at response rates only on the order of around 20% to 30%. Progression-free survival is typically on the order of 2 to 3 months, overall survival just over a year. So I would say that we still have a long way to go in terms of better treating those patients.

Transcript edited for clarity.