FGFR Inhibition: A Novel Therapeutic Strategy - Episode 8
Sumanta Pal, MD:When you approach bladder cancer, I think it’s important to realize that it’s one of the most highly enriched tumor types for tumor mutational burden. It’s right up there with melanoma and other diseases. We did a study with Foundation Medicine highlighting the fact that on average, folks are going to have between 6 and 8 mutations per megabase. So these patients are likely to find mutations if you’re going to do next-generation sequencing [NGS]. We have a multitude of exploitable targets in bladder cancer. FGFR3 [fibroblast growth factor receptor 3] is one of them, HER2 [human epidermal growth factor receptor 2] is another one that I might potentially act upon based on some emerging data. We can think of, for instance, inhibition of CDKN2A and other targets that seem to be quite prevalent in this disease. So I would argue that NGS sequencing, or next-generation sequencing, can be particularly helpful for advanced disease.
To date, and this has been a big issue in years past, I really haven’t had much in the way of issues for getting reimbursement for next-generation sequencing. In yesteryear, when there weren’t a lot of potential applications, I think that there probably was some degree of challenge. But now that we have labels for agents like larotrectinib, for NTRK fusions, now that we, for instance, have labels for pembrolizumab in the context of MSI [microsatellite-instability high] tumors, I think it really opens up the possibility for almost all patients with advanced disease benefitting from having NGS done. With that in mind, I think that we probably have lifted some of the financial barriers when it comes to tumor testing, at least in my opinion.
But having said that, we probably need to work on some of the logistical barriers to tumor testing. I think that oftentimes when tumor tissues are getting stored, we sort of forget about that attempt to use the tissue downstream for genetic testing. It’s very important that folks try to access that tissue to the fullest extent possible. Tissue procurement services from companies like Foundation, from Caris Life Sciences, are getting much better. So you have folks out there who will help you get your hands on that tissue if necessary. And of course, I think the other big barrier to utilization of tumor testing is the timeliness of it. If you’re not getting that testing done up front, the big challenge is that by the time you need to rely on the resultslet’s say that patient has progressed in bladder cancer beyond chemotherapy and immunotherapy and now you want to treat with a targeted agent—starting the process of genomic screening at that point may actually be a little bit too late. So getting this going as quickly as possible I think is of essence.
Richard Kim, MD:For us to treat patients with FGFR2 fusion, we need to find them, right? So the way we find them is by doing NGS testing. And this is an evolving field in the era of the cholangiocarcinoma. In your practice, when do you order NGS, and when do you use it? When do you test for it, can you give us any kind of guidance in that?
Rachna Shroff, MD, MS:I spend a large portion of my time trying to educate patients and referring providers about the importance of next-generation sequencing. To me, at the time of diagnosis is when we should be ordering this, and at least if it’s not already done when they get to my clinic, I order it. A lot of that is also just knowing the difficulties and the hurdles associated with ordering it and the fact that it can take time to get those results, and sometimes you get insufficient tissue and you don’t get the actual answer you want. And so I almost always immediately order it. And then if I need to start chemotherapy or a clinical trial in the meantime, I do that. But I order it in parallel because it is absolutely driving clinical decision making, at least as early as after GEM-CIS [gemcitabine/cisplatin]. And now with these trials that are coming, it’s going to drive decision making in the frontline setting.
Richard Kim, MD:I completely agree with you. I think all patients who are diagnosed with advanced cholangiocarcinoma should get NGS testing upfront, not only for FGFR fusions, but other action mutations as well. IDH1, there’s BRAF, MMR [major molecular response] status. So those are very helpful in terms of managing those patients. I completely agree with you, they have to be tested at the beginning. The only problem we see sometimes is lack of tissue. You know especially if you have perihilar tumor or distal, you may have just the FNA [fine needle aspiration]. I think that’s sort of the area where we struggle, we try to send for NGS but we don’t have enough tissue. What is your opinion on liquid biopsy? Do you use it in your practice? Do you think it’s helpful if you don’t have enough tissue left?
Rachna Shroff, MD, MS:I think liquid biopsies have become my backup plan. As you mentioned, the perihilar extrahepatic tumors are usually ones where we have the biggest difficulty with this. And so I always try for tissue first. Especially in the FGFR2 fusion world, that is probably the best way to identify those. There are so many partners for theFGFR2gene, and some of these panels don’t look for every single one of those partners. And you don’t want to miss an FGFR2 fusion obviously. But in the perihilar and extrahepatic setting, for instance, FGFR2 fusions are not as relevant. They’re seen in intrahepatic cholangiocarcinoma, and so I absolutely think something is better than nothing, and those are the situations in which I order the liquid biopsy option so that I can at least be looking for HER2 alterations or BRAF, as you mentioned, and those types of things. But it’s my second choice.
Transcript edited for clarity.