Clinical Updates on the Treatment of Advanced Cholangiocarcinoma - Episode 20
An overview of various treatment opportunities under study that are looking at using novel techniques to help personalize treatment for patients with bile duct cancers.
John L. Marshall, MD: Very good. You’ve got the floor. Why don’t you end talking about research and the future? Walk us through what the current studies are and what you’re seeing out there. Not asking you to bet on a horse, but I think we’ve got some pretty good evidence that these trials should prove positive if they’re properly enriched and well designed. Give us a sense of what currently is out there accruing.
Sameek Roychowdhury, MD, PhD: Oh, sorry. As we learn about the molecular classification of cholangiocarcinoma, certainly new therapies are coming, new ways to target the FGFR pathway, to target IDH, looking at novel subsets, for example, we alluded to earlier EGFR and ERBB2 family members, so can we come back and repurpose some existing drugs in this population. Again, mutations matter, and being able to do these studies collectively is challenging because it’s a rare cancer, looking at rarer subsets, but fortunately we’ve learned how to do this for FGFR, for IDH. The other advantage to these even smaller subsets, for example, BRAF in cholangiocarcinoma, is that the response rates, like you said in the highly selected population, are higher. So with an enrichment of the population in a disease where alternative therapies aren’t that beneficial, the bar is a little easier to do smaller studies, and that’s fortunate because we’re talking about smaller and smaller subsets of these populations. So new targeted therapies, work going on in immunotherapy as well in this population, but also new drugs that are improvements on gemcitabine or cisplatin. We’re excited to see these new opportunities, new combinations. Again, I come back to the earlier comment about keeping doctors away from our patients, who think our patients are not going to survive their cancer. There is hope, there are good therapies, don’t give up, whether it’s standard therapies or clinical trials, we’ve got great options for these patients. Don’t be afraid of this disease.
John L. Marshall, MD: Milind, I see a lot of these frontline studies are single agent versus GEM/CIS, so a non-chemo, whereas what we used to do is three drugs versus two drugs. Is it the toxicity? Is it you think they can stand alone and beat the current standard?
Milind Javle, MD: We learned from the infigratinib study, John, that patients who receive this agent in the second-line setting did much better in terms of response than the third- or subsequent-line setting. We do not know why. There may be a rationale to use these. And also they’re very effective. If you look at the response rate to gemcitabine and cisplatin, it’s in the 20% range, and in the frontline, the PFS is six months. With FGFR inhibitors, it’s certainly higher than that.
But a case can be made perhaps of combining agents. Of course, this is caveat of antiproliferative activity of IDH1, how will that combine with chemo. But it’s been done with leukemia. That’s how they use it in AML. So can we use those sort of agents in the first-line setting in combination with chemo? I think we’ll have to identify the right setting for the right drug. I certainly think first-line single agent FGFR makes sense, for some single agent, perhaps BRAF V600E makes sense. But some of the more static drugs with a low response rate, we’ll be looking at combination approaches.
John L. Marshall, MD: I’m assuming that all these frontline studies have crossover, you almost would have to.
Milind Javle, MD: Yes.
John L. Marshall, MD: So PFS being the primary endpoint?
Milind Javle, MD: Yes.
John L. Marshall, MD: Okay, alright.
Milind Javle, MD: And I would also make the comment that the FDA perhaps needs to change their standard(?) in this disease, with an accelerated approval been given in 100 patients, requiring a confirmatory like 400-patient study in, you know, 10% of cholangios. We have to be realistic in terms of expectations.
John L. Marshall, MD: Yeah, I get both sides of that argument, too. It’s nice to have safety, that when you play this out in the real world, do you learn something different than you do when you see them in centers like ours. So I do think you’re right, that somehow real-world evidence might be supporting versus these more controlled trials. But they’re real close by, I’ll drive up there and let them know that you said that. They are listening. I think to be fair, the FDA has never been, in my memory, more open to trying to get these medicines out for patients. They’ve in fact, I think, been pretty good partners, so maybe, in fact, they will listen to those kinds of pieces of advice from us in the trenches.
Sameek Roychowdhury, MD, PhD: … to the first-line studies comparing GEM/CIS and infigratinib and other formulations of that approach, meaning combination, of course, is being asked about, but also the idea of cyclical. I’ve seen a handful of patients who are great responders to GEM/CIS, then progress, get an FGFR drug in the second-line setting, do that therapy for a very long time, maybe two years, and with that long gap from their original GEM/CIS exposure, I’ve gone back to GEM/CIS and obtained responses, shrinkage of tumors. So the concept of either combination or maybe even cyclical therapy with GEM/CIS and FGFR therapy is a possibility. We don’t know yet, it has to obviously be studied in a trial to show are we really benefitting people. One advantage of doing that is we may, through a cyclical approach, lessen cumulative toxicities from either, right? Anyway, so the possibility with GEM/CIS, which is a very beneficial therapy, is out there and it’s to be determined how we’ll put them in order.
You also alluded earlier to the mutations, the subsequent mutations you think of now. You’re grateful that you’ve got multiple drugs for GIST. So we’re probably, after an FGFR inhibitor, a drug like futibatinib or other second-generation drugs. At some point, we will have an armamentarium, a mutation panel like we do for ABL, for KIT, and ALK, where we can sequentially go from different FGFR agent and retain benefit. That’s sort of in the next couple of years, that I hope we’ll start to see some of that data. But we’re excited that more FGFR drugs are coming. Even the first generation of drugs are benefitting our patients greatly, and so the second generation holds even better hope.
John L. Marshall, MD: As an aside, are we seeing FGFR fusions in other diseases and are we going to get to a pan-cancer kind of approvals for these, Milind?
Milind Javle, MD: As you know, erdafitinib is approved for bladder cancer with FGFR3 fusions, and I think we’re seeing that about 5% of patients, or perhaps even smaller, a lower number, are actually FGFR kinase mutations, in the kinase domain. Some of these drugs seem to be effective, for instance, futibatinib had some very nice data, now recently pemigatinib had a cancer discovery paper. So I think we will find multiple options in terms of both FGFR aberrations and the diseases. I’ve seen a patient with colon cancer with an FGFR fusion.
John L. Marshall, MD: I have, too. So this is going to be interesting to see how that evolves.
Sameek Roychowdhury, MD, PhD: There are a number of basket studies addressing that question right now, that’s far less common outside of cholangio and urothelial, the head-and-neck cancer, uterus cancer, that not only have fusions involving FGFR2 and 3, but also, as Milind alluded to, mutations in different parts of the gene, the kinase domain, the extracellular part of the gene and protein. My advice today is if you see a cholangiocarcinoma patient and they have an atypical FGFR mutation, find one of our academic consultants and we’ll get them on a clinical trial, because we want to know if those patients are going to benefit. In the absence of other drive mutations, a mutation that’s somatic in the tumor, that’s FGFR3, could be a novel mutation that’s actionable. I wouldn’t assume it, but we want to get those patients in clinical trials.
TRANSCRIPT EDITED FOR CLARITY