Precision Medicine: A New Frontier for Advanced Cholangiocarcinoma - Episode 11
Ghassan Abou-Alfa, MD, MBA: Let’s dissect the genetic makeup of those tumors more, and let’s talk a little bit more about those therapies. I’ll start with the FGFR2 [fibroblast growth factor receptor 2] fusion protein. Andrew, for all of us, it’s very important to denote that the collaboration in regard to cholangiocarcinoma is something that we are all very proud of. Because of the relative limitation of how many patients there are with the disease, this has been a very important collaborative effort that involved all the institutions, and of course, the aim is to be sure that we give the best for our patients. With this said, tell us a little bit more about the BGJ398 trial because this is something that we were both involved in.
Andrew Zhu, MD, PhD: This was perhaps the first FGFR inhibitor that was brought to clinical trial for patients with cholangiocarcinoma harboring the FGFR2 fusions. This well-conducted, multicenter phase II trial, as you correctly pointed out, really took multi-institutional effort. A lot of patients were being screened and successfully enrolled. We were able to demonstrate very definitively that in this previously heavily treated population, in which they don’t have any additional standard treatment options, when they receive this compound, they can actually produce a very impressive overall response rate approaching 20%.
Also, the data are maturing further. I think we are actually increasing the cohort; we’re having longer follow-ups. Perhaps the response rate can even be higher than what we initially reported. So I think with the response rate as well as the median progression-free survival in this cohort, there’s no doubt that this class of drug is having anti-tumor activity in this very well defined population.
Ghassan Abou-Alfa, MD, MBA: Fair enough. The BGJ398 phase II data were already reported in JCO [Journal of Clinical Oncology]. As we just heard from Dr. Zhu, the response rate was something that we’re all intrigued by. But there was also another concern brought up by the study regarding the adverse effects. But again, hands-on experience might differ per se. But let’s hear from Martin about the FGFR2s and adverse effects.
Martin Gutierrez, MD: You can classify the adverse effects seen, there are on-target and off-target adverse effects in FGFR overall. Clearly going off the off-target is mainly the diarrhea, although I have to say, one of the phase I on FGFR2s, we really didn’t encounter so much diarrhea to speak of. The on-target effects are actually more the hyperphosphatemia is the number 1 that you see, which is actually very easy to manage, stopping the drug, anti-phosphate agents, and diet control. Usually you can continue treating those patients. You can also see mucositis in some effect and some fatigue. Some hyponatremia as well, so some electrolyte abnormalities but just focus on those ones that are important.
There are some things in respect with the cornea and retina. I have to say we didn’t see any retinal detachments, although we see some changes in the cornea. Again, nothing to be greater than grade 2s or 3s.
Ghassan Abou-Alfa, MD, MBA: This is very important so we summarize that some of the adverse effects of the BGJ398 include the potential for diarrhea. We also heard about the hyperphosphatemia. We heard about stomatitis and we heard about the retinal detachment that can occur on a rare basis. Nonetheless, it’s interesting, I would like to hear Andrea’s thoughts on the hypophosphatemia. How do you react to that?
Andrea Wang-Gilliam, MD, PhD: Well, I think it’s fairly easily manageable. In a sense, it’s just regular clinical management. You do check their phosphate level pretty routinely. Sometimes it can be high, and sometimes it can be low actually. When it’s high and you sometimes give diuretics, they can counteract diet control. If it’s low, you replace it. Patients are actually aware of that, and it doesn’t really come as a barrier for patients to continue on treatment if you manage it well.
Ghassan Abou-Alfa, MD, MBA: Fair enough. Martin, I’ll go back to you on this point, and I think it’s from your expertise in regard to phase I, etcetera. But interestingly, we are very good at reacting to things, and with hyperphosphatemia it’s, “Oh, I have to fix it.” Then interestingly, they ultimately will end up with hypophosphatemia as reported on that study.
Martin Gutierrez, MD: Right. The dynamic’s really the effect, right? You start the drug from when, day 1 to day 21, right? Day 15 you see hyperphosphatemia. You correct the hyperphosphatemia at that moment. When the patient started the drug again, because they have a holiday every week, their phosphate level may be down. That means in phase I you really want to correct the grade 3s and 4s. You don’t want the 4s and 5s, so you correct those early on in the process. Yes, you could overcorrect it in that process.
Ghassan Abou-Alfa, MD, MBA: Absolutely. This is very important again to be very careful that sometimes we probably are over-reading things. In other words, we should not react only to numbers, but we should pay attention to patient symptomatology because understand, we can turn hyperphosphatemia into hypophosphatemia. I like what Andrea said about how at the end of the day, it’s manageable. The drug is definitely manageable. Many of us have actually had some experience with it, definitely careful attention, as it was mentioned, and make sure that their actions are the appropriate ones that definitely can make patients go through.
So, Andrew, with this said though, the GBJ398 is moving into the next step or next level. Where are we now?
Andrew Zhu, MD, PhD: Any time you have a drug that you have demonstrated that it works in the refractory setting, I think the question becomes very natural. Can you move the drug earlier, right? Because targeted agents with a relatively more favorable safety profile compared with the conventional combination chemotherapy definitely has the appeal. The question is very natural. Whether the drug can actually even perform well in the first-line setting, meaning, if you know the patient has the FGFR fusion, can you actually offer patient this drug versus the conventional chemotherapy? That’s exactly what the current clinical trial is aiming to target. So we have the ongoing trial looking at that specific question. Patients with well characterized FGFR2 fusion will be randomized to receive the FGFR2 inhibitor versus gemcitabine-cisplatin.
Ghassan Abou-Alfa, MD, MBA: This is as a first-line versus the standard of care.
Andrew Zhu, MD, PhD: Correct.
Ghassan Abou-Alfa, MD, MBA: OK.
Andrew Zhu, MD, PhD: I think the trial definitely has a very strong scientific rationale. I would definitely encourage all the investigators to consider this specific study.
Ghassan Abou-Alfa, MD, MBA: Absolutely, I totally agree, especially with the drive of the 30%-plus response rate that we saw in the GBJ398, it does make total sense. Of course, we are getting a lot of questions even from the patients, who ask, “If I have the certain fusion protein or certain mutation, why don’t I get the therapy?” That’s why these things also have reason to go into the first-line therapy.
Transcript Edited for Clarity