Case 4: Side Effects of FGFR2 Inhibitors in HCC



Ghassan Abou-Alfa, MD, MBA:I’ll go back to Amit for a second. You brought it up, but let’s dissect it a little further. Cholangiocarcinoma plus hepatocellular carcinoma [HCC]?

Amit Singal, MD:Yes, we’re seeing this more and more. We used to think of HCC and cholangiocarcinoma as primary liver cancers, but we thought of them as 2 distinct diseases. I think more and more we’re starting to see that it’s really probably a spectrum. As biopsy is starting to be used more, even for HCC, in our clinical practice, we’re seeing more of these mixed tumors. I think you see some that are predominantly HCC with a touch of cholangiocarcinoma, and then you see some that are predominantly cholangiocarcinoma with a touch of HCC.

I think it’s going to be an interesting time because for those mixed tumors, I don’t think we really know exactly what the optimal treatment is. I imagine it really depends on what your predominant tumor is within each of these. But we do see more mixed tumors. At least in our clinical practice, this is why we’ve become much more prone to biopsy, even things that may have characteristic imaging.

Ghassan Abou-Alfa, MD, MBA:Fascinating. Let’s talk about biopsies. I’ll go back to Farshid. For a patient with cholangiocarcinoma, a certain set of mutations progress. Another repeat biopsy?

Farshid Dayyani, MD:At the minimum, I would say liquid biopsy. As Riad already alluded to, tumors are dynamic. There are new mutations emerging, resistance mutations, so we do try at a minimum—if we can’t access the tumor for whatever reason, for safety reasons—to do a liquid biopsy. Now, these tests take time to come back. This is an aggressive disease, Amit said, so you want to do your homework early on and get early profiling. But upon progression, at a minimum, we try to get a liquid biopsy to see if there are any emerging mutations that might be targetable that were not in the original tumor. If feasible, obviously we would also do a tissue biopsy.

Ghassan Abou-Alfa, MD, MBA:I like what you said. Interestingly, there are data—and I’m sure you were aware—that came out of Massachusetts General Hospital. It was really a very nice piece on patients withFGFR2fusions who progressed; it’s fascinating. This is where they actually had a stat—autopsy collection of tissue from liver—and found out given the different locations of tumor, what are the changes in regard to the genetic mutations or the genetic fusions? It’s quite fascinating that really, yes, these changes do occur. We’re not necessarily vouching for making sure that we rebiopsy everybody. Ultimately, the science of it still needs to evolve. At the moment, actually, pathologists will tell us that not everybody will have an alteration in regard to their genetic makeup of the tumor. But then we’re learning more and more about this.

The fascinating part about it is, is it really something that happened by random—ie, it changed from 1 mutation to the other? Or is there a certain phenomenon that would make a tumor stressed enough to really alter to a different mutation? Time will tell, and we’ll see how it’s going to take us from there. Go back, however, to theFGFR2. Some of our colleagues get a little nervous about the anti-FGFR2sbecause of the adverse effects. What are the things that we are mostly worried about, and what are your thoughts?

Farshid Dayyani, MD:Retinopathy or serious retinopathy is something you need to pay attention to. That means closely working with an ophthalmologist, or eye doctor, referring the patients. And it’s manageable. You have to hold it, let it resolve, and then you can actually restart the patients. That’s something. You look at their laboratory results, phosphate level. Hyperphosphatemia is a very common adverse effect. With sevelamer and other phosphate binders, you can manage that. There are some skin and nail changes that you look for. There are adverse effects that you have to be aware of, but you have to closely monitor your patient and work very closely with the eye doctors at a minimum to manage these main adverse effects.

Ghassan Abou-Alfa, MD, MBA:I think you named the 3 key ones, which are hyperphosphatemia and the skin, nail changes, and retinal changes. And close monitoring would be key. It’s quite fascinating, though. Hypophosphatemia is also noted, but the best understanding we have is that really was physician driven. We were so excited about the hyperphosphatemia, enough that we caused the hypophosphatemia. So we should not treat numbers but rather treat symptoms. This is really where it’s very important to get a better understanding about the management of those symptoms.

Transcript edited for clarity.

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