Precision Medicine: A New Frontier for Advanced Cholangiocarcinoma - Episode 15

Final Thoughts on CCA


Ghassan Abou-Alfa, MD, MBA: We’re coming to a nice wrap-up of our meeting on cholangiocarcinoma. But I would like to ask again, Martin—and I will start with you because you have a lot of expertise and you help us quite a bit—in regard to the adverse events of the 2 examples we mentioned, BGJ398 and the ivosidenib, what is your take-home message in regard to the management of the adverse events? Please give 1 message for the patient, and 1 message for the physicians.

Martin Gutierrez, MD: The message for the patients is these drugs are easy to tolerate. The message for the physicians is they are not actually difficult to manage. It really has to focus on 2 or 3 adverse effects that really are with lab testing, and just to take the right approach, specifically around hyperphosphatemia. Obviously, don’t forget about the eye toxicity even though it tends to be uncommon. The drugs are well tolerated, easy to manage, and are here to stay.

Ghassan Abou-Alfa, MD, MBA: Very good. That’s a very important message, and we have to make sure we don’t make hasty decisions, but rather that we look and reflect on what you are seeing with the patients.

Andrea, I have another question to you, and you brought up a little of this in the beginning. I would love to rehash the anatomical differentiation between intrahepatic and extrahepatic cholangiocarcinoma and molecular. Your thoughts?

Andrea Wang-Gillam, MD, PhD: Yeah, I think there we’re already in the molecular age. We should be testing patients at even the initial diagnosis for a metastatic setting and classify them by molecular testing—not necessarily molecular classification, not necessarily anatomically. Looking at things anatomically does play a role sometimes in term of the surgical options—how much they resect, what type of surgery they should do. But by large, if we’re oncologists, I think that we should really emphasize molecular testing.

Ghassan Abou-Alfa, MD, MBA: Absolutely, and this is a very important point that we use, so all of us are watching for a new delineation of the disease. I remember almost 11 years ago when I started getting involved in the NCI [National Cancer Institute] Task Force for Hepatobiliary Cancers, first as the vice chair, now the chairman. The first question we had is, “Shall we split those diseases, or shall we lump them together?” Believe it or not, the question is not any more valid because we definitely are splitting them, but we’re splitting them not as we perceived it might be, which is anatomical differentiation, but rather based on the molecular testing, as we just heard. Accordingly, you treat them as such. It’s a very important point to put it on the practical level. Hopefully those drugs will become available for all our patients, but if a patient has a mutation, let’s say IDH1, and the tumor is extrahepatic, or as we just heard from Andrew delineating those, this is still to be treated.

Teresa, back to you, in regard to the IDH1 itself, we’re excited. We’re waiting for the data to be presented. But nonetheless, the phase I itself showed that the drug has a progression-free survival, has improvement to survival, and at the same time, is well tolerated. But tell us a little more about the improvement in PFS [progression-free survival] and OS [overall survival]. How are you going to translate them to your patients with the ivosidenib data?

Teresa Macarulla, MD, PhD: Yeah. I think it’s clear that it’s a drug for which we probably don’t see a lot of response rate. But we stop the evolution of the tumor, and for that reason probably the quality of life of a patient will be really improved with this drug because we can control the tumor. Of course, we have to put it together with a safety profile if it’s so good. If you put together, our patients can have control with a good quality of life.

Ghassan Abou-Alfa, MD, MBA: I really like what you said, and this is a very important reminder for all of us that even though the response rate is always what patients desire, certain drugs like ivosidenib can be more oncostatic rather than oncolytic. In other words, if a tumor is stable and the patient remains on therapy and it affects the PFS, this will definitely be a positive outcome that we’ll look for. Remember 1 thing, however: we spoke about that a little when we were discussing the ABC-02 trial. The PFS really depends when you take the measurement. If you don’t take a scan, you don’t have any kind of point on the curve for telling you where the PFS stands. As of such, we have to put this within the context of any study being you know ivosidenib or ABC-02 or what have we.

The last question is for you, Andrew. We spoke quite a bit about the FGFR fusions, and we proudly have done a lot of work together in regard to the BGJ398 trial. If anything, now it’s moving into a phase III trial. If anything, the point that I’m intrigued by is what you brought up a little earlier, the resistance mechanism, and at the same time, the aspiration that the phase III trials are carrying on.

Andrew Zhu, MD, PhD: Yeah. We clearly need to extend the experience that we have in the right indication. That’s why I think the ongoing phase III study clearly will actually test the hypotheses whether target agents will perform as well or even better than the conventional chemotherapy. Also we’re going to balance about the safety profile in the phase III trial. This will be actually incredibly critical. We have not done that in the cholangiocarcinoma field yet. So that study is very important.

Secondly, I do think that we have room to improve what we have already achieved with a single-agent FGFR inhibitor. Along that line, I still think figuring out the resistance mechanism is absolutely critical for us to think ahead. This is because these patients should benefit from this type of treatment not just by 5 months and not just by 7 months, but hopefully we can provide them with additional mileage with these therapeutic interventions.

Ghassan Abou-Alfa, MD, MBA: I totally agree. Andrew brought to our attention to a very important point. If a patient does not have a fusion protein for FGFR2, or indication for IDH1 or any other, it does not mean that, “Oops, we have no choices here.” Remember chemotherapy, and you have a lot of credit to give for all our colleagues, especially the team from the ABC-02 trial in the UK. At least we have a standard of care. It’s very important to remember that chemotherapy does help patients, and we should not ignore it as being something from the past. We like to move forward, as we see from what we were discussing today with regard to the molecular pathways and, at the same time, what effect targeted therapy might have. But remember, chemotherapy is here to stay. It’s not necessarily out of the picture, as the remaining standards of care or the sole standard of care for the disease until today.

With this said, this has been extremely informative. I would like to thank everybody 1 more time for their work and their answers. We ask Dr Gutierrez, we ask Dr Macarulla, and we ask Dr Zhu, and we ask everybody about where things stand in regard to the disease.

Transcript Edited for Clarity