Precision Medicine: A New Frontier for Advanced Cholangiocarcinoma - Episode 13

Ivosidenib for Advanced IDH1-Mutated CCA


Ghassan Abou-Alfa, MD, MBA: Let’s move on to IDH1. Before we go into the therapy, there has been some reporting, and admittedly some of it came from our institution, Memorial Sloan Kettering Cancer Center, that an IDH1 can be stressed out too. Your thoughts on that?

Teresa Macarulla, MD, PhD: Yeah, IDH1 is a more frequent mutation in intrahepatic cholangiocarcinoma. We can find around 20% to 25% of patients with IDH1. I think that’s really good news.

Ghassan Abou-Alfa, MD, MBA: Absolutely. In other words, the change from IDH1 to IDH2 can occur. Before we go there, Andrea, back to you. What’s IDH1? What does it do?

Andrea Wang-Gillam, MD, PhD: It’s targeting the cell metabolism, you know, the TCA [tricarboxylic acid] cycle. It’s targeting the isocitrate dehydrogenase. When you have an inhibitor and block it, and you have more produce of alpha-ketoglutarate.

Ghassan Abou-Alfa, MD, MBA: The alpha-ketoglutarate actually pushes more into 2-hydroxyglutarate—the 2-hydroxyglutarate being the oncometabolite that can cause oncogenic changes. You’re right. Actually, there is some kind of competition that can occur between 2-hydroxyglutarate and alpha-hydroxyglutarate, and can highjack the tumors or “those cells that are becoming the tumor.” With this said, Andrew, you were involved quite a bit, and we probably did this together. Tell us a little about the already-reported data from the phase I/II that had a cohort of cholangiocarcinoma.

Andrew Zhu, MD, PhD: In a phase I study, when we subject the first IDH inhibitor in this population, we’re actually able to observe a very impressive disease-control rate in this population. Also, there are patients achieving radiological responses as well. But more important, they seem to actually alter the disease stabilization. The median PFS [progression-free survival] was very reasonable. But interestingly, if you look at the tail of the curve, there seemed to be patients who are actually doing well for a prolonged period of time. With that encouraging data, as we know, the AG-120 inhibitor has been actually moved to the phase III trial, and then we’re going to hear more from this meeting [the European Society for Medical Oncology 2019 Congress].

Ghassan Abou-Alfa, MD, MBA: Fair enough. Before we go on to talk about that, let’s hear from Martin. The AG-120—now it’s called ivosidenib, which already is approved by the way for AML [acute myeloid leukemia] or some forms of AML. Is it tolerable? What’s your experience?

Martin Gutierrez, MD: I have to confess that I don’t really have any experience with the IDH1. I’m trying to get the phase I in our center, but I couldn’t. But the data from AML has this differentiation syndrome, which has pleural effusions, pericardial effusions, hypertension, and capillary leak syndrome—like presentation. We...a question for the phase I, and Andrew, you guys probably didn’t see that.

Andrew Zhu, MD, PhD: We did not see that in the cholangiocarcinoma space.

Martin Gutierrez, MD: Yeah, it’s my educated guess.

Andrew Zhu, MD, PhD: If anything, I think the safety profile was actually incredibly respectful. Meaning that these patients tolerate them very well. There are some very minor toxicities, GI [gastrointestinal]. On the other hand, it’s very hard to even attribute whether it’s truly drug related or not.

Ghassan Abou-Alfa, MD, MBA: I totally agree. If anything, our hands-on experience has been rather positive since the drug is super well tolerated. If anything, people probably experience some nausea, vomiting, and diarrhea. But in general, people can really live with a life without much of a limitation. Let’s go back, however, again to the phase I/Ia with the cohort of the cholangiocarcinoma that was already reported in The Lancet Gastroenterology and Hepatology. Andrea, 1 of the things patients ask us all the time is, “Did my tumor shrink?” Tumors did not shrink much on the ivosidenib. Your thoughts on this?

Andrea Wang-Gillam, MD, PhD: I generally tell patients, if a tumor doesn’t really shrink, and if it’s stable, it’s still good news. This is because by default, the tumor will grow. We need to control it and achieve quality of life as long as we can. I still think that’s a winning strategy. Now patients are accepting what we call living with a cancer, stable disease. Generally, patients don’t really frown upon you when you say, “Oh, you have stable disease.” They accept it as a treatment benefit.

Ghassan Abou-Alfa, MD, MBA: Fair enough. If anything, this translates what Andrea said nicely. Teresa, biologically, why should we not necessarily expect ivosidenib to shrink tumors, even though it’s definitely making people do great? Tell us about that.

Teresa Macarulla, MD, PhD: Yeah. It seems there are some biopsies in phase I, and it seems that this stabilization correlates with some changes in the histology of the tumor. I think, again, being able to stop the tumor in the second-line or third-line treatment—and the safety profile being so good—is good news. Maybe we can see in the future to add something else. Maybe think it could be a potential synergistic effect with other drugs, with other strategies.

Ghassan Abou-Alfa, MD, MBA: Right. If anything, we’re hearing very important points that, at the end of the day, ivosidenib is an oncometabolite inhibitor. It’s oncolytic, so the tumors can stabilize based on the tumor not growing. Maybe there are certain alterations, exactly as Teresa said, suggesting that could be happening within the tumor, but it’s not that savvy about size. This actually brings a very important point to our patients: how we assess the outcome of their disease and how they are doing are not necessarily by bigger or smaller, but rather by the perspective of how they’re doing. This is very important clinically, exactly as we just heard from Andrea a second ago. No. 2 is, yes, this could be supported by, or explained by the radiological outcome, which is more like a benchmark to tell us that the tumor is stable. This is great news because we don’t expect the tumor to necessarily shrink with the ivosidenib. Understandably, on top of that is, yes, maybe some of what we spoke about much earlier in regard to tumor markers. There could be some alterations, but not necessarily that it would be the driver. As we heard from all of us, it’s not necessarily an independent marker per se.

Transcript Edited for Clarity