Ghassan Abou-Alfa, MD, MBA: Andrew, you mentioned that based on the data, and if I do recall correctly, we had a PFS [progression-free survival] close to about 3.8 months in regard to the phase I data. Also, the survival was about 13.8 months. This moved to a phase III trial. Respectfully, and because we’re under embargo, we’re broadcasting today from Barcelona, Spain. This is actually at ESMO [European Society for Medical Oncology 2019 Congress] in Barcelona. We won’t be able to discuss the phase III trial because the data are under embargo by ESMO, and we have to respect that. Even though Andrew and myself were honored to lead that study that I’ll be presenting tomorrow at the Presidential Symposium here in Barcelona. Nonetheless, we can talk at least about some basics of the study because there was a press release in that regard. Tell us first, what was the study?

Andrew Zhu, MD, PhD: This is the so-called ClarIDHy phase III trial.

Ghassan Abou-Alfa, MD, MBA: I like the name by the way. IDH and ClarIDHy. Go ahead.

Andrew Zhu, MD, PhD: Yeah, I’ll refer to that. We’re obviously trying to address the question that for patients who failed a standard treatment, they have to fail up to 2 prior regimens. They have to contain either gemcitabine as well as fluoropyrimidine-based treatment.

Ghassan Abou-Alfa, MD, MBA: Either-or.

Andrew Zhu, MD, PhD: Either, yes. Patients will be randomized to receive either the IDH inhibitor versus the placebo. Clearly at the time of disease progression, which I think is unique for this study design, it will allow crossover. This means that for patients who actually randomized to the placebo, at the time of progression, they’re actually allowed to get the ivosidenib, IDH inhibitor.

The primary end point in this case, as you can imagine, is looking at progression-free survival. Because of the study design, we actually target the risk of reduction for progression as well as for death. As you heard from the press release, this was actually a positive study. This is because we’re able to demonstrate the risks of progression or death that’s actually reduced significantly by this very well-tolerated IDH-specific inhibitor. We’re going to hear more from the presentation, but I think it’s a very exciting trial. This is actually the first time we’re bringing a target agent potentially for this disease.

Ghassan Abou-Alfa, MD, MBA: You said a lot of important things, but let me dissect them further. These are extremely important points. Martin, first point and a question for you in regard to what you just heard from Andrew about crossover. In general, let’s forget about ivosidenib and forget about the whole story. At the end of the day, we spoke about this a little earlier, you have a patient with an IDH1 mutation. There’s a study. They get randomized to the placebo.

You say, “You got randomized to the placebo.” Remember, we don’t have to even say sorry because we don’t know if the drug works yet because the study is ongoing. But the patient insists, “I really need to get on that drug.” So we end up looking at the perspective that we’ll do a crossover. This, as we heard from Andrew, will limit us in regard to the primary end point, and now we’re looking at PFS. Do you think this will still be of value, or are we losing key points over here?

Martin Gutierrez, MD: Again, it’s a very good point. The overall survival gets contaminated with the crossover, and it’s very hard to interpret it. But the fact that you can prove that the PFS, again, is positive because of the press release has more value. This is because of the crossover phenomena. Perhaps the response rate or perhaps...of the disease, that gap is higher enough that it’s able to maintain the crossover of those patients. I personally would believe that it has a nice value to the study.

Ghassan Abou-Alfa, MD, MBA: But you would say so, and I totally agree. If anything, there are some statistical approaches that could be used to overcome that limitation, and if anything, it will be 1 way to interpret the overall survival as if there was no crossover. Would you be able to tell us what that means ultimately?

There is another point that was brought up by Andrew in regard to tolerance of drug, and this is going to be something that we’ll wait and see the phase III trial data. But I like that’s how he combined what we heard from the press release in regard to the outcome, along with the data from phase I that, I agree, showed that the drug is well tolerated. With this said, it brings in the point about the genetic testing again 1 more time. Andrea, you’re going to hear this tomorrow, and we’re going to talk about. It’s a positive study. It already was reported in the press release. How are you going to change your push for the genetic testing in that regard?

Andrea Wang-Gillam, MD, PhD: I think for EUS [endoscopic ultrasound], the oncologist is always pushing for the test, and I don’t think it’s the buyers, the insurance, or the others. The third party has intervened that. This will be providing evidence that we need to do this study for cholangiocarcinoma. Regardless of the insurance, they should approve it—whether it’s Medicaid, Medicare, and so forth. The patient should advocate where they are testing as well, because not every oncologist will know about it and not every oncologist will watch this. So I think it’s important that we let patients know that they need to be tested as well.

Ghassan Abou-Alfa, MD, MBA: I hear you. Teresa, proudly you were heavily involved in this trial. We’re very proud to have worked with you all along. Are you excited about tomorrow?

Teresa Macarulla, MD, PhD: Oh, yeah. Absolutely. Especially because it’s the first phase III trial positive in these target therapies in cholangiocarcinoma. So it’s the first 1. Yes, absolutely.

Ghassan Abou-Alfa, MD, MBA: I totally agree. If anything, I’m very happy you bring this up because actually, you and Andrew both have brought up a very critical and important point, which is at the end of the day, the introduction of that data on the ivosidenib—which we are proud to report tomorrow here at ESMO in Barcelona—is going to be the first time that we’ll bring on board a targeted therapy in cholangiocarcinoma that will definitely benefit the patient that ties the mutation, as we heard from Andrew, ranging around 20% to 25% at most.

By all means, at least we’re helping one-quarter of the patients. Of course, with the efforts that you are seeing in regard to the BGJ398, which also is in the phase III trial, it will be a very important opportunity for the patients with the FGFR2 mutations. Of course, this is what we hope for, and this is what we would like to see: more of those ongoing efforts in regard to the specific genetic changes that can occur being either a fusion protein, or mutation, and so forth.

We notice that it’s very important what our colleagues brought up on multiple occasions, that if a mutation is to occur, the genetic changes might be altered based on the treatment of that specific target and have a new alteration with regard to what the genetic mutations are. However, admittedly at this point in time, we’re not necessarily advocating for a second biopsy or repeated biopsies, because we don’t yet have an understanding of how often these can happen. This, however, is work that we all are doing and involved in until we have a better understanding of whether the genetic changes might occur and take it from there.

Transcript Edited for Clarity