Behind the FDA Approval: Ivosidenib for IDH1-Mutated Cholangiocarcinoma

Rachna Shroff, MD

In August, the FDA approved ivosidenib tablets (Tibsovo) for the treatment of IDH1-mutated cholangiocarcinoma, making it the first agent with such an indication. Since its approval, ivosidenib has offered patients with IDH1-mutated cholangiocarcinoma a second- or third-line option where none existed before.

The approval of ivosidenib is based on the phase 3 ClarIDHy trial (NCT02989857), which has an actual enrollment of 187 participants. The primary end point is progression-free survival (PFS). Secondary end points include adverse events, overall survival (OS), overall response rate, and quality of life. 

According to the survival analysis, the tablets were associated with a 21% reduction in the risk of death compared with the placebo. The median OS for those in the ivosidenib arm was 10.3 months compared with 7.5 months in the placebo arm (HR, 0.79; 95% CI, 0.56-1.12; 1-sided P = .093).

In an interview with Targeted OncologyTM, Rachna Shroff, MD, the associate dean of clinical and translational research, associate professor of Medicine, chief of the Section of Gastrointestinal (GI) Medical Oncology, leader of the GI Clinical Research Team, and director of Cancer Center Clinical Trials Office at the University of Arizona College of Medicine Tucson, discusses the impact of ivosidenib’s approval on the cholangiocarcinoma space in greater detail. 

TARGETED ONCOLOGY: What is ivosidenib’s mechanism of action?

SHROFF: Ivosidenib is an oral IDH1-targeting agent; it inhibits the IDH1 pathway. So, IDH1 plays a role in cellular metabolism. Cells obviously require energy and metabolic processes to grow and replicate and divide—the IDH1enzyme plays a role in controlling that process. And so, in the setting of somebody with an IDH1 mutation, basically that genetic programming gets altered. In the cells, instead of differentiating, as we call them are maturing, they remain relatively primitive and they proliferate quicker. As a result, dysregulation of cellular growth happens, and you can end up going through carcinogenesis and developing cancer processes. IDH1 inhibitors like ivosidenib help prevent that dysregulation.

What unmet need does this approval fill?

I think, in general, treatment for cholangiocarcinoma has been an incredibly unmet need. At the end of the day, prior to 2020, we had no FDA drugs approved. So, this has been a disease that affects 8000 individuals a year, yet we have very limited treatment options. As we have learned over time, through the advent of biomarker testing and better understanding the molecular landscape of this disease, IDH1 mutations are found in about 20% of patients with cholangiocarcinoma. That is a significant percentage when you think about it, especially when you compare it with some of the other alterations that we discuss when it comes to cholangiocarcinoma and that have drugs available and are FDA approved. So this hits a very large portion of that cholangiocarcinoma population and provides a therapeutic option for them. Ivosidenib is the first oral targeted therapy for IDH1-mutated cholangiocarcinoma.

Now, not only do we have chemotherapy to offer these patients, but in the second- and third-line setting after they progress on the standard-of-care chemotherapies, we have a treatment that is a pill, it's an oral drug, as opposed to some of our intravenous chemotherapies. I think that the unmet need that it hits is that A, there’s more drugs now available, but B, it's also, from a patient perspective, well tolerated and easy to take.

What data supported the approval of ivosidenib?

The approval came from the pivotal ClarIDHy study. The ClarIDHy study was the randomized phase 3 study that led to our understanding of the impact of ivosidenib in patients with IDH1-mutated cholangiocarcinoma. The phase 3 was born out of a phase 1 study that involves 73 patients with IDH1-positive cholangiocarcinoma. The phase 3 was really impactful in the sense that it was very well thought out; it was discussed with key opinion leaders, with patients, with patient advocacy groups, because it was really important for us to be able to not only design a trial that could answer the important question of does ivosidenib work, but also how can we design a feasible study?

The ClarIDHy study was a double-blinded, randomized, placebo-controlled study. Patients who had progressed on frontline therapies, at least gemcitabine-based therapy or 2 lines of therapy—so this was for second- and third-line patients—were allowed to be enrolled if they had central confirmation of IDH1 mutation. Then they were randomized 1:1 to receive ivosidenib versus placebo. Because it was a blinded study, patients did not know what they were getting. But because there was a placebo arm, we felt it was very important to have a crossover option. So, at the time of progression, if patients were still eligible and they were on the placebo arm, they could cross over to receive ivosidenib. Because of the crossover, the primary end point was PFS. The secondary end points included, of course, things like OS. There were some also important secondary end points like understanding health-related quality of life.

The primary end point was absolutely met. The hazard ratio for PFS was 0.37. So, there was a 63% risk reduction of progression on the ivosidenib compared with placebo. But what I think was really striking was when you look at those Kaplan-Meier curves, the PFS at 6 and 12 months, that separation of the curves between the placebo arm and the ivosidenib arm was really striking because 32% of patients remained progression free at 6 months and 22% at 12 months, as opposed to 0 on placebo arm.

When you look at the OS data, you have to keep in mind that 70% of patients were able to cross over from placebo to receiving ivosidenib. It's important to be able to give these patients this drug if they're eligible. But that, of course, obscures the OS data. So, on the intention-to-treat analysis, the OS was numerically improved compared with placebo, but not necessarily statistically significant. But when you do a statistical modeling called the rank-preserving structural failure time modeling, which basically accounts for that 70% crossover and hopefully takes out that noise [to be] able to really understand what the placebo arm would have looked like if patients had not crossed over there. You see a near doubling, from 5 months to about 10 months, in terms of OS. So I think that there is clearly a survival benefit. While it's not statistically significant, and in the intention to treat, that numerical improvement is absolutely meaningful, especially when you take it in context of how well tolerated this drug was in terms of its safety profile, and its impact on quality of life.

What impact will this drug have on the cholangiocarcinoma space?

First and foremost, it will bring a recognition that we need to be biomarker testing every single patient with cholangiocarcinoma. We have drugs approved and these are relevant and important drugs that absolutely impact survival and quality of life in our patients. It has been a slow process to educate the community about the importance of biomarker testing and obtaining next-generation sequencing at the time of diagnosis, which is really important. And so hopefully, that is the number 1 impact it will have is that we can help people recognize the importance of doing this right when the patients walk in the door.

Then I think also, again, it's another treatment option. It's another drug in our armamentarium. In the era of us only previously having gemcitabine and cisplatin, for 20% of patients, we have an oral targeted therapy for IDH1-mutated cholangiocarcinoma in the form of ivosidenib. I think once we get them to understand the importance of biomarker testing and identifying that IDH1 mutation, the impact is obvious because they have another drug at their disposal for second- and third-line patients.

What should oncologists be aware of when it comes to this drug?

The beauty in my opinion of what we learned from the ClarIDHy data is that not only does ivosidenib have good efficacy data in terms of PFS and things like that, it also really was a well-tolerated drug. In terms of adverse events—first of all, there was a very small percentage of what we call grade 3 or greater adverse events. Even in all patients, the adverse events were things that can oftentimes come from the disease, like abdominal pain, fatigue, there was some nausea, and nothing really unexpected or dramatic, which I think is really important. And importantly, when you look at the safety data, there was a pretty small percentage of patients who had to have treatment interruptions, dose reductions, or had to discontinue treatment due to safety-related issues or adverse events.

Then again, that's further supported by the quality-of-life data where they followed patients at the start and then at cycle 2, and there was a preservation of physical functioning and other key metrics that we look at as oncologists that we think is a good example of how we were able to preserve quality of life with treatment. So, I think the beauty of ivosidenib is that not only is it helping delay progression, but it is also preserving quality of life and is really well tolerated.

The most important thing to me is that when you think about where we started and where we've come [from]. The trajectory for drug development in cholangiocarcinoma is just incredible. I applaud the community, I applaud the researchers, the physicians, the industries, who are really putting in time, effort, and money into designing smart trials that really are patient facing and help us improve the lives and care of these patients. The ClarIDHy study, I think, is a landmark study, not only because it was a randomized phase 3 pivotal trial that led to the approval of the first oral targeted therapy for IDH1 mutated cholangiocarcinoma, but because it really did take all of those factors into account. It was patient facing right from the get-go. I think that's really important and impactful.

_REFERNCE:

_{Zhu AX, Macarulla T, Javle MM, et al. Final results from ClarIDHy, a global, phase III, randomized, double-blind study of ivosidenib (IVO) versus placebo (PBO) in patients (pts) with previously treated cholangiocarcinoma (CCA) and an isocitrate dehydrogenase 1 (IDH1) mutation. J Clin Oncol. 2021;39(suppl 3):266. doi:10.1200/JCO.2021.39.3_suppl.266}