IDH Targeting in Advanced Cholangiocarcinoma

John L. Marshall, MD: Katie, back to you to kind of back up to another major target, and that’s the IDH. Take us a little bit through that if you would.
 

R. Kate Kelley, MD: IDH is a different gene and IDH mutations, IDH1 mutations in particular, rather than driving a purely proliferative signaling pathway in the tumor cells, they actually cause the accumulation of a downstream oncometabolite, 2-hydroxyglutarate, in the cell microenvironment, that causes a differentiation block. That differentiation block leads to proliferation of these baby, immature cells that haven’t fully formed as an epithelial cell, and that’s the proliferative stimulus, is just a collection of baby cells in the environment that leads to the oncogenesis. So it’s sort of a novel way of causing a cancer, and the IDH1 inhibitor, ivosidenib, is novel in that it is trying to reestablish this normal differentiation. So not so much of a cytotoxic mechanism, but rather causing cells to differentiate the way they should into mature cholangiocytes. This is a really fascinating biology, obviously. But what we see in the clinic, again just to reiterate that around 15% of intrahepatic cholangiocarcinomas have an IDH1 mutation. We think this is probably also a distinct clinical phenotype, just like FGFR maybe, and targeting the IDH1 mutation with ivosidenib in a phase 1 trial showed not so much a lot of responses as we might expect with the mechanism as I mentioned, but a prolongation of progression-free survival compared to what we expect with second-line therapy, which, unfortunately, most of our second-line regimens have a PFS, in this chemo realm, that is like FOLFOX and FOLFIRI, in the two- to three-month range really. So based on the phase 1/2 data, the ClarIDHy trial was a randomized phase 3 trial that looked at ivosidenib versus placebo in patients with second- or third-line intrahepatic cholangiocarcinoma with IDH1 mutations. They didn’t have to be intrahepatic, but as I mentioned earlier, almost all of IDH1 mutations are intrahepatic, occur in intrahepatic locations. The ClarIDHy trial primary endpoint was progression-free survival, and they showed a very significant, statistically significant improvement in progression-free survival for ivosidenib over placebo.
 

Now, there were a lot of challenges to interpreting this data, including the heterogeneity of second- and third-line patients being included, the fact that scans were done every six weeks, and ultimately the PFS absolute values were relatively low, with PFS in the treatment arm of only around three months versus in the one-month range, 1.4 months I believe for placebo. But the hazard ratio was very significant, and if we look, there’s distinctly a tale of the curve. We think this is a statistically positive trial, and although the absolute numbers are low, there’s a subset of patients that seem to be deriving a benefit.
 

John L. Marshall, MD: Yeah. Sameek, let me turn to you to comment on this. This is a drug that’s approved for our AML patients, I think, so many of our listeners may actually have some experience with the drug. The way I pulled the data out was about 25% positive rate from those who screened, that found a mutation, and as Katie pointed out, I think about 90-plus percent were intrahepatic, but not exclusively intrahepatic. Is this something, you get one of these tests back and you get this IDH1 mutation, is there where you’re calling the guy to say can I get this drug for my patient? Where are we with this?
 

Sameek Roychowdhury, MD, PhD: It’s not yet approved to my knowledge.
 

John L. Marshall, MD: Not that I know of either yet, for this indication.
 

Sameek Roychowdhury, MD, PhD: In my practice, we generally try to qualify people for clinical trials if we can, but certainly if they’re not trial eligible, we’re certainly willing to go outside the normal realm to use our expert experience and use therapy that we think could benefit our patients. I agree, going above and beyond to try to help our patients or to get them access to a therapy that we think and we know has data that can help them, I’d be very supportive of that. I also say this is very promising and exciting for this subset of cholangiocarcinoma, but there’s new therapies coming.
 

Sometimes the first generation of a drug isn’t always the best generation and there’s going to be some refinements not only to IDH drugs, but also FGFR drugs. One example is the RET inhibitors that we’ve seen, the latest RET inhibitor is producing far greater responses in some of our patients than the first generation of RET inhibitors from maybe a decade ago now. So I think this is early promising signs, these patients are benefitting clinically, the toxicity I’ll let Milind talk about, but I think it’s a very well tolerated drug, and I’d advocate wholeheartedly for our patients for this.

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