Lirafugratinib + LITESPARK011

Today, we have a new drug to talk about that was approved in time for last week's episode, but the PI was not available yet, and that is liraflugratinib, which is an FGFR2 inhibitor.

And this is approved in the second line setting for advanced cholangiocarcinomas.

Usually these are intrahepatic bile duct or gallbladder cancers that are FGFR2, either gene fusion or rearrangement.

And it's an FGFR2 alteration.

And that's present in 10% to 15% of intrahepatic cholangios.

This is the third FGFR inhibitor approved for cholangiocarcinoma, and the fourth one that has some data.

I'll start with ertifetinib, which is one of the older FGFR inhibitors.

It's not FDA approved for cholangio.

It does have good data for bladder cancer.

It is a kind of a pan inhibitor of FGFR 1, 2, 3, and 4.

Pemigatinib is a reversible inhibitor of FGFR 1, 2, and 3.

Fudibatinib is an irreversible inhibitor of FGFR1, 2, 3, 4.

And lirafugratinib is an inhibitor of FGFR2 irreversibly, much more so than 1, 3, and 4.

So it's more specific to FGFR2, which is what you're trying to target in FGFR-altered cholangiocarcinoma.

One of the on-target side effects of FGFR inhibitors is hyperphosphatemia and ocular disorders.

So as a brief review, I'm going to go through the rates of hyperphosphatemia reported in the warnings and precautions section of the monographs for these four drugs.

So futibatinib is 88%.

Pimigatinib, 93%, ertifitinib, 73%, loriflugretinib, 21% hyperphosphatemia.

Now, 75% of people did have their phos go up, but not enough that it increased to the point that it was in like a toxic range or where you would get to a grade one toxicity, for example.

So it seems that this FGFR2 specificity does spare some of the toxicity hyperphosphatemia.

Now, if we look at the rates of retinal pigment epithelial detachment, that is 9% with fudibatinib, 11% with pemigatinib, 22% with ertifitinib, and that also includes some other retinopathies, and then 31% with lirafrugatinib, which seems to be higher than the rest.

So perhaps this specificity for FGFR2 is more toxic for the eye, but less toxic in the kidney with phosphate reabsorption and secretion.