FGFR2 Inhibitors in Advanced Cholangiocarcinoma

Saeed Sadeghi, MD: FGFR2 disease is quite an interesting area. There’s been quite a bit of excitement for this specific subset of patients. As recent as April of this year, there was an FDA approval of a pan-FGFR1, FGFR2, and FGFR3 inhibitor, pemigatinib. The drug’s approval was based on a trial known as the FIGHT-202 trial, which was a trial of 146 patients. These patients included a group of patients who had FGFR2 fusions or rearrangements. In fact, those patients accounted for about 107 of the patients in the trial. What the trial demonstrated was that pemigatinib resulted in an overall response rate of 35.5%. Among those patients, 3 had actually achieved a complete response. The duration of response was 7.5 months, and the progression-free survival was 6.9 months.

The drug did have some toxicity. As a class of medications, these drugs can cause hyperphosphatemia, which is manageable. There was also a minority of patients who did develop detachment of the retinal epithelial membrane, indicating the need for these patients to undergo ocular examinations while they’re on the drug. Other toxicities were included, including diarrhea in 47% of the patients. But overall, it was a highly tolerable regimen, and this drug was approved based on this data.

The other compound that also is in the same class is the drug infigratinib. This is also an inhibitor of FGFR1, FGFR2, and FGFR3. This drug has been given fast-track designation by the FDA, mainly based on the data that have been presented most recently at ESMO [the European Society for Medical Oncology Congress]. This was a single-arm trial looking at infigratinib given daily for 21 days with a 1-week rest period following that. The primary objective of the trial was to look at overall response rate, then duration of response and progression-free survival. This trial also included 3 cohorts of patients. The first cohort of patients are patients who have an FGFR2 fusion or rearrangement, the second group is patients who have other FGF abnormalities, and a third group is patients who have actually progressed on an FGFR2 inhibitor and are being considered for the infigratinib trial.

One of the interesting things I pointed out to you is that it appears that patients who are exposed to infigratinib earlier may have a better response rate. And so the thought was to design a phase 3 trial to look at infigratinib in the first-line setting. The PROOF trial is open and is accruing patients. The trial includes patients who have unresectable recurrent or metastatic cholangiocarcinoma who have not had any prior systemic therapy in the metastatic setting. These patients all need to have had an FGFR2 fusion. This can be either tested centrally or locally, and they need to have a very good performance status.

These patients have been randomized in a 2:1 fashion to receive either the oral infigratinib compound or receive standard-of-care chemotherapy with gemcitabine and cisplatin. The patients are actually followed until radiographic progression of disease. At that time, patients who are on the chemotherapy arm have an opportunity to cross over to infigratinib. This trial has started to accrue patients. There are patients on the study for whom we do not have any information regarding efficacy or safety results.

Transcript edited for clarity.