Rachna Shroff, MD: It’s a really exciting time right now for cholangiocarcinoma with recent FDA fast-track approvals and breakthrough designations. That’s because, first of all, we’ve never had an FDA-approved drug for cholangiocarcinoma. So with the FDA approval of pemigatinib, more than anything, it highlights the ability to take a drug to clinic for patients, and it demonstrates that if we really put our noses to the ground and work in a concerted manner to run clinical trials in a smart way, we can get new drugs to our patients. It’s also an exciting area because now not only do we have chemotherapy options, but we have FDA-approved options for patients with targeted therapies. From a patient perspective, we have heard time and time again that that is really nice to have an oral drug available to them that doesn’t require multiple IV [intravenous] infusions, especially in the era of COVID-19 [coronavirus disease 2019] as we’re dealing with right now, in terms of coming to a cancer center and sitting in a clinic. From a multitude of perspectives, in my opinion, having these drugs available is exciting because it highlights the disease and the ability to do things for this disease, but it also is better for our patients.
The FIGHT-202 trial I think is a really fantastic trial. Number 1) It’s robust. Over 100 patients were put on this study, which again speaks to the fact that we can do trials in cholangiocarcinoma in a small, somewhat rare, subset of a population. But it’s also most importantly a proof of principle that we can target the FGFR2 [fibroblast growth factor receptor 2] pathway, and we can target it effectively with response rates that frankly at least mirror chemotherapy, combination chemotherapy and/or are better, especially in a refractory patient population, which is what the FIGHT-202 study included. I think not only was the overall response rate exciting, being over 30%, but it also was a duration of response, so this is not just a drug that works and then stops working quickly. This is a drug that works and is durable, which again affords patients not only, hopefully, prolonged survival, but also time off of IV chemotherapy and hopefully a meaningful quality of life.
The fast-track designation for infigratinib is an equally exciting breakthrough, if you will. First of all, again, it’s another drug that we can hopefully get our hands on for our patients. I think it underscores the fact that the FDA is recognizing the importance of these drugs and this target and that they have all eyes on the drug and on the frontline study that is ongoing, which is the PROOF study. I think it will hopefully be a way that, if the PROOF study is successful, we can get these drugs to our patients faster in a newly diagnosed setting, but again, it’s also the ability to have access to more drugs and for the FDA recognizing the importance of FGFR-directed therapies for these patients. To me, it is representative of the fact that people are seeing that this is an important disease and that this is an important target.
The PROOF trial is a novel approach to thinking about cholangiocarcinoma for our FGFR2 fusion-positive patients. We know that FGFR2 fusions are seen in intrahepatic cholangiocarcinomas primarily, in about 10% to 15% of patients. The prior studies, both with infigratinib and pemigatinib, were done in a refractory patient population, so patients who had already seen gemcitabine-based chemotherapy. The concept of the PROOF trial is, in these patients who are FGFR2 fusion-positive, do we really need upfront IV combination chemotherapy and all of the adverse effects that come with it? The PROOF study is a randomized study for FGFR2 fusion-positive cholangiocarcinoma. Patients have to be newly diagnosed and cannot have received any prior therapy, and they are randomized to receive infigratinib versus the standard of care, gemcitabine and cisplatin.
What I think is great about this study design is that patients are randomized 2:1, so that is really appealing to patients. For every 2 out of 3 patients, you have a chance of infigratinib. Equally exciting and important from a patient perspective is that there is crossover allowed, so patients who do get randomized to the gemcitabine and cisplatin arm, if and when they progress on gemcitabine and cisplatin, and assuming they continue to meet eligibility criteria, they can cross over and have access to infigratinib. From a physician perspective, we don’t feel that we are depriving patients of the opportunity to get an FGFR inhibitor.
I think this will answer the question of do we need chemotherapy up front in these patients? There are some data in some natural history work that’s been going on for patients with FGFR2 fusions, that they don’t actually respond as well to gemcitabine and cisplatin. It will be an important study for us to learn about the biology of this disease as well as the potential to substitute a targeted therapy for chemotherapy. The primary end point is progression-free survival because of the crossover, but we will of course be looking at other efficacy time points that are of interest to us as physicians, like response and survival.
The initial phase 2 data with infigratinib has unfolded over time with the initial BGJ398 publication in the ourJourrnnnf Journal of Clinical Oncology, followed by the updated data that were presented at ESMO [the European Society for Medical Oncology annual meeting]. What I think has been exciting to see, because I think of infigratinib as leading the way, as it was the first drug tested in our patients with FGFR2 fusion-positive cholangiocarcinoma, and what has been great to see is the initial excitement we had in terms of response rates in the mid-to-upper 20% range, the durability of that response, and the toxicity profile. That has played out and has remained constant.
I think the important thing to point out is that is the study where, first of all, we learned proof of principle that targeting patients with FGFR2 fusions with these FGFR inhibitors can work. This was a very refractory patient population. This was not a primarily second-line patient population. To see that kind of response rate in second-line, third-line, fourth-line patients I think really speaks volumes about the drug and its ability to effectively target the FGFR2 pathway. The duration of response is similar to what we’re seeing in this class of drugs, and there was nothing surprising in terms of toxicity that would make us more concerned, for instance, about the toxicity profile of an infigratinib versus some of the other FGFR inhibitors. I think the most important and salient point is that it was a very refractory population, and it still stood up.
Transcript edited for clarity.