Targeting IDH and FGFR Mutations for Cholangiocarcinoma

Timothy Pawlik, MD, The Ohio State Wexner Medical Center, Columbus, OH, discusses the molecular targets of isocitrate dehydrogenase (IDH) and fibroblast growth factor receptor (FGFR) for cholangiocarcinoma. Dr Pawlik talks about the promise of IDH and FGFR inhibitors, as well as the potential of patients developing resistance to these therapies.

Transcript:

Hello, my name's Tim Pawlik. I'm a surgical oncologist and I'm chair of the Department of Surgery here at the Ohio State Wexner Medical Center in and the James Comprehensive Cancer Center. Today I am going to talk to you a little bit about one of our recent review articles on FGFR and IDH inhibitors in the treatment of cholangiocarcinoma therapy.

Cholangiocarcinoma is a relatively uncommon cancer. It is a cancer, however, that unfortunately, has a high case fatality. Only a subset of patients are eligible for surgical resection. Many patients present with advanced disease, and even amongst those patients who present with resectable disease and undergo curative intent resection, unfortunately many of those patients will recur either with intrahepatic disease or extrahepatic disease. Traditionally, patients have been treated with systemic chemotherapy in the setting of advanced disease or recurrent disease, with gemcitabine and cisplatin based on data from the ABC or the Advanced Biliary Cancer Trial.

More recently, we have come to understand specific molecular underpinnings of cholangiocarcinoma and specific genetic perturbations, including IDH1, IDH2 mutations and FGFR mutations and fusions, that can have both prognostic importance as well as be targeted therapeutically. And in particular, if you look at IDH, IDH mutation can occur in roughly 15% to 20% of patients who have a cholangiocarcinoma, and in particular those individuals who have an intrahepatic cholangiocarcinoma. And the data relative to the prognostic impact of IDH1 mutation, has been a little mixed.

Some studies have reported that patients with IDH-mutated cholangiocarcinoma have a longer overall survival, but there's been other papers that have demonstrated that IDH mutations may be more common in tumors with poor histology and be associated with worse overall survival. Relative to FGFR genetic alterations, several studies have shown that perhaps patients who have FGFR genetic alterations, may have a unique subtype of cholangiocarcinoma and maybe more common in patients who are younger and have a more favorable biology.

Relative to the therapeutic implications, both of these genetic alterations and perturbations, both IDH and FGFR genetic alterations infusions, have been the focus of several clinical trials in an attempt to target either one of them. In particular, relative to IDH, there was the CLARIFIED study, was a phase 3 randomized controlled trial that looked at 185 patients who had been previously treated for an IDH1 mutated cholangiocarcinoma. And in this study, patients randomized to either an IDH1 inhibitor, ivosidenib or a placebo. And in patients who received the IDH1 inhibitor, those individuals had a longer progression-free survival than individuals who received placebo.

However, interestingly, there was no statistical difference in overall survival, but there was some crossover between the groups that may have impacted the overall survival results in the interpretation. So currently the NCCN Guidelines recommend ivosidenib for second-line treatment for patients with cholangiocarcinoma with IDH1 mutations following disease progression on first-line therapy.

With regards to FGFR, the most common genetic alterations are usually FGFR1 amplifications or FGFR2 fusions. And there's been several trials looking at the safety pharmacokinetics and efficacy of agents targeting FGFR fusions or mutations in particular. And specifically, the FIGHT-1 Study looked at an FGFR1/2 and 3 inhibitor as a monotherapy or part of combination therapy for advanced malignancies, who either did or did not have FGFR genetic alterations. And interestingly in this study, patients who had FGFR fusions had a benefit with regards to outcomes. In particular, median progression-free survival and overall survival for patients with FGFR alterations in particular fusions, with 7 months and 21 months respectively, whereas patients who had either no FGFR alterations or who had mutations, did not benefit from treatment with FGFR inhibitor pemigatinib.

There is currently another trial that is open the FIGHT-302 study that is recruiting, which will compare pemigatinib to conventional chemotherapy, i.e. gemcitabine-cisplatin to evaluate the efficacy of FGFR targeting among patients with unresectable or metastatic cholangiocarcinoma who have FGFR2 rearrangements.

One of the challenges and drawbacks, both with IDH and FGFR targeted therapy is that many of these patients will develop resistance. So even though patients may have an initial response to therapy, there can be acquired resistance to FGFR therapy in particular, which can be problematic and lead to only short-term benefits of these therapies. In the future, there'll have to be a greater understanding of the resistance pathways of how patients develop resistance to IDH and FGFR therapies, and how we can overcome these resistant pathways in the future, so that we can have more durable responses from targeted therapy.

That being said, patients who present with cholangiocarcinoma now and in particular intraoperative cholangiocarcinoma, the standard of care really should be to molecularly profile these tumors to look for IDH mutations and FGFR genetic alterations, and in particular fusions, to see if patients may benefit from targeted therapy, either as second-line therapy or possibly be candidates for accrual to several ongoing trials that continue to investigate the role of targeted therapy for cholangiocarcinoma.

Source:

Brown ZJ, Ruff SM, and Pawlik TM. Developments in FGFR and IDH inhibitors for cholangiocarcinoma therapy. Expert Rev Anticancer Ther. Published February 9, 2023. doi:10.1080/14737140.2023.2176846