The Lynx Group
Cholangiocarcinoma News

FGFR Inhibition in Cholangiocarcinoma: Overcoming Acquired Resistance

December 2020, Vol 1, No 3

In April 2020, the FDA granted accelerated approval to pemigatinib (Pemazyre), the first targeted therapy for cholangiocarcinoma (CCA). The FGFR inhibitor was approved for adults with CCA and FGFR2 fusion.

After decades in which patients with CCA had only chemotherapy treatment options, the FDA approval of pemigatinib represents a major milestone in the treatment of this disease, according to Lipika Goyal, MD, MPhil, Assistant Professor, Medicine, Harvard Medical School, Boston, MA. However, although pemigatinib has demonstrated remarkable clinical efficacy, treatment responses are still short-lived. Only 18% of patients included in the landmark clinical trial that led to the drug’s approval had a response lasting ≥12 months.

At the 2020 Annual Cholangiocarcinoma Summit, Dr Goyal discussed the mechanisms of resistance to FGFR inhibition and strategies for improving the current approaches to treatment.

“CCA is only the third gastrointestinal cancer with a biomarker specific targeted therapy approved, so we’re excited about our [recent progress],” said Dr Goyal. “We’re seeing great responses in many patients; however, they’re not as prolonged as we would like them to be.”

But, she added, “We may not be squeezing as much out of this lemon as we can.”

Overcoming Acquired Resistance

According to Dr Goyal, FGFR2 fusions and rearrangements are seen in approximately 10% to 15% of patients with intrahepatic CCA. The FIGHT-202 study, which led to the approval of pemigatinib, an adenosine triphosphate (ATP)-competitive, reversible selective FGFR inhibitor, demonstrated an overall response rate of 35.5%, a disease control rate of 82%, and a duration of response of 7.5 months.

“Such good response rates and durations of response are great for CCA, and certainly better than what we see with chemotherapy in an unselected population, but it doesn’t quite match up to what we see in other ‘oncogene-addicted’ tumors,” said Dr Goyal. She noted that the response rates can exceed 70% in patients with lung cancer and EGFR mutations who receive treatment with EGFR inhibitors.

A better understanding of acquired resistance could help extend durations of response, she said. Recent studies have shown, for example, that in patients whose disease progressed after receiving treatment with an ATP-competitive inhibitor, such as pemigatinib, 1 or more FGFR2 kinase domain mutations may emerge.

One of the most common alterations is in the FGFR2 V565 residue, the so-called gatekeeper alteration, but researchers have also seen multiple mutations in the “molecular brake.” In fact, Dr Goyal and colleagues believe that polyclonal resistance is one explanation for the short duration of response seen with FGFR inhibition.

“We have found that patients with polyclonal resistance have a lower median progression free survival than those who develop monoclonal resistance,” said Dr Goyal. “The 2 residues that we want to make sure we target with the next-generation inhibitors are the gatekeeper and the molecular break, V565 and V550.”

Improving Treatment Sequencing

Understanding tumor heterogeneity and addressing it up front will be important in preventing resistance in patients with CCA, Dr Goyal explained. One approach to overcoming tumor heterogeneity is sequential treatment with different FGFR inhibitors based on their spectrum of activity and the different genetic alterations that emerge during disease progression. This strategy could potentially prolong the duration of benefit from FGFR inhibition.

“Giving futibatinib, a covalent inhibitor, up front is one possibility,” she said. “Because pemigatinib is now approved, however, we should consider doing postprogression analysis for resistance to see if patients might be candidates for a covalent inhibitor.”

Given the different spectrums of activity of FGFR inhibitors, serial circulating tumor DNA (ctDNA) analysis could help clinicians determine how to sequence these agents more effectively based on which alterations emerge during disease progression. Many clinical trials are currently using ctDNA to understand resistance.

“The next generation inhibitors with potency against the FGFR2 kinase domain mutations are going to be key to prolonging response in this disease,” said Dr Goyal. “We also need to think about combination strategies.”

“This is a rare disease,” Dr Goyal added. “The only path forward is if we all work together.”

Related Items

Targeted Therapies in Cholangiocarcinoma: Next-Generation Sequencing Is a Must
December 2020, Vol 1, No 3
The recent FDA approval of the first FGFR inhibitor, pemigatinib (Pemazyre), and the positive results from the phase 3 study of the first IDH1 inhibitor, ivosidenib (Tibsovo), represent major breakthroughs in the treatment of patients with cholangiocarcinoma (CCA), a rare cancer associated with poor outcomes. However, the duration of response with these agents is still relatively short.
Gallbladder Cancer: Novel Approaches to Therapy Are Needed
December 2020, Vol 1, No 3
The current standard of care for the systemic treatment of patients with advanced gallbladder cancer is the chemotherapy combination of gemcitabine and cisplatin, which is suboptimal, yielding only modest benefit, said Richard Kim, MD, Section Chief, Gastrointestinal Medical Oncology, Moffitt Cancer Center, Tampa, FL, at the 2020 Cholangiocarcinoma Summit.
Emerging Molecular Targets in Cholangiocarcinoma: IDH1, HER2, BRAF, and Beyond
December 2020, Vol 1, No 3
Targeted therapy has improved survival for patients with cancer across a broad spectrum of disease sites, but until recently, progress has been slow in the treatment of patients with cholangiocarcinoma (CCA).
Improving Chemotherapy Combinations and Novel Treatments Are Needed in Advanced Biliary Tract Cancer
December 2020, Vol 1, No 3
New cytotoxic chemotherapy regimens and novel combinations are being evaluated in clinical trials in an effort to improve the outcomes of chemotherapy in the adjuvant and palliative settings in patients with biliary tract cancer, including cholangiocarcinoma (CCA), said Angela Lamarca, MD, PhD, MSc, Consultant, Medical Oncology, the Christie NHS Foundation Trust, Manchester, United Kingdom. She discussed the future of cytotoxic chemotherapy for this patient population at the 2020 Cholangiocarcinoma Summit.
Role of Liver Transplant in Patients with Cholangiocarcinoma
December 2020, Vol 1, No 3
Liver transplant is emerging as a treatment option in patients with unresectable hilar or intrahepatic cholangiocarcinoma (CCA), with accumulating data supporting transplant protocols in patients with early-stage CCA.
The Oncology Pipeline Offers Hope for Patients with Cholangiocarcinoma
December 2020, Vol 1, No 3
Despite the onslaught of the COVID-19 pandemic, researchers are hard at work to develop innovative therapies that will make a difference in the lives of patients with cancer.
Genomic Testing in Cholangiocarcinoma: Look for Actionable Molecular Alterations
December 2020, Vol 1, No 3
At the 2020 Cholangiocarcinoma Summit, Nabeel El-Bardeesy, PhD, Associate Professor, Medicine, Harvard Medical School, and Associate Geneticist, Center for Cancer Research, Massachusetts General Hospital Cancer Center, Boston, MA, moderated a session titled “Molecular Biomarkers in CCA: Focus on Current and Emerging Technologies.” The session focused on how best to integrate the array of genomic testing platforms into clinical practice. The session included 2 presenters who discussed this topic.
Zanidatamab Addresses an Unmet Need in Patients with HER2-Amplified Biliary Tract Cancer
December 2020, Vol 1, No 3
Patients with relapsed or refractory HER2-amplified biliary tract cancer have few treatment options after first-line therapy. Shubham Pant, MD, Associate Professor, Gastrointestinal Oncology, M.D. Anderson Cancer Center, Houston, TX, presented the results of a phase 1 clinical trial he and his colleagues conducted. The study examined the safety and antitumor activity of zanidatamab, a bispecific (ie, binding to 2 distinct sites on the HER2 receptor) HER2-targeted antibody. The unique antibody geometry of zanidatamab enables it to activate several mechanisms of action after binding to the HER2 receptor.
Increasing Number of Biomarkers Being Studied in Cholangiocarcinoma Clinical Trials
December 2020, Vol 1, No 3
At diagnosis, the majority of patients with intrahepatic cholangiocarcinoma (CCA) present with advanced disease and a poor prognosis. Comprehensive genomic profiling (CGP) of intrahepatic CCA has revealed multiple potential therapeutic targets, including FGFR2, ERBB2 (HER2), and IDH1. Therefore, performing CGP early in the disease course is critical to increasing first-line clinical trial enrollment and access to treatment with FGFR inhibitors.
Telotristat Ethyl and First-Line Chemotherapy Combination Investigated for Advanced Biliary Tract Cancer
December 2020, Vol 1, No 3
The metabolism of serotonin is dysregulated in cholangiocarcinoma (CCA) cell lines compared with normal cholangiocytes and in tissue and bile from patients with CCA.1 Telotristat ethyl (Xermelo) is a tryptophan hydroxylase inhibitor that is indicated for the treatment of patients with carcinoid syndrome–related diarrhea not well-controlled by somatostatin analog. Telotristat ethyl is currently being investigated for the treatment of patients with biliary tract cancer, including CCA tumors that express serotonin.

Subscribe to CCA News

Stay up to date with personalized medicine by subscribing to recieve the free CCA News print publication or weekly e‑Newsletter.

I'd like to recieve: