The Lynx Group
Cholangiocarcinoma News

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.

At the 2020 Annual Cholangiocarcinoma Summit, Ghassan Abou-Alfa, MD, MBA, Attending Physician, Memorial Sloan Kettering Cancer Center, New York, NY, discussed the growing list of molecular targets for CCA, the role of gatekeeper mutations and FGFR alterations, and strategies for building on recent advances.

“We are all delighted to see these major achievements, which highlight the clinical relevance of tumor mutation profiling in the management of CCA. As we continue to develop molecular targets, genetic testing is going to be very critical,” said Dr Abou-Alfa.

The phase 3 ClarIDHy study showed a 63% reduction in disease progression risk or death with ivosidenib compared with placebo in patients with advanced CCA and IDH1 mutation. Although overall survival data are difficult to interpret because of the study’s crossover design, there was an “evident improvement” in progression-free survival (PFS) with ivosidenib, Dr Abou-Alfa said.

FGFR Inhibition

Ivosidenib joins a treatment armamentarium that remains focused on FGFR fusions, specifically FGFR2. Pemigatinib, the first targeted therapy approved for CCA, demonstrated a 36% response rate and 21-month median overall survival in patients with CCA and FGFR2 mutation.

“We are all amazed by these numbers,” said Dr Abou-Alfa. “These data highlight the importance of genetic alterations in survival.”

Additional FGFR inhibitors are under investigation. In a recent phase 2 single-arm clinical trial, infigratinib, an FGFR2 inhibitor currently under FDA review, outperformed standard chemotherapy as late-line treatment in patients with CCA and FGFR2 fusion, with an overall response rate of 21%. In another study, futibatinib, an FGFR1-4 inhibitor, had a median PFS of 7.2 months, at a median follow-up of 11.4 months.

Derazantinib has also demonstrated a “robust response rate,” according to Dr Abou-Alfa. Another investigative drug, DB1347, showed responses, but these data are still limited.

New Approach to Clinical Trials Needed

Despite these promising findings, given how rare CCA is and how rare are genetic alterations in patients with CCA, novel clinical trial designs are likely needed to achieve meaningful progress, Dr Abou-Alfa noted.

“Comparing molecular targeted therapies to standard of care in the first-line setting poses big challenges with respect to accrual, because we may be ultimately competing with each other,” said Dr Abou-Alfa. “With anti-FGFR2 agents, I think we should abandon the idea of randomizing against a standard of care.”

More important than the improved survival rates associated with anti-FGFR2 therapy versus gemcitabine plus cisplatin, which may be limited, is the timing of the targeted therapy, he added.

“Is giving anti-FGFR2 in the first line, followed by systemic chemotherapy, better than giving it in the second line, after getting systemic chemotherapy?” Dr Abou-Alfa asked. “We need to study sequencing to get the answers that our patients are in dire need of.”

He noted that cooperative groups should also speak with agencies about obtaining approval based on PFS as a primary end point.

Next-Generation Sequencing Is Key

Finally, Dr Abou-Alfa reported “incredible responses” with the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) in patients with biliary tract cancers and BRAF V600E mutation.

“If you have a patient with a BRAF V600E mutation, there’s no doubt that you should offer that therapy,” said Dr Abou-Alfa. “Don’t wait for a phase 3 trial, because it’s not going to happen for a mutation that occurs in less than 5% of patients.”

Dr Abou-Alfa emphasized that the results from studies of CCA and BRAF V600E mutation also underscore the need for next-generation sequencing as early as possible in the disease course.

“When a patient with CCA walks in the door, the first thing you should do is get next-generation sequencing. There is now a minimum 25% chance of being able to treat CCA with a targeted therapy,” Dr Abou-Alfa said.

“Next-generation sequencing is not a choice any longer—it’s a must. If we don’t have data on next-generation sequencing when we read the CCA pathology, we have an incomplete report,” he emphasized.

Related Items

Hot Topics in Cholangiocarcinoma and Biliary Tract Cancers: ASCO Highlights
September/October 2021, Vol 2, No 3
At the CCA Summit during the 2021 Annual Meeting of the American Society of Clinical Oncology (ASCO), Mitesh J. Borad, MD, Associate Professor of Medicine, Mayo Clinic, Phoenix, AZ, reviewed some of the key topics presented at ASCO 2021 related to cholangiocarcinoma (CCA) and other biliary tract cancers. Before turning to the specific presentations, Dr Borad welcomed the May 28, 2021, FDA approval of infigratinib (Truseltiq) for patients with advanced or metastatic CCA and FGFR2 fusions or rearrangements. Infigratinib follows pemigatinib (Pemazyre) as the second targeted therapy now available for this patient population.
Important Role of Screening for Genomic Alterations in Cholangiocarcinoma
September/October 2021, Vol 2, No 3
Comprehensive molecular profiling has demonstrated a diverse landscape of oncogenic genomic alterations in cholangiocarcinoma (CCA), which are often the drivers of CCA. In a recent review article, Tanios S. Bekaii-Saab, MD, FACP, Vice Chair and Section Chief for Medical Oncology, Department of Internal Medicine, Mayo Clinic Cancer Center, Phoenix, AZ, and colleagues provided an overview of the molecular heterogeneity of CCA, discussing the role of molecular tests for the diagnosis of patients with intrahepatic CCA, and the implications of the genomic alterations in the treatment of patients with this aggressive disease.
Tibsovo First Targeted Therapy FDA Approved for Advanced or Metastatic CCA with IDH1 Mutation
September/October 2021, Vol 2, No 3
On August 25, 2021, the FDA approved ivosidenib (Tibsovo; Servier Pharmaceuticals), an oral IDH1 inhibitor, for the treatment of adults with previously treated, locally advanced or metastatic cholangiocarcinoma (CCA) and an IDH1 mutation, as detected by an FDA-approved test. The FDA granted ivosidenib a priority review for this indication and an orphan drug designation.
Role of Intraductal Treatment and Endoscopic Oncologists in the Management of Unresectable Extrahepatic Cholangiocarcinoma
September/October 2021, Vol 2, No 3
Although cholangiocarcinoma (CCA) is a rare cancer that originates in the bile ducts, its incidence rate continues to rise in the United States, and many patients are diagnosed late, with unresectable tumor and poor prognosis. The majority of patients with extrahepatic CCA, including the perihilar subtype, require referral to a center with expertise in endoscopic retrograde cholangiopancreatography (ERCP) and interventional radiology, because of the complexities in obtaining a definitive diagnosis and durable biliary drainage.
Role of Radiology in Intrahepatic Cholangiocarcinoma Addressed at 2 Interventional Oncology and Radiology Meetings
September/October 2021, Vol 2, No 3
Key topics related to intrahepatic cholangiocarcinoma (CCA) were presented at the 2021 Society of Interventional Oncology (SIO) and the Society of Interventional Radiology (SIR) meetings and were discussed at the CCA Summit. Bruno C. Odisio, MD, FSIR, Interventional Radiologist and Co-Director of Research, Interventional Radiology, M.D. Anderson Cancer Center, Houston, TX, reviewed the findings.
Ivosidenib Approved for Advanced or Metastatic Cholangiocarcinoma
Web Exclusives
Ivosidenib has been approved by the FDA for adult patients with previously treated, locally advanced or metastatic cholangiocarcinoma with an isocitrate dehydrogenase-1 mutation as detected by an FDA-approved test.
Recent Developments in Genomic-Driven Therapies for Cholangiocarcinoma
June/July 2021, Vol 2, No 2
Personalized medicine has expanded the treatment options for patients with cholangiocarcinoma (CCA). At the 2021 Annual Meeting of the Cholangiocarcinoma Foundation (CCF), Ghassan K. Abou-Alfa, MD, MBA, Professor of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, discussed recent developments in personalized therapies, highlighting genomic alterations that are informing the new therapies for patients with CCA.
FDA Grants Accelerated Approval to Infigratinib for Metastatic Cholangiocarcinoma
June/July 2021, Vol 2, No 2
The FDA granted accelerated approval to the kinase inhibitor infigratinib (Truseltiq) for the treatment of adult patients with previously treated, locally advanced or metastatic cholangiocarcinoma (CCA) that harbors an FGFR2 fusion or other rearrangement.
Futibatinib in Intrahepatic Cholangiocarcinoma with FGFR2 Fusions or Rearrangements: Primary Results of FOENIX-CCA2 Presented at AACR 2021
June/July 2021, Vol 2, No 2
The primary results of the phase 2 FOENIX-CCA2 clinical trial of futibatinib in patients with previously treated intrahepatic cholangiocarcinoma (CCA) and FGFR2 fusions or rearrangements were presented by Lipika Goyal, MD, MPhil, Assistant Professor of Medicine, Massachusetts General Hospital, Boston, at the 2021 Annual Meeting of the American Association for Cancer Research (AACR).
Truseltiq (Infigratinib) New Targeted Therapy FDA Approved for Advanced or Metastatic Cholangiocarcinoma Harboring FGFR2 Alterations
By Loretta Fala
June/July 2021, Vol 2, No 2
Cholangiocarcinoma (CCA) represents a group of heterogeneous cancers that originate in the bile ducts that connect the liver and gallbladder to the small intestine. Although the exact prevalence of CCA is unknown, CCA is a rare cancer; approximately 8000 new cases of CCA are diagnosed annually in the United States.

Subscribe to CCA News

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

I'd like to receive: