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Ivosidenib Added to NCCN’s 2020 Hepatobiliary Cancers Guidelines Update

August 2020, Vol 1, No 1

The National Comprehensive Cancer Network (NCCN) added the targeted agent ivosidenib (Tibsovo) to its recent 2020 hepatobiliary cancers guidelines update, which was published on June 1, 2020.1 Recommendations within the NCCN’s hepatobiliary cancers guidelines are derived from critical evaluation of evidence, integrated with the clinical expertise and consensus of a multidisciplinary panel of cancer specialists, clinical experts, and researchers.

When new clinical data become available that have the potential to be appropriate for the guidelines, the NCCN Guidelines Panel meets to assess the information and consider whether it is applicable for inclusion in the guidelines.

A New IDH1 Inhibitor

Ivosidenib is an oral targeted inhibitor of isocitrate dehydrogenase-1 (IDH1) mutation, which is approved by the US Food and Drug Administration (FDA) for the treatment of newly diagnosed patients with acute myeloid leukemia (AML) and IDH1 mutation who are aged ≥75 years or who are ineligible for intensive induction chemotherapy, as well as for the treatment of patients with relapsed or refractory AML.2

As of the time of this publication, ivosidenib has not been approved in any other country, including the United States, for the treatment of patients with cholangiocarcinoma (CCA). Off-label drug use is a frequent component of care for patients with cancer.

The NCCN has sometimes included recommendations for drug use in its clinical guidelines for off-label use when appropriate evidence is available. The NCCN’s recommendations for use beyond the FDA-approved indications rely on the robustness of the evidence supporting such inclusion, with a significant subset of these drugs later becoming approved by the FDA for those indications.

The NCCN Panel Recommendation

Recommendation The NCCN Guidelines Panel reviewed the recent evidence for ivosidenib, including data from the phase 1 and phase 3 clinical trials that support the use of ivosidenib as a treatment option for patients with unresectable or metastatic (CCA) who received 1 or 2 previous regimens and have an IDH1 mutation.3,4

Based on this evidence, the NCCN panel recommended the inclusion of ivosidenib in the NCCN’s recent hepatobiliary cancers guidelines update as a treatment option for certain patients with intrahepatic or extrahepatic CCA.

Up to 25% of patients with CCA, most often patients with intrahepatic CCA, have an IDH1 mutation.3 The phase 1 clinical trial of ivosidenib included heavily pretreated patients with advanced CCA and IDH1 mutation.3 In this study, ivosidenib was found to be safe and a benefit was observed in patients who received ivosidenib,3 which then supported the progression to a phase 3 clinical trial.4

In the phase 3 ClarIDHy clinical trial, ivosidenib was investigated as a treatment option in patients with previously treated CCA and IDH1 mutation,4 which is a patient population that has limited treatment options and thus a high, unmet need.

The NCCN panel that reviewed the data from these clinical trials designated the use of ivosidenib as Category 2A recommendations.1

The NCCN Drugs & Biologics Compendium recommendation for ivosidenib specifically recommends it as “Subsequent treatment as a single agent (useful in certain circumstances) for progression on or after systemic treatment for unresectable or metastatic disease with an isocitrate dehydrogenase (IDH1) mutation.”5

The compendium classifies it as a Category 2A.5 Under the NCCN Categories of Evidence and Consensus, Category 2A states that, “Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.”6

Furthermore, “Useful in certain circumstances” is defined by the NCCN Categories of Evidence and Consensus as “other interventions that may be used for selected patient populations (defined with recommendation).”6

The panel consensus did not support a recommendation of Category 1 for this agent. Category 1 states that “based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.”

There is a significant, unmet need for new therapies for patients with unresectable or metastatic CCA, regardless of the molecular aberration they may have. Approximately 8000 patients are newly diagnosed with CCA in the United States annually.7 Of that number, 25% represents 2000 new patients with an IDH1 mutation.

Before this new NCCN recommendation, the only treatment option available for patients with CCA and IDH1 mutation was the standard of care. The inclusion of ivosidenib in the 2020 NCCN hepatobiliary cancers guidelines represents a new treatment option for patients with CCA and IDH1 mutation and is an important step in offering hope to patients with a poor prognosis.

Expert Commentary

In an interview with CCA News, Al B. Benson III, MD, FACP, FASCO, Professor of Medicine and Associate Director for Clinical Investigations, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, commented on the NCCN’s inclusion of ivosidenib in its most recent guidelines for hepatobiliary cancers.

“This is another example of developing treatment regimens that are specific for particular biological profiles in select patients,” Dr Benson said.

“This also supports the use of next-generation testing for this disease. Many oncologists are using next-generation testing for patients with cholangiocarcinoma, but this represents a chance to identify even more patients with mutations, because oncologists will now be requesting pathologists to look for IDH1 mutations,” he added.

Furthermore, “This is also a disease where there are limited treatment options. This will serve as a step forward for a subset of patients to have additional therapeutic opportunities when they have progressed after standard therapy,” Dr Benson concluded.


  1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Hepatobiliary Cancers. Version 4.2020. June 19, 2020. Accessed July 22, 2020.
  2. Tibsovo (ivosidenib tablets), for oral use [prescribing information]. Cambridge, MA: Agios Pharmaceuticals; May 2019.
  3. Lowery MA, Burris HA III, Janku F, et al. Safety and activity of ivosidenib in patients with IDH1-mutant advanced cholangiocarcinoma: a phase 1 study. Lancet Gastroenterol Hepatol. 2019;4:711-720.
  4. Abou-Alfa GK, Macarulla Mercade T, Javle M, et al. ClarIDHy: a global, phase III, randomized, double-blind study of ivosidenib (IVO) vs placebo in patients with advanced cholangiocarcinoma (CC) with an isocitrate dehydrogenase 1 (IDH1) mutation. Ann Oncol. 2019;30(suppl 5):Abstract LBA10_PR.
  5. National Comprehensive Cancer Network. NCCN Drugs and Biologics Compendium-Ivosidenib.pdf. Accessed June 1, 2020.
  6. National Comprehensive Cancer Network. NCCN Categories of Evidence and Consensus. Accessed July 22, 2020.
  7. American Cancer Society. Key statistics for bile duct cancer. Accessed July 22, 2020.

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