NCCN Guidelines® Insights: Biliary Tract Cancers, Version 2.2023

Featured Updates to the NCCN Guidelines

Authors:
Al B. Benson III Robert H. Lurie Comprehensive Cancer Center of Northwestern University

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Michael I. D’Angelica Memorial Sloan Kettering Cancer Center

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Thomas Abrams Dana-Farber/Brigham and Women’s Cancer Center

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Daniel E. Abbott University of Wisconsin Carbone Cancer Center

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Aijaz Ahmed Stanford Cancer Institute

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Daniel A. Anaya Moffitt Cancer Center

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Robert Anders The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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Chandrakanth Are Fred & Pamela Buffett Cancer Center

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Melinda Bachini The Cholangiocarcinoma Foundation

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David Binder University of Colorado Cancer Center

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Mitesh Borad Mayo Clinic Comprehensive Cancer Center

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Christopher Bowlus UC Davis Comprehensive Cancer Center

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Daniel Brown Vanderbilt-Ingram Cancer Center

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Adam Burgoyne UC San Diego Moores Cancer Center

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Jason Castellanos Fox Chase Cancer Center

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Prabhleen Chahal Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute

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Jordan Cloyd The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute

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Anne M. Covey Memorial Sloan Kettering Cancer Center

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Evan S. Glazer The University of Tennessee Health Science Center

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William G. Hawkins Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

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Renuka Iyer Roswell Park Comprehensive Cancer Center

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Rojymon Jacob O’Neal Comprehensive Cancer Center at UAB

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Lawrence Jennings Robert H. Lurie Comprehensive Cancer Center of Northwestern University

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R. Kate Kelley UCSF Helen Diller Family Comprehensive Cancer Center

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Robin Kim Huntsman Cancer Institute at the University of Utah

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Matthew Levine Abramson Cancer Center at the University of Pennsylvania

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Manisha Palta Duke Cancer Institute

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James O. Park Fred Hutchinson Cancer Center

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Steven Raman UCLA Jonsson Comprehensive Cancer Center

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Sanjay Reddy Fox Chase Cancer Center

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Sean Ronnekleiv-Kelly University of Wisconsin Carbone Cancer Center

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Vaibhav Sahai University of Michigan Rogel Cancer Center

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Gagandeep Singh City of Hope National Medical Center

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Stacey Stein Yale Cancer Center/Smilow Cancer Hospital

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Anita Turk Indiana University Melvin and Bren Simon Comprehensive Cancer Center

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Jean-Nicolas Vauthey The University of Texas MD Anderson Cancer Center

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Alan P. Venook UCSF Helen Diller Family Comprehensive Cancer Center

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Adam Yopp UT Southwestern Simmons Comprehensive Cancer Center

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Nicole McMillian National Comprehensive Cancer Network

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Ryan Schonfeld National Comprehensive Cancer Network

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Cindy Hochstetler National Comprehensive Cancer Network

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Full access

In 2023, the NCCN Guidelines for Hepatobiliary Cancers were divided into 2 separate guidelines: Hepatocellular Carcinoma and Biliary Tract Cancers. The NCCN Guidelines for Biliary Tract Cancers provide recommendations for the evaluation and comprehensive care of patients with gallbladder cancer, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma. The multidisciplinary panel of experts meets at least on an annual basis to review requests from internal and external entities as well as to evaluate new data on current and emerging therapies. These Guidelines Insights focus on some of the recent updates to the NCCN Guidelines for Biliary Tract Cancers as well as the newly published section on principles of molecular testing.

NCCN Continuing Education

Target Audience: This activity is designed to meet the educational needs of oncologists, nurses, pharmacists, and other healthcare professionals who manage patients with cancer.

Accreditation Statements

In support of improving patient care, National Comprehensive Cancer Network (NCCN) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

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Physicians: NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Nurses: NCCN designates this educational activity for a maximum of 1.0 contact hour.

Pharmacists: NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: JA4008196-0000-23-007-H01-P

PAs: NCCN has been authorized by the American Academy of PAs (AAPA) to award AAPA Category 1 CME credit for activities planned in accordance with AAPA CME Criteria. This activity is designated for 1.0 AAPA Category 1 CME credit. Approval is valid until July 10, 2024. PAs should only claim credit commensurate with the extent of their participation.

All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: (1) review the educational content; (2) take the posttest with a 66% minimum passing score and complete the evaluation at https://education.nccn.org/node/92923; and (3) view/print certificate.

Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Before completing these requirements, be sure your NCCN profile has been updated with your NAPB e-profile ID and date of birth. Your credit cannot be reported without this information. If you have any questions, please email education@nccn.org.

Release date: July 10, 2023; Expiration date: July 10, 2024

Learning Objectives:

Upon completion of this activity, participants will be able to:

  • • Integrate into professional practice the updates to the NCCN Guidelines for Biliary Tract Cancers

  • • Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Biliary Tract Cancers

Disclosure of Relevant Financial Relationships

None of the planners for this educational activity have relevant financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.

Individuals Who Provided Content Development and/or Authorship Assistance:

The faculty listed below have no relevant financial relationship(s) with ineligible companies to disclose.

Michael I. D’Angelica, MD, Panel Vice Chair

Nicole R. McMillian, MS, CHES, Senior Guidelines Coordinator, NCCN

Ryan Schonfeld, Guidelines Layout/Support Specialist, NCCN

Cindy Hochstetler, PhD, Oncology Scientist/Medical Writer, NCCN

The faculty listed below have the following relevant financial relationship(s) with ineligible companies to disclose. All of the relevant financial relationships listed for these individuals have been mitigated.

Al B. Benson, III, MD, Panel Chair, has disclosed receiving grant/research support from AbbVie, Inc., Amgen Inc., Apexigen, Artemida Pharma, Cardiff Oncology, Elevar Therapeutics, Infinity Pharmaceuticals, Inc., ITM Solucin, MedImmune Inc., Janssen Pharmaceutica Products, LP, Merck Sharpe & Dohme Ltd, Pfizer Inc., Rafael Pharmaceuticals, ST Pharm Co. Ltd, SynCore Biotechnology, and TYME Technologies, Inc.; receiving consulting fees from Aveo Oncology, Boston Scientific Corporation, Bristol-Myers Squibb Company, GlaxoSmithKline, GRAIL, HalioDx, Janssen Pharmaceutica Products, LP, Mirati Therapeutics, Inc., Nuvation Bio, Inc., Pfizer Inc., Samsung Bioepis, SeaGen, Taiho Pharmaceuticals Co., Ltd., and Xencor; and serving as a scientific advisor for AIM ImmunoTech, Array BioPharma Inc., Astellas Pharma US, Inc., Boston Scientific Corporation, HUTCHMED, Mirati Therapeutics, Inc., Natera Inc., Novartis Pharmaceuticals Corporation, SeaGen, Tempus, and TheraBionic.

To view all of the conflicts of interest for the NCCN Guidelines panel, go to NCCN.org/guidelines/guidelines-panels-and-disclosure/disclosure-panels

This activity is supported by educational grants from AstraZeneca; Exact Sciences; Novartis; and Taiho Oncology, Inc. This activity is supported by an independent educational grant from Daiichi Sankyo. This activity is supported by independent medical education grants from Illumina, Inc. and Regeneron Pharmaceuticals, Inc.

Overview

Gallbladder cancer and cholangiocarcinomas (CCAs) are collectively known as biliary tract cancers (BTCs). In 2023, it is estimated that 41,210 people in the United States will be diagnosed with liver cancer and intrahepatic bile duct cancer and an additional 12,220 people will be diagnosed with gallbladder cancer or other BTC.1 Furthermore, approximately 29,380 deaths from liver or intrahepatic bile duct cancer and 4,510 deaths due to gallbladder cancer or other BTC are anticipated.

The prognosis of patients with advanced BTCs is poor and the median survival for those undergoing supportive care alone is short.2 Treatment options for advanced BTCs may include systemic therapy, enrollment in a clinical trial, palliative radiation therapy (RT), RT with concurrent fluoropyrimidine, consideration of locoregional therapy (RT or arterially directed therapies), and best supportive care, depending on the disease stage and specific disease subtype. Selection of subsequent-line systemic therapy for progressive disease depends on clinical factors including previous treatment regimen/agent, somatic molecular testing results, and extent of liver dysfunction.

Primary Systemic Treatment of Unresectable and Metastatic Disease

The phase III TOPAZ-1 trial, which randomized 685 patients with unresectable or metastatic BTC with no prior treatment 1:1 to either treatment with durvalumab in combination with gemcitabine + cisplatin or treatment with placebo in combination with gemcitabine + cisplatin, demonstrated that addition of durvalumab to gemcitabine + cisplatin significantly improved overall survival (OS) (hazard ratio [HR], 0.80; P=.021) and progression-free survival (PFS) (HR, 0.75; P=.001).3 The objective response rate (ORR) was 26.7% for the durvalumab group and 18.7% in the placebo group. Additionally, 75.7% of patients treated with durvalumab in combination with gemcitabine + cisplatin experienced a grade 3 or 4 adverse event compared with 77.8% of patients treated with placebo in combination with gemcitabine + cisplatin.

Following the publication of the data for durvalumab in combination with gemcitabine + cisplatin, the panel revised the recommendation for this regimen from a category 2B, other recommended regimen to a category 1, preferred regimen for first-line systemic treatment of unresectable or metastatic BTCs (see BIL-C 2 of 5, page 702). This regimen is also a recommended treatment option for patients who developed recurrent disease >6 months after surgery with curative intent and >6 months after completion of adjuvant therapy. At the annual meeting, the panel revised the category of evidence and consensus for this regimen as a subsequent-line systemic therapy option (other recommended regimen) for progressive disease from a category 2B to a category 1 recommendation in patients who have not been previously treated with a checkpoint inhibitor. Given that gemcitabine in combination with cisplatin was the comparator arm for the TOPAZ-1 trial and durvalumab + gemcitabine + cisplatin showed superiority in the endpoints discussed earlier, the panel consensus was to revise the category of preference for gemcitabine + cisplatin from preferred regimen to other recommended regimen. One panel member brought up the fact that 5-fluorouracil with cisplatin or capecitabine with cisplatin, both category 2B recommendations, were not used in clinic. Others agreed and there was a unanimous decision to remove these 2 regimens.

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The phase IIb NIFTY trial showed that treatment with liposomal irinotecan with fluorouracil + leucovorin in patients with confirmed metastatic BTC with disease progression on gemcitabine + cisplatin significantly improved median PFS (7.1 months) compared with treatment with fluorouracil + leucovorin (1.4 months; HR, 0.56; P=.0019).4 In an updated analysis, the median PFS, as assessed by masked independent central review, was 4.2 months for patients treated with liposomal irinotecan with fluorouracil + leucovorin compared with 1.7 months (HR, 0.61; P=.004) for patients treated with fluorouracil + leucovorin.5 Following an external request, the panel voted to include the combination of liposomal irinotecan with fluorouracil + leucovorin as a category 2B, subsequent-line systemic therapy option (other recommended regimen) for unresectable or metastatic progressive disease (see BIL-C 2 of 5, page 702).

Targeted Therapy

BTCs are known to harbor clinically relevant molecular alterations that are differentially expressed in gallbladder cancer and intrahepatic and extrahepatic CCAs. Given the evolving molecular landscape for BTCs, a subcommittee was formed to evaluate data and provide recommendations for a new “Principles of Molecular Testing” section, which includes testing modalities and considerations for various alterations (see BIL-B 16 of 8, pages 696–701). The highlights of this new section were presented during the annual meeting and panel members reviewed this section during the update process. Given emerging evidence regarding actionable targets for treating BTCs, comprehensive molecular profiling is recommended in patients with unresectable or metastatic BTC who are candidates for systemic therapy (see “Principles of Molecular Testing” for additional information regarding testing modalities and considerations; BIL-B 16 of 8, pages 696–701). The panel members noted that the rarity of individual subgroups limits precise incidence and frequency estimates.

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Although most BTCs are considered sporadic, up to 10% to 15% may be associated with an inherited cancer predisposition syndrome.6,7 Because evidence remains insufficient for definitive recommendations regarding specific criteria to guide genetic risk assessment in hepatobiliary cancers or for universal germline testing, genetic counseling referral and potential germline testing should be considered in patients with BTCs with any of the following characteristics: young age at diagnosis, a strong personal or family history of cancer, no known risk factors for liver disease, or the presence of mutations identified during tumor testing which are suspected to be possible germline alterations. For patients who do harbor a known germline mutation associated with a cancer predisposing syndrome (ie, Lynch syndrome or hereditary breast and ovarian cancer syndrome), there is currently insufficient evidence to support screening for biliary tract malignancies.

NTRK Fusions

Two NTRK inhibitors have been approved by the FDA for a tumor-agnostic indication in NTRK fusion–positive solid tumors: larotrectinib8 and entrectinib.9 Entrectinib and larotrectinib are useful in certain circumstances, first-line or subsequent-line (for progressive disease) systemic therapy options for unresectable or metastatic NTRK gene fusion–positive tumors.

Testing for NTRK fusions is recommended in patients with unresectable or metastatic gallbladder cancer, intrahepatic CCA, or extrahepatic CCA. These assessments are feasible in the context of multitarget assessment in next-generation sequencing (NGS) gene panels currently in clinical use, and NTRK fusion–positive CCAs have demonstrated responses in clinical trials.

Immunotherapy Biomarkers (MSI-H/dMMR/ TMB-H/PD-L1)

Pembrolizumab is a useful in certain circumstances first-line or subsequent-line (for progressive disease and with no prior treatment with a checkpoint inhibitor) systemic therapy option for unresectable or metastatic microsatellite instability–high (MSI-H), mismatch repair–deficient (dMMR), or tumor mutational burden–high (TMB-H) (for subsequent-line therapy) BTCs, although the panel cautions that data to support this recommendation are limited, particularly in the first-line setting.10 Dostarlimab-gxly is a category 2B, useful in certain circumstances, subsequent-line systemic therapy option for patients with MSI-H/dMMR recurrent or advanced tumors that have progressed on or following prior treatment, who have no satisfactory alternative treatment options, and who have not been previously treated with a checkpoint inhibitor.

The panel received an external request to consider the inclusion of nivolumab + ipilimumab as a treatment option for tissue TMB-H hepatobiliary cancers. The phase II CheckMate 848 trial randomized patients with advanced or metastatic TMB-H solid tumors with no prior immunotherapy and who had disease refractory to standard local therapies 2:1 to receive the combination of nivolumab + ipilimumab or nivolumab monotherapy.11 Published in an abstract, the data revealed an ORR of 35.3%, a median OS of 14.5 months, and a median PFS of 4.1 months in patients with tissue TMB-H tumors. Based on the data, the panel voted to include nivolumab + ipilimumab as a useful in certain circumstances, first-line (category 2B) or subsequent-line (for progressive disease and with no prior treatment with a checkpoint inhibitor) systemic therapy option for patients with unresectable or metastatic TMB-H tumors (see BIL-C 3 of 5, page 703). In the subsequent-line setting, the recommendation is for patients with disease refractory to standard therapies or who have no standard treatment options available.

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Testing for MSI or dMMR is recommended in patients with unresectable or metastatic gallbladder cancer, intrahepatic CCA, or extrahepatic CCA. Further recommendations for MSI/MMR testing can be found in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer. Testing for TMB is recommended in patients with unresectable or metastatic gallbladder cancer, intrahepatic CCA, or extrahepatic CCA based upon clinical benefit observed across advanced solid tumors.

In advanced BTCs, tumor or tumor plus immune cell PD-L1 expression has shown trends toward higher rates of objective radiographic response in single-arm phase II studies of pembrolizumab or nivolumab as monotherapy, although rates of objective radiographic response are low overall and data from these small, uncontrolled studies are insufficient to warrant a recommendation for testing.12,13

BRAF V600E Mutations

Dabrafenib + trametinib received accelerated approval for BRAF V600E–mutated advanced solid tumors.14,15 The oral combination of dabrafenib + trametinib is a useful in certain circumstances, subsequent-line systemic therapy option for unresectable or metastatic progressive disease with BRAF V600E mutations.

Testing for BRAF V600E mutations is recommended in patients with unresectable or metastatic gallbladder cancer, intrahepatic CCA, or extrahepatic CCA.

FGFR2 Fusions/Other FGFR Pathway Aberrations

Results from the phase II FOENIX-CA2 trial demonstrated an ORR of 42% with futibatinib in patients with previously treated unresectable or metastatic intrahepatic CCA with FGFR2 fusions/rearrangements.16 The median OS, median PFS, median duration of response (DoR), and disease control rate were 21.7 months, 9.0 months, 9.7 months, and 83%, respectively. Pemigatinib’s approval was based on the FIGHT-202 study, an open-label study including 107 patients with advanced, pretreated FGFR2 fusion–positive or FGFR2-rearranged CCA.17,18 The ORR was 35.5%, with a median PFS of 6.9 months and median DoR of 7.5 months.18 Following FDA approval of futibatinib in 2022, the panel voted to include this regimen. Futibatinib and pemigatinib are useful in certain circumstances, subsequent-line systemic therapy options for unresectable or metastatic progressive CCA with FGFR2 fusions or rearrangements (see BIL-C 3 of 5, page 703). Following an internal query, the panel voted to remove infigratinib as a treatment option due to its discontinuation in the United States.

Testing for FGFR2 fusions or rearrangements is recommended in patients with unresectable or metastatic intrahepatic or extrahepatic CCA and should be considered for patients with unresectable or metastatic gallbladder cancer.

IDH1 Mutations

In a randomized phase III study with 185 patients with IDH1-mutated CCA that progressed on standard chemotherapy, ivosidenib resulted in prolongation of PFS over placebo, with a median PFS of 2.7 versus 1.4 months (HR, 0.37; P<.0001).19 Patients with ivosidenib had significantly less decline in physical functioning scores than those treated with placebo. In the intention-to-treat population, the median OS for the ivosidenib and placebo arms were 10.3 months (HR, 0.79; P=.09) and 7.5 months, respectively.20 After taking into account 43 patients who crossed from the placebo arm to the ivosidenib arm, the median OS for the placebo arm was 5.1 months (HR, 0.49; P<.001). Ascites was the most frequently reported grade ≥3 treatment-emergent adverse event in both groups. Ivosidenib has been approved by the FDA for previously treated, locally advanced or metastatic CCA harboring IDH1 mutations. The panel voted on an external request to revise the category of evidence and consensus for ivosidenib from 2A to category 1. Ivosidenib is now listed as a category 1, useful in certain circumstances subsequent-line systemic therapy option for unresectable or metastatic progressive CCA with IDH1 mutations (see BIL-C 3 of 5, page 703).

Testing for IDH1 mutations is recommended in patients with unresectable or metastatic intrahepatic CCA or extrahepatic CCA and should be considered for patients with unresectable or metastatic gallbladder cancer.

HER2/ERBB2 Overexpression/Amplification/Activating Mutations

Early clinical trials of HER2-targeted therapy in BTCs failed to show efficacy,21,22 but these studies were unselected for HER2 overexpression/amplification or mutation. Two phase II studies and a phase I study have reported promising results of HER2-targeted therapy in BTCs.2325 The MyPathway study included 39 patients with HER2-amplified and/or HER2-overexpressed, previously treated, metastatic BTCs.26 Patients received pertuzumab + trastuzumab, and 9 patients achieved a partial response (ORR, 23%) and an additional 11 showed stable disease for >4 months.

Following an external request to add fam-trastuzumab deruxtecan-nxki as an option for HER2-positive tumors in the subsequent-line setting, the panel evaluated the data and noted that there are challenges with rare molecular subgroups in the context of disease progression. Because this request was based on the results of a small study conducted outside of the United States and the data are only in abstract form,27 the panel decided not to add the regimen but agreed to mention the study in the discussion section until more data become available. Results of the phase II HERB trial from Japan, published in an abstract, showed that of 22 evaluable patients with HER2-positive BTCs refractory or intolerant to a gemcitabine-based regimen, 36.4% achieved a significantly improved ORR (P=.01) following treatment with trastuzumab deruxtecan, a HER2-targeted therapy.27 The median OS, PFS, and disease control rate were 7.1 months, 4.4 months, and 81.8%, respectively. Encouraging data were also reported in patients with HER2-low disease (ORR, 12.5%; median OS, 8.9 months; median PFS, 4.2 months; disease control rate, 75.0%). Due to the limited available data, there are currently no HER2-targeted therapies that have been FDA-approved for BTCs. The panel voted to add the combination of trastuzumab + pertuzumab as a useful in certain circumstances, subsequent-line systemic therapy option for unresectable or metastatic progressive disease with HER2-positive tumors (see BIL-C 3 of 5, page 703).

Testing for HER2 (ERBB2) overexpression/amplification is recommended in patients with unresectable or metastatic gallbladder cancer, intrahepatic CCA, or extrahepatic CCA.

Other Biomarkers (RET/ROS1, KRAS G12C/Other KRAS, Other Tumor-Agnostic Markers)

In addition to the genomic alterations described in the previous sections, NGS testing may uncover other potentially actionable molecular alterations that could help determine eligibility for ongoing clinical trials in patients with advanced BTCs. Although there is insufficient evidence to recommend universal assessment, alterations for which targeted therapies exist and have been FDA-approved in other tumor types, including KRAS G12C mutation,2830 MET amplification,3133 and ALK,34 RET,35 or ROS1 fusions,36 among others,37 have been described with variable but overall rare frequency in biliary tract carcinomas and hepatocellular carcinoma.38 However, limited data currently exist regarding the efficacy of targeted therapy in these situations, due to their rarity. In the phase I/II ARROW study, pralsetinib, a selective RET inhibitor, demonstrated an ORR of 57% in patients with RET fusion–positive tumors other than non–small cell lung cancer and thyroid cancer and who received prior treatment or were ineligible for standard therapies.35 The median OS, median PFS, and median DoR were 14 months, 7 months, and 12 months, respectively. A response was observed in 2 of 3 patients who had CCA. The panel voted to include pralsetinib as a category 2B, useful in certain circumstances, first-line or subsequent-line (for progressive disease) systemic therapy option for unresectable or metastatic disease with RET gene fusion–positive tumors (see BIL-C 3 of 5, opposite page).

Selpercatinib, a selective RET kinase inhibitor, was investigated in the phase I/II LIBRETTO-001 clinical trial in patients with RET fusion–positive tumors.39 Of 41 patients evaluable for efficacy and with tumors other than lung or thyroid, the ORR, as assessed by an independent review committee, was 43.9%. An objective response was obtained in the one patient who had CCA. Following the tumor-agnostic approval of selpercatinib for patients with advanced RET fusion–positive tumors, the panel voted to include selpercatinib as a useful in certain circumstances, first-line (category 2B) or subsequent-line (for progressive disease) systemic therapy option for unresectable or metastatic intrahepatic or extrahepatic CCA with RET gene fusion–positive tumors (see BIL-C 3 of 5, above).

Testing for RET fusions is recommended in patients with unresectable or metastatic gallbladder cancer, intrahepatic CCA, or extrahepatic CCA. A comprehensive NGS panel may identify additional alterations for which targeted therapies exist and have FDA-approved treatments in other tumor types.

Conclusions

The NCCN Guidelines for Biliary Tract Cancers are based on the evaluation of published and emerging data and provide recommendations for the management of gallbladder cancer, intrahepatic CCA, and extrahepatic CCA. These NCCN Guidelines Insights highlight some of the updated recommendations in recent years. Given the rapidly evolving landscape for BTCs, molecular testing can potentially guide targeted treatment, and treatment selection depends on clinical factors including previous treatment regimen/agent, somatic molecular testing results, and the extent of liver dysfunction. Ongoing clinical trials are underway to investigate novel agents, and emerging data may help inform the panel’s recommendations.

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  • 8.

    Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med 2018;378:731739.

  • 9.

    Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1–2 trials. Lancet Oncol 2020;21:271282.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Sicklick JK, Kato S, Okamura R, et al. Molecular profiling of cancer patients enables personalized combination therapy: the I-PREDICT study. Nat Med 2019;25:744750.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Schenker M, Burotto M, Richardet M, et al. CheckMate 848: a randomized, open-label, phase 2 study of nivolumab in combination with ipilimumab or nivolumab monotherapy in patients with advanced or metastatic solid tumors of high tumor mutational burden. Cancer Res 2022;82(12 Suppl):Abstract CT022.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Piha-Paul SA, Oh DY, Ueno M, et al. Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: results from the KEYNOTE-158 and KEYNOTE-028 studies. Int J Cancer 2020;147:21902198.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Kim RD, Chung V, Alese OB, et al. A phase 2 multi-institutional study of nivolumab for patients with advanced refractory biliary tract cancer. JAMA Oncol 2020;6:888894.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Subbiah V, Lassen U, Élez E, et al. Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial. Lancet Oncol 2020;21:12341243.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Salama AKS, Li S, Macrae ER, et al. Dabrafenib and trametinib in patients with tumors with BRAFV600E mutations: results of the NCI-MATCH trial Subprotocol H. J Clin Oncol 2020;38:38953904.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Goyal L, Meric-Bernstam F, Hollebecque A, et al. Futibatinib for FGFR2-rearranged intrahepatic cholangiocarcinoma. N Engl J Med 2023;388:228239.

  • 17.

    Silverman IM, Hollebecque A, Friboulet L, et al. Clinicogenomic analysis of FGFR2-rearranged cholangiocarcinoma identifies correlates of response and mechanisms of resistance to pemigatinib. Cancer Discov 2021;11:326339.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Abou-Alfa GK, Sahai V, Hollebecque A, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol 2020;21:671684.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Abou-Alfa GK, Macarulla T, Javle MM, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 2020;21:796807.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Zhu AX, Macarulla T, Javle MM, et al. Final overall survival efficacy results of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation: the phase 3 randomized clinical ClarIDHy trial. JAMA Oncol 2021;7:16691677.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Ramanathan RK, Belani CP, Singh DA, et al. A phase II study of lapatinib in patients with advanced biliary tree and hepatocellular cancer. Cancer Chemother Pharmacol 2009;64:777783.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Peck J, Wei L, Zalupski M, et al. HER2/neu may not be an interesting target in biliary cancers: results of an early phase II study with lapatinib. Oncology 2012;82:175179.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Hainsworth JD, Meric-Bernstam F, Swanton C, et al. Targeted therapy for advanced solid tumors on the basis of molecular profiles: results from MyPathway, an open-label, phase IIa multiple basket study. J Clin Oncol 2018;36:536542.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Hyman DM, Piha-Paul SA, Won H, et al. HER kinase inhibition in patients with HER2- and HER3-mutant cancers. Nature 2018;554:189194.

  • 25.

    Meric-Bernstam F, Beeram M, Hamilton E, et al. Zanidatamab, a novel bispecific antibody, for the treatment of locally advanced or metastatic HER2-expressing or HER2-amplified cancers: a phase 1, dose-escalation and expansion study. Lancet Oncol 2022;23:15581570.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Javle M, Borad MJ, Azad NS, et al. Pertuzumab and trastuzumab for HER2-positive, metastatic biliary tract cancer (MyPathway): a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol 2021;22:12901300.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Ohba A, Morizane C, Kawamoto Y, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing unresectable or recurrent biliary tract cancer (BTC): an investigator-initiated multicenter phase 2 study (HERB trial). J Clin Oncol 2022;40(Suppl):Abstract 4006.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Ou SI, Jänne PA, Leal TA, et al. First-in-human phase I/IB dose-finding study of adagrasib (MRTX849) in patients with advanced KRASG12C solid tumors (KRYSTAL-1). J Clin Oncol 2022;40:25302538.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Hong DS, Fakih MG, Strickler JH, et al. KRASG12C inhibition with sotorasib in advanced solid tumors. N Engl J Med 2020;383:12071217.

  • 30.

    Skoulidis F, Li BT, Dy GK, et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med 2021;384:23712381.

  • 31.

    Goyal L, Zheng H, Yurgelun MB, et al. A phase 2 and biomarker study of cabozantinib in patients with advanced cholangiocarcinoma. Cancer 2017;123:19791988.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Pant S, Saleh M, Bendell J, et al. A phase I dose escalation study of oral c-MET inhibitor tivantinib (ARQ 197) in combination with gemcitabine in patients with solid tumors. Ann Oncol 2014;25:14161421.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med 2018;379:5463.

  • 34.

    Zhou Y, Lizaso A, Mao X, et al. Novel AMBRA1-ALK fusion identified by next-generation sequencing in advanced gallbladder cancer responds to crizotinib: a case report. Ann Transl Med 2020;8:1099.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.

    Subbiah V, Cassier PA, Siena S, et al. Pan-cancer efficacy of pralsetinib in patients with RET fusion-positive solid tumors from the phase 1/2 ARROW trial. Nat Med 2022;28:16401645.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36.

    Gu TL, Deng X, Huang F, et al. Survey of tyrosine kinase signaling reveals ROS kinase fusions in human cholangiocarcinoma. PLoS One 2011;6:e15640.

  • 37.

    Argani P, Palsgrove DN, Anders RA, et al. A novel NIPBL-NACC1 gene fusion is characteristic of the cholangioblastic variant of intrahepatic cholangiocarcinoma. Am J Surg Pathol 2021;45:15501560.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38.

    Augustin J, Gabignon C, Scriva A, et al. Testing for ROS1, ALK, MET, and HER2 rearrangements and amplifications in a large series of biliary tract adenocarcinomas. Virchows Arch 2020;477:3345.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39.

    Subbiah V, Wolf J, Konda B, et al. Tumour-agnostic efficacy and safety of selpercatinib in patients with RET fusion-positive solid tumours other than lung or thyroid tumours (LIBRETTO-001): a phase 1/2, open-label, basket trial. Lancet Oncol 2022;23:12611273.

    • PubMed
    • Search Google Scholar
    • Export Citation

NCCN CATEGORIES OF EVIDENCE AND CONSENSUS

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

PLEASE NOTE

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. The NCCN Guidelines Insights highlight important changes in the NCCN Guidelines recommendations from previous versions. Colored markings in the algorithm show changes and the discussion aims to further the understanding of these changes by summarizing salient portions of the panel’s discussion, including the literature reviewed.

The NCCN Guidelines Insights do not represent the full NCCN Guidelines; further, the National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application of the NCCN Guidelines and NCCN Guidelines Insights and disclaims any responsibility for their application or use in any way.

The complete and most recent version of these NCCN Guidelines is available free of charge at NCCN.org.

© 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.

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    Siegel RL, Miller KD, Wagle NS, et al. Cancer statistics, 2023. CA Cancer J Clin 2023;73:1748.

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    Oh DY, He AR, Qin S, et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer. NEJM Evid 2022;1:EVIDoa2200015.

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    Yoo C, Kim KP, Jeong JH, et al. Liposomal irinotecan plus fluorouracil and leucovorin versus fluorouracil and leucovorin for metastatic biliary tract cancer after progression on gemcitabine plus cisplatin (NIFTY): a multicentre, open-label, randomised, phase 2b study. Lancet Oncol 2021;22:15601572.

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    Hyung J, Kim I, Kim KP, et al. Treatment with liposomal irinotecan plus fluorouracil and leucovorin for patients with previously treated metastatic biliary tract cancer: the phase 2b NIFTY randomized clinical trial. JAMA Oncol. Published online March 23, 2023. doi:10.1001/jamaoncol.2023.0016

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    Maynard H, Stadler ZK, Berger MF, et al. Germline alterations in patients with biliary tract cancers: a spectrum of significant and previously underappreciated findings. Cancer 2020;126:19952002.

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    Samadder NJ, Riegert-Johnson D, Boardman L, et al. Comparison of universal genetic testing vs guideline-directed targeted testing for patients with hereditary cancer syndrome. JAMA Oncol 2021;7:230237.

    • PubMed
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    • Export Citation
  • 8.

    Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med 2018;378:731739.

  • 9.

    Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1–2 trials. Lancet Oncol 2020;21:271282.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Sicklick JK, Kato S, Okamura R, et al. Molecular profiling of cancer patients enables personalized combination therapy: the I-PREDICT study. Nat Med 2019;25:744750.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Schenker M, Burotto M, Richardet M, et al. CheckMate 848: a randomized, open-label, phase 2 study of nivolumab in combination with ipilimumab or nivolumab monotherapy in patients with advanced or metastatic solid tumors of high tumor mutational burden. Cancer Res 2022;82(12 Suppl):Abstract CT022.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Piha-Paul SA, Oh DY, Ueno M, et al. Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: results from the KEYNOTE-158 and KEYNOTE-028 studies. Int J Cancer 2020;147:21902198.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Kim RD, Chung V, Alese OB, et al. A phase 2 multi-institutional study of nivolumab for patients with advanced refractory biliary tract cancer. JAMA Oncol 2020;6:888894.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Subbiah V, Lassen U, Élez E, et al. Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial. Lancet Oncol 2020;21:12341243.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Salama AKS, Li S, Macrae ER, et al. Dabrafenib and trametinib in patients with tumors with BRAFV600E mutations: results of the NCI-MATCH trial Subprotocol H. J Clin Oncol 2020;38:38953904.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Goyal L, Meric-Bernstam F, Hollebecque A, et al. Futibatinib for FGFR2-rearranged intrahepatic cholangiocarcinoma. N Engl J Med 2023;388:228239.

  • 17.

    Silverman IM, Hollebecque A, Friboulet L, et al. Clinicogenomic analysis of FGFR2-rearranged cholangiocarcinoma identifies correlates of response and mechanisms of resistance to pemigatinib. Cancer Discov 2021;11:326339.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Abou-Alfa GK, Sahai V, Hollebecque A, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol 2020;21:671684.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Abou-Alfa GK, Macarulla T, Javle MM, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 2020;21:796807.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Zhu AX, Macarulla T, Javle MM, et al. Final overall survival efficacy results of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation: the phase 3 randomized clinical ClarIDHy trial. JAMA Oncol 2021;7:16691677.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Ramanathan RK, Belani CP, Singh DA, et al. A phase II study of lapatinib in patients with advanced biliary tree and hepatocellular cancer. Cancer Chemother Pharmacol 2009;64:777783.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Peck J, Wei L, Zalupski M, et al. HER2/neu may not be an interesting target in biliary cancers: results of an early phase II study with lapatinib. Oncology 2012;82:175179.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Hainsworth JD, Meric-Bernstam F, Swanton C, et al. Targeted therapy for advanced solid tumors on the basis of molecular profiles: results from MyPathway, an open-label, phase IIa multiple basket study. J Clin Oncol 2018;36:536542.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Hyman DM, Piha-Paul SA, Won H, et al. HER kinase inhibition in patients with HER2- and HER3-mutant cancers. Nature 2018;554:189194.

  • 25.

    Meric-Bernstam F, Beeram M, Hamilton E, et al. Zanidatamab, a novel bispecific antibody, for the treatment of locally advanced or metastatic HER2-expressing or HER2-amplified cancers: a phase 1, dose-escalation and expansion study. Lancet Oncol 2022;23:15581570.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Javle M, Borad MJ, Azad NS, et al. Pertuzumab and trastuzumab for HER2-positive, metastatic biliary tract cancer (MyPathway): a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol 2021;22:12901300.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Ohba A, Morizane C, Kawamoto Y, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing unresectable or recurrent biliary tract cancer (BTC): an investigator-initiated multicenter phase 2 study (HERB trial). J Clin Oncol 2022;40(Suppl):Abstract 4006.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Ou SI, Jänne PA, Leal TA, et al. First-in-human phase I/IB dose-finding study of adagrasib (MRTX849) in patients with advanced KRASG12C solid tumors (KRYSTAL-1). J Clin Oncol 2022;40:25302538.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Hong DS, Fakih MG, Strickler JH, et al. KRASG12C inhibition with sotorasib in advanced solid tumors. N Engl J Med 2020;383:12071217.

  • 30.

    Skoulidis F, Li BT, Dy GK, et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med 2021;384:23712381.

  • 31.

    Goyal L, Zheng H, Yurgelun MB, et al. A phase 2 and biomarker study of cabozantinib in patients with advanced cholangiocarcinoma. Cancer 2017;123:19791988.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Pant S, Saleh M, Bendell J, et al. A phase I dose escalation study of oral c-MET inhibitor tivantinib (ARQ 197) in combination with gemcitabine in patients with solid tumors. Ann Oncol 2014;25:14161421.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med 2018;379:5463.

  • 34.

    Zhou Y, Lizaso A, Mao X, et al. Novel AMBRA1-ALK fusion identified by next-generation sequencing in advanced gallbladder cancer responds to crizotinib: a case report. Ann Transl Med 2020;8:1099.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.

    Subbiah V, Cassier PA, Siena S, et al. Pan-cancer efficacy of pralsetinib in patients with RET fusion-positive solid tumors from the phase 1/2 ARROW trial. Nat Med 2022;28:16401645.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36.

    Gu TL, Deng X, Huang F, et al. Survey of tyrosine kinase signaling reveals ROS kinase fusions in human cholangiocarcinoma. PLoS One 2011;6:e15640.

  • 37.

    Argani P, Palsgrove DN, Anders RA, et al. A novel NIPBL-NACC1 gene fusion is characteristic of the cholangioblastic variant of intrahepatic cholangiocarcinoma. Am J Surg Pathol 2021;45:15501560.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38.

    Augustin J, Gabignon C, Scriva A, et al. Testing for ROS1, ALK, MET, and HER2 rearrangements and amplifications in a large series of biliary tract adenocarcinomas. Virchows Arch 2020;477:3345.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39.

    Subbiah V, Wolf J, Konda B, et al. Tumour-agnostic efficacy and safety of selpercatinib in patients with RET fusion-positive solid tumours other than lung or thyroid tumours (LIBRETTO-001): a phase 1/2, open-label, basket trial. Lancet Oncol 2022;23:12611273.

    • PubMed
    • Search Google Scholar
    • Export Citation
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