Kheder ES, Hong DS. Emerging targeted therapy for tumors with NTRK fusion proteins. Clin Cancer Res. 2018 Jul 9. doi: 10.1158/1078-0432.CCR-18-1156. [Epub ahead of print]
Khotskaya YB, Holla VR, Farago AF, et al. Targeting TRK family proteins in cancer. Pharm Ther. 2017;173:58-66.
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;378:731-739.
Greco A, Miranda C, Pierotti MA. Rearrangements of NTRK1 gene in papillary thyroid cancer. Mol Cell Endocrinol. 2010;321:44-49.
Prasad ML, Vyas M, Horne MJ, et al. NTRK fusion oncogenes in pediatric papillary thyroid carcinoma in northeast United States. Cancer. 2016;22:1097-1107.
Stransky N, Cerami E, Schalm S, et al. The landscape of kinase fusions in cancer. Nat Commun. 2014;5:2846.
Shah N, Lankerovich M, Lee H. Exploration of the gene fusion landscape of glioblastoma using transcriptome sequencing and copy number data. BMC Genomics. 2013;14:818.
Zheng Z, Liebers M, Zhelyazkova, et al. Anchored multiplex PCR for targeted next-generation sequencing. Nat Med. 2014;20:1479-1484.
Pietrantonio F, Di Nicolantonio F, Schrock AB, et al. ALK, ROS1, and NTRK rearrangements in metastatic colorectal cancer. J Natl Cancer Inst. 2017;109.
Jennings LJ, Arcila ME, Corless C, et al. Guidelines for validation of next-generation sequencing-based oncology panels: a joint consensus recommendation of the Association for Molecular Pathology and College of American Pathologists. J Mol Diagnos. 2017;19(3):341-365.
Bourgeois JM, Knezevich SR, Mathers JA, et al. Molecular detection of the ETV6-NTRK3 gene fusion differentiates congenital fibrosarcoma from other childhood spindle cell tumors. Am J Surg Pathol. 2000;24: 937-946.
Hechtman JF, Benayed R, Hyman DM, et al. Pan-Trk immunohistochemistry is an efficient and reliable screen for the detection of NTRK fusions. Am J Surg Pathol. 2017;41:1547-1551.
Murphy DA, Ely HA, Shoemaker R, et al. Detecting gene rearrangements in patient populations through a 2-step diagnostic test comprised of rapid IHC enrichment followed by sensitive next-generation sequencing. Appl Immunohistochem Mol Morphol. 2017;25(7):513-523.
Drilon A, Ou SI, Cho BC, et al. Repotrectinib (TPX-0005) is a next-generation ROS1/TRK/ALK inhibitor that potently inhibits ROS1/TRK/ALK solvent-front mutations. Cancer Discov. 2018;8(10):1227-1236.
Vitrakvi (larotrectinib) [prescribing information]. Stamford, CT: Loxo Oncology, Inc; November 2018.
US Food and Drug Administration. FDA approves larotrectinib for solid tumors with NTRK gene fusions. Available at: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm626720.htm. Accessed November 29, 2018.
Keytruda (pembrolizumab) [prescribing information]. Whitehouse Station, NJ: Merck & Co., Inc; November 2018.
Lassen UN, Albert CM, Kummar S, et al. Larotrectinib efficacy and safety in TRK fusion cancer: an expanded clinical dataset showing consistency in an age and tumor agnostic approach. ESMO 2018 Congress; October 21, 2018; Munich, Germany. Abstract 4090.
Laetsch TW, DuBois SG, Mascarenhas L, et al. Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study. Lancet Oncol. 2018;19:705-714.
Ardini E, Menichincheri M, Banfi P, et al. Entrectinib, a pan-TRK, ROS1, and ALK inhibitor with activity in multiple molecularly defined cancer indications. Mol Cancer Ther. 2016;15(4):628-639.
Liu D, Offin M, Harnicar S, et al. Entrectinib: an orally available, selective tyrosine kinase inhibitor for the treatment of NTRK, ROS1, and ALK fusion-positive solid tumors. Ther Clin Risk Manag. 2018;14:1247-1252.
Drilon A, Siena S, Ou SI, et a. Safety and antitumor activity of the multitargeted pan-TRK, ROS1, and ALK inhibitor entrectinib: combined results from two phase I trials (ALKA-372-001 and STARTRK-1). Cancer Discov. 2017;7(4):400-409.
Demetri GD, Paz-Ares L, Farago AF, et al. Efficacy and safety of entrectinib in patients with NTRK fusion-positive tumours: pooled analysis of STARTRK-2, STARTRK-1 and ALKA-372-001. ESMO 2018 Congress. October 21, 2018; Munich, Germany. Abstract LBA17.
Drilon A, Nagasubramanian R, Blake JF, et al. A next-generation TRK kinase inhibitor overcomes acquired resistance to prior TRK kinase inhibition in patients with TRK fusion-positive solid tumors. Cancer Discov. 2017;7(9):963-972.
Clinicaltrials.gov. Phase 1/2 study of LOXO-195 in patients with previously treated NTRK fusion cancers. Available at: https://clinicaltrials.gov/ct2/show/NCT03215511. Accessed October 30, 2018.
Clinicaltrials.gov. A study of TPX-0005 in patients with advanced solid tumors harboring ALK, ROS1, or NTRK1-3 rearrangements (TRIDENT-1). Available at: https://clinicaltrials.gov/ct2/show/NCT03093116. Accessed October 30, 2018.

CME / ABIM MOC

Diagnostic Considerations in Personalizing Cancer Treatment: Guiding Treatment Decisions

Authors: David S. Hong, MD
CME / ABIM MOC Released: 12/21/2018
THIS ACTIVITY HAS EXPIRED FOR CREDIT
Valid for credit through: 12/21/2019, 11:59 PM EST

Target Audience and Goal Statement

This activity is intended for hematologists/oncologists, pathologists, and pulmonologists.

The goal of this activity is to improve knowledge regarding the identification of neurotrophic tyrosine receptor kinase (NTRK) fusions and the role of tyrosine receptor kinase (TRK) inhibitor therapy.

Upon completion of this activity, participants will:

Have increased knowledge regarding the
- Gene fusions and translocations that occur across multiple tumor types in patients with cancer
- Clinical trial data (design, pharmacokinetics, efficacy, safety) surrounding use of TRK inhibitors in patients with cancer
Have greater competence related to
- Diagnostic testing strategies to identify NTRK fusions in patients with cancer

Disclosures

As an organization accredited by the ACCME, Medscape, LLC, requires everyone who is in a position to control the content of an education activity to disclose all relevant financial relationships with any commercial interest. The ACCME defines "relevant financial relationships" as financial relationships in any amount, occurring within the past 12 months, including financial relationships of a spouse or life partner, that could create a conflict of interest.

Medscape, LLC, encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content.

Faculty

David S. Hong, MD

Professor and Deputy Chair
The University of Texas MD Anderson Cancer Center
Houston, Texas

Disclosures

Disclosure: David S. Hong, MD, has disclosed the following relevant financial relationships:
Served as an advisor or consultant for: Baxter; Bayer HealthCare; Genentech, Inc.; Janssen Pharmaceuticals; MolecularMatch Inc.; Takeda Pharmaceuticals North America, Inc.
Received grants for clinical research from: AbbVie Inc.; Amgen Inc.; Adaptimmune Therapeutics plc; AstraZeneca Pharmaceuticals LP; Bayer HealthCare; Bristol-Myers Squibb Company; Daiichi Sankyo, Inc.; Eisai Inc.; Genentech, Inc.; Genmab A/S; Ignyta; Infinity Pharmaceuticals, Inc.; Kite Pharma Inc.; Kyowa Pharmaceutical, Inc.; Lilly; Loxo Oncology; MedImmune Inc.; Merck & Co., Inc.; Mirati Therapeutics; Molecular Templates; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Takeda Pharmaceuticals North America, Inc.
Other: Founder, Oncoresponse

Steering Committee

Frederique Penault-Llorca, MD, PhD

Director, Pathology/Molecular Biology
Clermont, Aquitaine France

Disclosures

Disclosure: Frederique Penault-Llorca, MD, PhD, has disclosed the following relevant financial relationships:
Served as an advisor or consultant for: AstraZeneca Pharmaceuticals LP; Bristol-Myers Squibb Company; Merck Sharp & Dohme GmbH; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Roche
Received grants for clinical research from: AstraZeneca Pharmaceuticals LP; Bristol-Myers Squibb Company; Merck Sharp & Dohme GmbH; Roche

David Hyman, MD

Medical Oncologist
Chief, Early Drug Development Service
Memorial Sloan Kettering
New York, New York, United States

Disclosures

Disclosure: David Hyman, MD, has disclosed the following relevant financial relationships:
Served as an advisor or consultant for: ArQule; AstraZeneca Pharmaceuticals LP; Atara Biotherapeutics; Bayer HealthCare; Boehringer Ingelheim Pharmaceuticals, Inc.; Chugai Pharma USA, LLC; CytomX Therapeutics, Inc.; Debiopharm Group; Pfizer Inc.

George D. Demetri, MD

Professor, Medicine, Harvard Medical School
Director, Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute
Boston, Massachusetts

Disclosures

Disclosure: George D. Demetri, MD, has disclosed the following relevant financial relationships:
Served as an advisor or consultant for: AbbVie Inc.; Bayer HealthCare; Bessor Pharma; Blueprint Medicines; Caris Life Sciences; Champions Biotechnology, Inc.; Daiichi Sankyo, Inc.; EMD Serono, Inc.; Epizyme^®, Inc.; Erasca, Inc.; G1 Therapeutics; Janssen Pharmaceuticals; Loxo Oncology; Merrimack Pharmaceuticals, Inc.; Mirati Therapeutics, Inc.; Novartis Pharmaceuticals Corporation; Pfizer Inc.; PharmaMar; Polaris Group; Roche; Sanofi; WIRB-Copernicus Group; ZIOPHARM Oncology, Inc.
Received grants for clinical research from: AbbVie Inc.; Adaptimmune Therapeutics plc; Bayer HealthCare; Epizyme^®, Inc.; GlaxoSmithKline; Janssen Pharmaceuticals; Loxo Oncology; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Roche
Owns stock, stock options, or bonds from: Bessor Pharma; Blueprint Medicines; Caris Life Sciences; Champions Biotechnology, Inc.; Erasca, Inc.; G1 Therapeutics; Merrimack Pharmaceuticals, Inc.
Other: Member, Board of Directors: Blueprint Medicines; Caris Merrimack Pharmaceuticals, Inc.
Patent licensed to Novartis Pharmaceuticals Corporation

Charles Ryan, MD

Professor of Medicine, Division of Hematology, Oncology and Transplantation
University of Wisconsin Medical School
Madison, Wisconsin

Disclosures

Disclosure: Charles Ryan, MD, has disclosed the following relevant financial relationships:
Served as an advisor or consultant for: Bayer HealthCare; Sanofi
Served as a speaker or a member of a speakers bureau for: Janssen Pharmaceuticals

Editors

Sarah Williams, PhD

Lead Scientific Director, Medscape, LLC

Disclosures

Disclosure: Sarah Williams, PhD, has disclosed no relevant financial relationships.

Lisa M. Cockrell, PhD

Freelance Medical Writer, Centreville, Virginia

Disclosures

Disclosure: Lisa M. Cockrell, PhD, has disclosed no relevant financial relationships.

CME Reviewer(s)

Nafeez Zawahir, MD

CME Clinical Director, Medscape, LLC

Disclosures

Disclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships.

Peer Reviewer

This activity has been peer reviewed and the reviewer has disclosed no relevant financial relationships.

Accreditation Statements

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For Physicians

Medscape, LLC designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit(s)™ . Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Medscape, LLC staff have disclosed that they have no relevant financial relationships.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 1.0 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Aggregate participant data will be shared with commercial supporters of this activity.

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This activity is designed to be completed within the time designated on the title page; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity online during the valid credit period that is noted on the title page. To receive AMA PRA Category 1 Credit™, you must receive a minimum score of 75% on the post-test.

Follow these steps to earn CME/CE credit*:

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From Medscape Education Oncology

CME / ABIM MOC

Diagnostic Considerations in Personalizing Cancer Treatment: Guiding Treatment Decisions

Authors: David S. Hong, MDFaculty and Disclosures

THIS ACTIVITY HAS EXPIRED FOR CREDIT

CME / ABIM MOC Released: 12/21/2018

Valid for credit through: 12/21/2019, 11:59 PM EST

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Educational Impact Challenge

The goal of this activity is to improve knowledge regarding the identification of NTRK fusions and the role of TRK inhibitor therapy.

Before you begin this activity, please assess your clinical knowledge by completing this brief survey. Answering these questions again after the activity will allow you to see what you learned and to compare your answers with those of your peers.

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CME / ABIM MOC Information

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Disclaimer

The educational activity presented above may involve simulated case-based scenarios. The patients depicted in these scenarios are fictitious and no association with any actual patient is intended or should be inferred.

The material presented here does not necessarily reflect the views of Medscape, LLC, or companies that support educational programming on medscape.org. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational activity.

References

Faculty and Disclosures

Faculty

David S. Hong, MD

Steering Committee

Frederique Penault-Llorca, MD, PhD

David Hyman, MD

George D. Demetri, MD

Charles Ryan, MD

Editors

Sarah Williams, PhD

Lisa M. Cockrell, PhD

CME Reviewer(s)

Nafeez Zawahir, MD

Peer Reviewer

CME / ABIM MOC

Diagnostic Considerations in Personalizing Cancer Treatment: Guiding Treatment Decisions

Target Audience and Goal Statement

Disclosures

Faculty

David S. Hong, MD

Steering Committee

Frederique Penault-Llorca, MD, PhD

David Hyman, MD

George D. Demetri, MD

Charles Ryan, MD

Editors

Sarah Williams, PhD

Lisa M. Cockrell, PhD

CME Reviewer(s)

Nafeez Zawahir, MD

Peer Reviewer

Accreditation Statements

For Physicians

Instructions for Participation and Credit

Diagnostic Considerations in Personalizing Cancer Treatment: Guiding Treatment Decisions

Educational Impact Challenge