Clinical Activity of Selitrectinib in a Patient With Mammary Analogue Secretory Carcinoma of the Parotid Gland With Secondary Resistance to Entrectinib

Authors:
Vaia Florou Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah; and

Search for other papers by Vaia Florou in
Current site
Google Scholar
PubMed
Close
 MD
,
Christopher Nevala-Plagemann Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah; and

Search for other papers by Christopher Nevala-Plagemann in
Current site
Google Scholar
PubMed
Close
 MD
,
Jonathan Whisenant Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah; and

Search for other papers by Jonathan Whisenant in
Current site
Google Scholar
PubMed
Close
 MD
,
Patricia Maeda Bayer Healthcare Pharmaceuticals, Whippany, New Jersey

Search for other papers by Patricia Maeda in
Current site
Google Scholar
PubMed
Close
 MD
,
Glynn W. Gilcrease Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah; and

Search for other papers by Glynn W. Gilcrease in
Current site
Google Scholar
PubMed
Close
 MD
, and
Ignacio Garrido-Laguna Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah; and

Search for other papers by Ignacio Garrido-Laguna in
Current site
Google Scholar
PubMed
Close
 MD, PhD
Restricted access

NTRK gene fusions are found in <1% of all cancers but are uniformly present in mammary analog secretory carcinomas (MASC) of the salivary glands. Two selective histology-agnostic tropomyosin receptor kinase (TRK) inhibitors are currently approved for malignancies with these oncogenic fusions. Resistance to TRK inhibition has been recognized, and the mediating mechanisms are presently being studied. This report describes a patient diagnosed with an MASC of the parotid gland who after undergoing multiple lines of treatment was found to have an ETV6-NTRK3 fusion and initiated TRK-targeted therapy using entrectinib. Upon disease progression, we performed tumor genetic sequencing that showed a secondary resistance mutation. The patient subsequently responded to selitrectinib, a next-generation TRK inhibitor.

Submitted November 1, 2020; accepted for publication February 1, 2021.

Disclosures: Dr. Maeda has disclosed being employed by and owning stock in Bayer Healthcare Pharmaceuticals. Dr. Garrido-Laguna has disclosed receiving grant/research support from Bayer/Loxo Oncology. The remaining authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: Research reported in this article was supported by the Foundation for the NIH under award number P30CA042014.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Correspondence: Vaia Florou, MD, Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah School of Medicine, 2000 Circle of Hope, Salt Lake City, UT 84112. Email: vaia.florou@hci.utah.edu
  • Collapse
  • Expand
  • 1.

    Skálová A, Vanecek T, Sima R, et al. Mammary analogue secretory carcinoma of salivary glands, containing the ETV6-NTRK3 fusion gene: a hitherto undescribed salivary gland tumor entity. Am J Surg Pathol 2010;34:599608.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Majewska H, Skálová A, Stodulski D, et al. Mammary analogue secretory carcinoma of salivary glands: a new entity associated with ETV6 gene rearrangement. Virchows Arch 2015;466:245254.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Seethala RR, Stenman G. Update from the 4th edition of the World Health Organization Classification of Head and Neck Tumours: tumors of the salivary gland. Head Neck Pathol 2017;11:55–67.

    • Crossref
    • PubMed
    • Export Citation
  • 4.

    Skálová A, Vanecek T, Majewska H, et al. Mammary analogue secretory carcinoma of salivary glands with high-grade transformation: report of 3 cases with the ETV6-NTRK3 gene fusion and analysis of TP53, β-catenin, EGFR, and CCND1 genes. Am J Surg Pathol 2014;38:2333.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Solomon JP, Benayed R, Hechtman JF, et al. Identifying patients with NTRK fusion cancer. Ann Oncol 2019;30(Suppl 8):viii16–22.

    • PubMed
    • Export Citation
  • 6.

    Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol 2018;15:731747.

  • 7.

    Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov 2015;5:2534.

  • 8.

    Okamura R, Boichard A, Kato S, et al. Analysis of NTRK alterations in pan-cancer adult and pediatric malignancies: implications for NTRK-targeted therapeutics. JCO Precis Oncol 2018;2018:120.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Hong DS, DuBois SG, Kummar S, et al. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol 2020;21:531540.

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

    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.

  • 11.

    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.

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

    Hyman D, Kumar S, Farago A, et al. Phase I and expanded access experience of LOXO-195 (BAY 2731954), a selective next-generation TRK inhibitor (TRKi) [abstract]. Presented at American Association for Cancer Research Annual Meeting; March 29–April 3, 2019; Atlanta, Georgia. Abstract CT127.

    • Crossref
    • PubMed
    • Export Citation
  • 13.

    Drilon A, Siena S, Ou SI, et al. 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;7:400409.

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

    Drilon A, Li G, Dogan S, et al. What hides behind the MASC: clinical response and acquired resistance to entrectinib after ETV6-NTRK3 identification in a mammary analogue secretory carcinoma (MASC). Ann Oncol 2016;27:920926.

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

    Drilon AE, DuBois SG, Farago AF, et al. Activity of larotrectinib in TRK fusion cancer patients with brain metastases or primary central nervous system tumors [abstract]. J Clin Oncol 2019;37(Suppl):Abstract 2006.

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

    Sasaki E, Masago K, Fujita S, et al. Salivary secretory carcinoma harboring a novel ALK fusion: expanding the molecular characterization of carcinomas beyond the ETV6 gene. Am J Surg Pathol 2020;44:962969.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Drilon A, Oxnard G, Wirth L, et al. Registrational results of LIBRETTO-001: a phase 1/2 trial of LOXO-292 in patients with RET fusion-positive lung cancers [abstract]. J Thorac Oncol 2019;14:S67. Abstract PL02.08.

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

    Wirth LJ, Sherman E, Robinson B, et al. Efficacy of selpercatinib in RET-altered thyroid cancers. N Engl J Med 2020;383:825835.

  • 19.

    Drilon A, Oxnard GR, Tan DSW, et al. Efficacy of selpercatinib in RET fusion-positive non-small-cell lung cancer. N Engl J Med 2020;383:813824.

  • 20.

    Drilon A, Zhai D, Deng W, et al. Repotrectinib, a next generation TRK inhibitor, overcomes TRK resistance mutations including solvent front, gatekeeper and compound mutations [abstract]. Presented at the American Association for Cancer Research Annual Meeting; March 29–April 3, 2019; Atlanta, Georgia. Abstract 442.

    • Crossref
    • PubMed
    • Export Citation
  • 21.

    Cocco E, Schram AM, Kulick A, et al. Resistance to TRK inhibition mediated by convergent MAPK pathway activation. Nat Med 2019;25:14221427.

  • 22.

    Vaishnavi A, Scherzer MT, Kinsey CG, et al. Inhibition of MEK1/2 forestalls the onset of acquired resistance to entrectinib in multiple models of NTRK1-driven cancer. Cell Rep 2020;32:107994.

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

    Hemming ML, Nathenson MJ, Lin J-R, et al. Response and mechanisms of resistance to larotrectinib and selitrectinib in metastatic undifferentiated sarcoma harboring oncogenic fusion of NTRK1. JCO Precis Oncol 2020;4:7990.

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

    Long GV, Flaherty KT, Stroyakovskiy D, et al. Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. Ann Oncol 2017;28:16311639.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Prahallad A, Sun C, Huang S, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 2012;483:100103.

  • 26.

    Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N Engl J Med 2019;381:16321643.

  • 27.

    Kopetz S, Grothey A, Van Cutsem E, et al. Encorafenib plus cetuximab with or without binimetinib for BRAF V600E metastatic colorectal cancer: updated survival results from a randomized, three-arm, phase III study versus choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC) [abstract]. J Clin Oncol 2020;38(Suppl):Abstract 4001.

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

    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.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 6065 715 18
PDF Downloads 2230 284 21
EPUB Downloads 0 0 0