Top

Published in:

Open Access 01-12-2018 | Research highlight

Basket trial of TRK inhibitors demonstrates efficacy in TRK fusion-positive cancers

Authors: Yu Chen, Ping Chi

Published in: Journal of Hematology & Oncology | Issue 1/2018

Abstract

Unlike many conventional cancers with preferential patterns of oncogenic genetic alterations, TRK fusions resulting from NTRK1/2/3 genetic alterations drive oncogenic transformations in more than 20 different malignancies over diverse tissue/cell lineages, in both children and adults. A recent “basket” study of larotrectinib, a TRK inhibitor, has demonstrated significant efficacy in TRK fusion-positive tumors of all types from infants to the elderly. Here, we discuss the larotrectinib study and perspectives and challenges in developing “tumor-agnostic” targeted therapies in rare tumors.

Hyman DM, Puzanov I, Subbiah V, et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med. 2015;373:726–36.CrossRefPubMedPubMedCentral

Prahallad A, Sun C, Huang S, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 2012;483:100–3.CrossRefPubMed

Corcoran RB, Ebi H, Turke AB, et al. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discovery. 2012;2:227–35.CrossRefPubMedPubMedCentral

Chao MV. Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat Rev Neurosci. 2003;4:299–309.CrossRefPubMed

Martin-Zanca D, Hughes SH, Barbacid M. A human oncogene formed by the fusion of truncated tropomyosin and protein tyrosine kinase sequences. Nature. 1986;319:743–8.CrossRefPubMed

Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discovery. 2015;5:25–34.CrossRefPubMed

Amatu A, Sartore-Bianchi A, Siena S. NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open. 2016;1:e000023.CrossRefPubMedPubMedCentral

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;378:731–9.CrossRefPubMedPubMedCentral

Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Transl Med. 2012;4:120ra17.CrossRefPubMedPubMedCentral

10.

Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005;352:786–92.CrossRefPubMed

11.

Core LJ, Martins AL, Danko CG, Waters CT, Siepel A, Lis JT. Analysis of nascent RNA identifies a unified architecture of initiation regions at mammalian promoters and enhancers. Nat Genet. 2014;46:1311–20.CrossRefPubMedPubMedCentral

12.

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 Discovery. 2017;7:963–72.CrossRefPubMedPubMedCentral

13.

Hyman DM, Smyth LM, Donoghue MTA, et al. AKT inhibition in solid tumors with AKT1 mutations. J Clin Oncol. 2017;35:2251–9.CrossRefPubMedPubMedCentral

14.

Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357:409–13.CrossRefPubMedPubMedCentral

15.

Hyman DM, Piha-Paul SA, Won H, et al. HER kinase inhibition in patients with HER2- and HER3-mutant cancers. Nature. 2018;554:189–94.CrossRefPubMedPubMedCentral

16.

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;41:1547–51.CrossRefPubMed

17.

Rudzinski ER, Lockwood CM, Stohr BA, et al. Pan-Trk immunohistochemistry identifies NTRK rearrangements in pediatric mesenchymal tumors. Am J Surg Pathol. 2018;

18.

Roberts KG, Li Y, Payne-Turner D, et al. Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med. 2014;371:1005–15.CrossRefPubMedPubMedCentral

19.

Braghiroli MI, Nash GM, Morris M, et al. Genomic profiling and efficacy of anti-EGFR therapy in appendiceal adenocarcinoma. J Clin Oncol. 2016;34(Suppl 4S):abstr 574.CrossRef

20.

Jones DT, Hutter B, Jager N, et al. Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat Genet. 2013;45:927–32.CrossRefPubMedPubMedCentral

21.

Stransky N, Cerami E, Schalm S, Kim JL, Lengauer C. The landscape of kinase fusions in cancer. Nat Commun. 2014;5:4846.CrossRefPubMedPubMedCentral

22.

Ross JS, Wang K, Gay L, et al. New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing. Oncologist. 2014;19:235–42.CrossRefPubMedPubMedCentral

23.

Creancier L, Vandenberghe I, Gomes B, et al. Chromosomal rearrangements involving the NTRK1 gene in colorectal carcinoma. Cancer Lett. 2015;365:107–11.CrossRefPubMed

24.

Ardini E, Bosotti R, Borgia AL, et al. The TPM3-NTRK1 rearrangement is a recurring event in colorectal carcinoma and is associated with tumor sensitivity to TRKA kinase inhibition. Mol Oncol. 2014;8:1495–507.CrossRefPubMedPubMedCentral

25.

Shi E, Chmielecki J, Tang CM, et al. FGFR1 and NTRK3 actionable alterations in “wild-type” gastrointestinal stromal tumors. J Transl Med. 2016;14:339.CrossRefPubMedPubMedCentral

26.

Brenca M, Rossi S, Polano M, et al. Transcriptome sequencing identifies ETV6-NTRK3 as a gene fusion involved in GIST. J Pathol. 2016;238:543–9.CrossRefPubMed

27.

Frattini V, Trifonov V, Chan JM, et al. The integrated landscape of driver genomic alterations in glioblastoma. Nat Genet. 2013;45:1141–9.CrossRefPubMedPubMedCentral

28.

Zheng Z, Liebers M, Zhelyazkova B, et al. Anchored multiplex PCR for targeted next-generation sequencing. Nat Med. 2014;20:1479–84.CrossRefPubMed

29.

Wu G, Diaz AK, Paugh BS, et al. The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat Genet. 2014;46:444–50.CrossRefPubMedPubMedCentral

30.

Rubin BP, Chen CJ, Morgan TW, et al. Congenital mesoblastic nephroma t(12;15) is associated with ETV6-NTRK3 gene fusion: cytogenetic and molecular relationship to congenital (infantile) fibrosarcoma. Am J Pathol. 1998;153:1451–8.CrossRefPubMedPubMedCentral

31.

Knezevich SR, Garnett MJ, Pysher TJ, Beckwith JB, Grundy PE, Sorensen PH. ETV6-NTRK3 gene fusions and trisomy 11 establish a histogenetic link between mesoblastic nephroma and congenital fibrosarcoma. Cancer Res. 1998;58:5046–8.PubMed

32.

El Demellawy D, Cundiff CA, Nasr A, et al. Congenital mesoblastic nephroma: a study of 19 cases using immunohistochemistry and ETV6-NTRK3 fusion gene rearrangement. Pathology. 2016;48:47–50.CrossRefPubMed

33.

Bourgeois JM, Knezevich SR, Mathers JA, Sorensen PH. Molecular detection of the ETV6-NTRK3 gene fusion differentiates congenital fibrosarcoma from other childhood spindle cell tumors. Am J Surg Pathol. 2000;24:937–46.CrossRefPubMed

34.

Vaishnavi A, Capelletti M, Le AT, et al. Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nat Med. 2013;19:1469–72.CrossRefPubMedPubMedCentral

35.

Tognon C, Knezevich SR, Huntsman D, et al. Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell. 2002;2:367–76.CrossRefPubMed

36.

Krings G, Joseph NM, Bean GR, et al. Genomic profiling of breast secretory carcinomas reveals distinct genetics from other breast cancers and similarity to mammary analog secretory carcinomas. Mod Pathol. 2017;30:1086–99.CrossRefPubMed

37.

Skalova 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;34:599–608.PubMed

38.

Bishop JA, Yonescu R, Batista D, Begum S, Eisele DW, Westra WH. Utility of mammaglobin immunohistochemistry as a proxy marker for the ETV6-NTRK3 translocation in the diagnosis of salivary mammary analogue secretory carcinoma. Hum Pathol. 2013;44:1982–8.CrossRefPubMedPubMedCentral

39.

Skalova A, Vanecek T, Simpson RH, et al. Mammary analogue secretory carcinoma of salivary glands: molecular analysis of 25 ETV6 gene rearranged tumors with lack of detection of classical ETV6-NTRK3 fusion transcript by standard RT-PCR: report of 4 cases harboring ETV6-X gene fusion. Am J Surg Pathol. 2016;40:3–13.CrossRefPubMed

40.

Wiesner T, He J, Yelensky R, et al. Kinase fusions are frequent in Spitz tumours and spitzoid melanomas. Nat Commun. 2014;5:3116.CrossRefPubMedPubMedCentral

41.

Chiang S, Cotzia P, Hyman DM, et al. NTRK fusions define a novel uterine sarcoma subtype with features of fibrosarcoma. Am J Surg Pathol. 2018;42:791–8.CrossRefPubMed

42.

Musholt TJ, Musholt PB, Khaladj N, Schulz D, Scheumann GF, Klempnauer J. Prognostic significance of RET and NTRK1 rearrangements in sporadic papillary thyroid carcinoma. Surgery. 2000;128:984–93.CrossRefPubMed

43.

Wajjwalku W, Nakamura S, Hasegawa Y, et al. Low frequency of rearrangements of the ret and trk proto-oncogenes in Japanese thyroid papillary carcinomas. Jpn J Cancer Res. 1992;83:671–5.CrossRefPubMedPubMedCentral

44.

Prasad ML, Vyas M, Horne MJ, et al. NTRK fusion oncogenes in pediatric papillary thyroid carcinoma in northeast United States. Cancer. 2016;122:1097–107.CrossRefPubMed

45.

Ricarte-Filho JC, Li S, Garcia-Rendueles ME, et al. Identification of kinase fusion oncogenes in post-Chernobyl radiation-induced thyroid cancers. J Clin Invest. 2013;123:4935–44.CrossRefPubMedPubMedCentral

46.

Leeman-Neill RJ, Kelly LM, Liu P, et al. ETV6-NTRK3 is a common chromosomal rearrangement in radiation-associated thyroid cancer. Cancer. 2014;120:799–807.CrossRefPubMed

Title: Basket trial of TRK inhibitors demonstrates efficacy in TRK fusion-positive cancers
Authors: Yu Chen
Ping Chi
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: Journal of Hematology & Oncology / Issue 1/2018
Electronic ISSN: 1756-8722
DOI: https://doi.org/10.1186/s13045-018-0622-4

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2018

Control of triple-negative breast cancer using ex vivo self-enriched, costimulated NKG2D CAR T cells

miR-519a enhances chemosensitivity and promotes autophagy in glioblastoma by targeting STAT3/Bcl2 signaling pathway

Decreasing mortality and hospitalizations with rising costs related to gastric cancer in the USA: an epidemiological perspective

Activity of pembrolizumab in relapsed/refractory NK/T-cell lymphoma

The PIK3CA E542K and E545K mutations promote glycolysis and proliferation via induction of the β-catenin/SIRT3 signaling pathway in cervical cancer

miR-153 suppresses IDO1 expression and enhances CAR T cell immunotherapy

Keynote webinar | Spotlight on antibody–drug conjugates in cancer