Canadian Consensus for Biomarker Testing and Treatment of TRK Fusion Cancer in Adults

D Gwyn Bebb, Shantanu Banerji, Normand Blais, Patrice Desmeules, Sharlene Gill, Andrea Grin, Harriet Feilotter, Aaron R Hansen, Martin Hyrcza, Monika Krzyzanowska, Barbara Melosky, Jonathan Noujaim, Bibiana Purgina, Dean Ruether, Christine E Simmons, Denis Soulieres, Emina Emilia Torlakovic, Ming-Sound Tsao, D Gwyn Bebb, Shantanu Banerji, Normand Blais, Patrice Desmeules, Sharlene Gill, Andrea Grin, Harriet Feilotter, Aaron R Hansen, Martin Hyrcza, Monika Krzyzanowska, Barbara Melosky, Jonathan Noujaim, Bibiana Purgina, Dean Ruether, Christine E Simmons, Denis Soulieres, Emina Emilia Torlakovic, Ming-Sound Tsao

Abstract

The tyrosine receptor kinase (TRK) inhibitors larotrectinib and entrectinib were recently approved in Canada for the treatment of solid tumours harbouring neurotrophic tyrosine receptor kinase (NTRK) gene fusions. These NTRK gene fusions are oncogenic drivers found in most tumour types at a low frequency (<5%), and at a higher frequency (>80%) in a small number of rare tumours (e.g., secretory carcinoma of the salivary gland and of the breast). They are generally mutually exclusive of other common oncogenic drivers. Larotrectinib and entrectinib have demonstrated impressive overall response rates and tolerability in Phase I/II trials in patients with TRK fusion cancer with no other effective treatment options. Given the low frequency of TRK fusion cancer and the heterogeneous molecular testing landscape in Canada, identifying and optimally managing such patients represents a new challenge. We provide a Canadian consensus on when and how to test for NTRK gene fusions and when to consider treatment with a TRK inhibitor. We focus on five tumour types: thyroid carcinoma, colorectal carcinoma, non-small cell lung carcinoma, soft tissue sarcoma, and salivary gland carcinoma. Based on the probability of the tumour harbouring an NTRK gene fusion, we also suggest a tumour-agnostic consensus for NTRK gene fusion testing and treatment. We recommend considering a TRK inhibitor in all patients with TRK fusion cancer with no other effective treatment options.

Trial registration: ClinicalTrials.gov NCT02122913 NCT02637687 NCT02576431.

Keywords: NTRK; TRK fusion; entrectinib; larotrectinib; molecular testing; oncogenic drivers; targeted therapy; tumour-agnostic.

Conflict of interest statement

We have read and understood Current Oncology’s policy on conflicts of interest disclosure and declare the following interests: D.G.B.: Advisory Boards: A.Z., B.I., Lilly, B.M.S., Merck, Amgen, Pfizer, Novartis, Roche, Bayer; Research Funding: A.Z., B.I., Pfizer; Meeting Sponsorships: POET Annual Meeting: Takeda, A.Z., B.I., Lilly, B.M.S., Merck, Pfizer, Novartis, Roche, Bayer, Illumina, Glans-Look Lung Cancer Research Day: A.Z., B.I., Roche. Ownership and Director, Medical Affairs: OncoHelix. S.B.: Advisory Board/Honorarium: AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers-Squibb, GlaxoSmithKline, Lilly, Merck, Novartis, Pfizer, Roche, Takeda. N.B.: Nothing to disclose. P.D.: Consultant (Astra-Zeneca, Eli Lilly); Presentations (Pfizer, Astra-Zeneca); Research funding (Pfizer, Novartis, Roche). S.G.: Advisory Boards and Speaking honoraria: Bayer, Amgen, Roche, Pfizer. A.G.: Nothing to disclose. H.F.: has received honoraria for either advisory boards or speaking engagements from EMD Serono, Pfizer, Bayer, Amgen, Astellas, Merck, Roche and Astra Zeneca; has current research and clinical lab support from EMD Serono and Astra Zeneca, past research support from Thermo Fisher, and her clinical lab has a contract arrangement with Bayer. A.R.H.: institutional support for clinical trials conduct from Novartis, Bristol-Myers Squibb, Pfizer, Boerhinger-Ingelheim, GlaxoSmithKline, Roche/Genentech, Karyopharm, AstraZeneca/ Medimmune, Merck, Astellas and Bayer and compensated consulting/advisory boards for AstraZeneca, Merck and GlaxoSmithKline. M.H.: Advisory Board Honoraria: Bayer, Merck, Roche. M.K.: Honoraria: Novartis, Eisai, Bayer; Consulting or Advisory Role: Eisai; Research Funding: Eisai (Inst), Exelixis (Inst), Ipsen (Inst). B.M.: Advisory Board/Honorarium: Bayer, Pfizer, Astra Zeneca, Boehringer Ingleheim, Roche. J.N.: Nothing to disclose. B.P.: I have received stipends from Bayer. D.R.: Nothing to disclose. C.S.: Nothing to disclose. D.S.: Ad boards participation with Bayer. E.T.: Torlakovic reports grants and other from BMS, grants from Pfizer, grants and other from Merck, grants and other from Roche, grants and other from AstraZeneca, outside the submitted work. M.S.T.: Honoraria: Bayer, Hoffmann La Roche; Research Grant: Bayer.

Figures

Figure 1
Figure 1
Biomarker testing and treatment for neurotrophic tyrosine receptor kinase (NTRK) gene fusions in thyroid carcinoma. White boxes with black outlines represent either NTRK gene fusion testing or treatment with a TRKi. Black boxes with white text indicate all other steps that do not include either NTRK gene fusion testing or treatment with a TRKi. a Consider obtaining fresh tissue to confirm diagnosis and provide more recent tissue for biomarker testing. ATC = anaplastic thyroid carcinoma; DTC = differentiated thyroid carcinoma; EBRT = external beam radiation therapy; FNA = fine needle aspiration; IHC = immunohistochemistry; L = line; MTC = medullary thyroid carcinoma; NGS = next generation sequencing; RAI = radioactive iodine; TRK = tyrosine receptor kinase; TRKi = TRK inhibitor. Brenner et al. 2020 [34].
Figure 2
Figure 2
Biomarker testing and treatment for neurotrophic tyrosine receptor kinase (NTRK) gene fusions in colorectal carcinoma. White boxes with black outlines represent either NTRK gene fusion testing or treatment with a TRKi. Black boxes with white text indicate all other steps that do not include either NTRK gene fusion testing or treatment with a TRKi. BRAF = B-Raf proto-oncogene, serine/threonine kinase; CRC = colorectal carcinoma; d = deficient; FOLFIRI = folinic acid, fluorouracil, and irinotecan; FOLFOX = folinic acid, fluorouracil, and oxaliplatin; IHC = immunohistochemistry; L = line; MLH1 = mutL homolog 1; MMR = mismatch repair; MSI = microsatellite instability; MSI-H = MSI high; MSS = microsatellite sable; NGS = next generation sequencing; p = proficient; PCR = polymerase chain reaction; RAS = RAS type GTPase family; TRK = tyrosine receptor kinase; TRKi = TRK inhibitor. Brenner et al. 2020 [34]; Chou et al. 2019 [44]; Cocco et al. 2019 [54].
Figure 3
Figure 3
Biomarker testing and treatment for neurotrophic tyrosine receptor kinase (NTRK) gene fusions in lung cancer. White boxes with black outlines represent either NTRK gene fusion testing or treatment with a TRKi. Black boxes with white text indicate all other steps that do not include either NTRK gene fusion testing or treatment with a TRKi. a Patients with ECOG PS 3 were eligible for enrollment in the larotrectinib clinical trials [16]. ALK = ALK receptor tyrosine kinase; BRAF = B-Raf proto-oncogene, serine/threonine kinase; ECOG PS = Eastern Cooperative Oncology Group performance status; EGFR = epidermal growth factor receptor; ERBB2 = erb-b2 receptor tyrosine kinase 2; FISH = fluorescence in situ hybridization; IHC = immunohistochemistry; KRAS = KRAS proto-oncogene, GTPase; L = line; MET = MET proto-oncogene, receptor tyrosine kinase; NGS = next generation sequencing; NRG1 = neuregulin 1; NSCLC = non-small cell lung carcinoma; PD-L1 = programmed death ligand 1; RET = ret proto-oncogene; ROS1 = ROS proto-oncogene 1, receptor tyrosine kinase; TRK = tyrosine receptor kinase; TRKi = TRK inhibitor. Brenner et al. 2020 [34]; Farago et al. 2018 [61]; Solomon et al. 2019 [83]; Benayed et al. 2019 [84].
Figure 4
Figure 4
Biomarker testing and treatment for neurotrophic tyrosine receptor kinase (NTRK) gene fusions in sarcoma. White boxes with black outlines represent either NTRK gene fusion testing or treatment with a TRKi. Black boxes with white text indicate all other steps that do not include either NTRK gene fusion testing or treatment with a TRKi. BRAF = B-Raf proto-oncogene, serine/threonine kinase; GIST = gastrointestinal stromal tumour; IHC = immunohistochemistry; KIT = KIT proto-oncogene, receptor tyrosine kinase; L = line; NGS = next generation sequencing; PDGFRA = platelet derived growth factor receptor alpha; STS = soft tissue sarcoma; TRK = tyrosine receptor kinase; TRKi = TRK inhibitor. Ducimetière et al. 2011 [88]; Canadian Cancer Society [91].
Figure 5
Figure 5
Biomarker testing and treatment for neurotrophic tyrosine receptor kinase (NTRK) gene fusions in salivary tumours. White boxes with black outlines represent either NTRK gene fusion testing or treatment with a TRKi. Black boxes with white text indicate all other steps that do not include either NTRK gene fusion testing or treatment with a TRKi. FISH = fluorescence in situ hybridization; L = line; HER2 = erb-b2 receptor tyrosine kinase 2; IHC = immunohistochemistry; NGS = next generation sequencing; NOS = not otherwise specified; SDC = salivary ductal carcinoma; TRK = tyrosine receptor kinase; TRKi = TRK inhibitor; VEGFR TKI = vascular endothelial growth factor receptor tyrosine kinase inhibitor. Canadian Cancer Society [112]; Luk et al. 2015 [113]; Majewska et al. 2015 [114]; Black et al. 2019 [115]; Ito et al. 2015 [116]; Skalova et al. 2018 [117].
Figure 6
Figure 6
Biomarker testing and treatment for neurotrophic tyrosine receptor kinase (NTRK) gene fusions. White boxes with black outlines represent either NTRK gene fusion testing or treatment with a TRKi. Black boxes with white text indicate all other steps that do not include either NTRK gene fusion testing or treatment with a TRKi. ETV6 = ETS variant transcription factor 6; IHC = immunohistochemistry; NGS = next generation sequencing; SOC = standard of care; TRK = tyrosine receptor kinase; TRKi = TRK inhibitor.

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