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

Sébastien Perreault, Rose Chami, Rebecca J Deyell, Dina El Demellawy, Benjamin Ellezam, Nada Jabado, Daniel A Morgenstern, Aru Narendran, Poul H B Sorensen, Jonathan D Wasserman, Stephen Yip, Sébastien Perreault, Rose Chami, Rebecca J Deyell, Dina El Demellawy, Benjamin Ellezam, Nada Jabado, Daniel A Morgenstern, Aru Narendran, Poul H B Sorensen, Jonathan D Wasserman, Stephen Yip

Abstract

Neurotrophic tyrosine receptor kinase gene fusions (NTRK) are oncogenic drivers present at a low frequency in most tumour types (<5%), and at a higher frequency (>80%) in a small number of rare tumours (e.g., infantile fibrosarcoma [IFS]) and considered mutually exclusive with other common oncogenic drivers. Health Canada recently approved two tyrosine receptor kinase (TRK) inhibitors, larotrectinib (for adults and children) and entrectinib (for adults), for the treatment of solid tumours harbouring NTRK gene fusions. In Phase I/II trials, these TRK inhibitors have demonstrated promising overall response rates and tolerability in patients with TRK fusion cancer who have exhausted other treatment options. In these studies, children appear to have similar responses and tolerability to adults. In this report, we provide a Canadian consensus on when and how to test for NTRK gene fusions and when to consider treatment with a TRK inhibitor for pediatric patients with solid tumours. We focus on three pediatric tumour types: non-rhabdomyosarcoma soft tissue sarcoma/unspecified spindle cell tumours including IFS, differentiated thyroid carcinoma, and glioma. We also propose a tumour-agnostic consensus based on the probability of the tumour harbouring an NTRK gene fusion. For children with locally advanced or metastatic TRK fusion cancer who have either failed upfront therapy or lack satisfactory treatment options, TRK inhibitor therapy should be considered.

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

S.P.: Advisory board/Conference-Bayer-Larotrectinib, Research support-Novartis-Trametinib; R.J.D.: Advisory board member and travel allowance from Bayer; D.A.M.: Consultancy/advisory board member: Bayer, Roche, Boehringer-Ingelheim, EUSA Pharma, ymAbs Therapeutics, Clarity Pharmaceuticals. Speaker fees: EUSA Pharma, ymAbs Therapeutics. Institutional research funding: BMS; P.H.B.S.: has received honoraria fees from Bayer Pharmaceuticals Canada for speaking engagements on NTRK fusions; J.D.W.: Advisory board member: Bayer; S.Y.: Advisory board member and have received travel allowance from—Amgen, AstraZeneca, Bayer, Pfizer, Roche, Serono.

Figures

Figure 1
Figure 1
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. a At discretion of lab; b Consider re-biopsy and molecular test to confirm acquired resistance mutation. ETV6 = ETS variant transcription factor 6; IFS = infantile fibrosarcoma; IHC = immunohistochemistry; L = line; NGS = next generation sequencing; RMS = rhabdomyosarcoma; STS = soft tissue sarcoma; TRK = tyrosine receptor kinase; TRKi = TRK inhibitor; VA = vincristine and adriamycin; VAC = vincristine, adriamycin, and cyclophosphamide. Knezevich et al. 1998 [47]; National Cancer Institute [56]; Knezevich et al. 1998 [60]; Bourgeois et al. 2000 [61]; Rubin et al. 1998 [62]; Sheng et al. 2001 [63]; Loh et al. 2002 [64].
Figure 2
Figure 2
Biomarker testing and treatment for neurotrophic tyrosine receptor kinase (NTRK) gene fusions in differentiated thyroid 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 Consider re-biopsy and molecular test to confirm acquired resistance mutation. ALK = ALK receptor tyrosine kinase; ATA = American Thyroid Association; BRAF = B-Raf proto-oncogene, serine/threonine kinase; DTC = differentiated thyroid carcinoma; L = line; MET = MET proto-oncogene, receptor tyrosine kinase; RAI = radioactive iodine; RET = ret proto-oncogene; TRK = tyrosine receptor kinase; TRKi = TRK inhibitor. National Cancer Institute [56]; Francis et al. 2015 [82]; Kazahaya et al. 2020 [85]; Schmidt et al. 2017 [87].
Figure 3
Figure 3
Biomarker testing and treatment for neurotrophic tyrosine receptor kinase (NTRK) gene fusions in glioma. 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 Rare cases of NTRK fusion and H3K27M mutation have been described; b Consider re-biopsy and molecular test to confirm acquired resistance mutation. BRAF = B-Raf proto-oncogene, serine/threonine kinase; FFPE = formalin-fixed paraffin-embedded; HGG = high grade glioma; IHC = immunohistochemistry; LGG = low grade glioma; TMZ/CCNU = temozolomide and lomustine; TRK = tyrosine receptor kinase; TRKi = TRK inhibitor. National Cancer Institute [56].
Figure 4
Figure 4
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. a Consider re-biopsy and molecular test to confirm acquired resistance mutation. NGS = next generation sequencing; SOC = standard of care; TRK = tyrosine receptor kinase; TRKi = TRK inhibitor.

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