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

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.

Reflex ROS1 IHC Screening with FISH Confirmation for Advanced Non-Small Cell Lung Cancer—A Cost-Efficient Strategy in a Public Healthcare System

“…The limitations of our study include the use of three single-gene assays for EGFR, ALK, and ROS-1, a current reality in our public system, in comparison to the growing practice of broader NGS testing for multiple targets now relevant in the care of advanced NSCLC patients (Figure 5, [41]). The costs of additional genomic targets in BRAF, NTRK, RET, MET, and emerging targets in KRAS, ERBB2, and NRG-1 were not included in our model as these are not yet funded as a standard of care in our jurisdiction.…”

“…Footnote: * At our institution, comprehensive NGS testing in addition to reflex PD-L1 IHC testing is now standard practice, but this has not been implemented across the province or country at the time this manuscript was written. This figure was adapted with modifications from [41].…”

Somatic Genomic Testing in Patients With Metastatic or Advanced Cancer: ASCO Provisional Clinical Opinion

“…128 NTRK fusions are relatively common in select rare solid tumors, including secretory breast cancer, 129 mammary analogue secretory carcinoma of the salivary gland, congenital infantile fibrosarcoma, and congenital mesoblastic nephroma. 128 For these diseases, NTRK fusion testing should be routinely performed. NTRK fusions are found less commonly, but at clinically relevant frequencies (> 1%), in several other tumor types, including inflammatory myofibroblastic tumor (17.7%) 130 and thyroid cancer (2.3%).…”

Systematic population-based identification of NTRK and RET fusion-positive thyroid cancers

“…However, appropriate and cost-effective screening algorithms to identify and stratify patients with kinase fusion-positive cancers still need to be developed for specific cancer types. A Canadian consensus for adult patients recommends NTRK1-3 gene fusion testing at diagnosis in unresectable or metastatic/advanced patients with all thyroid histologies and at recurrence after surgery ± RAI treatment if not already performed ( 20 ). However, since resensitization for RAI treatment ( 21 ) and treatment with the RET inhibitor, selpercatinib ( 5 ), are additional options for these patients, integrated molecular stratification strategies are required that allow stratification for all currently available treatment options.…”