Expert consensus on the diagnosis and treatment of NTRK gene fusion solid tumors in China

Abstract

Gene fusions can drive tumor development for multiple types of cancer. Currently, many drugs targeting gene fusions are being approved for clinical application. At present, tyrosine receptor kinase (TRK) inhibitors targeting neurotrophic tyrosine receptor kinase ( NTRK ) gene fusions are among the first “tumor agnostic” drugs approved for pan‐cancer use. Representative TRK inhibitors, including larotrectinib and entrectinib, have shown high efficacy for many types of cancer. At the same time, several second‐generation drugs designed to overcome first‐generation drug resistance are undergoing clinical development. Due to the rarity of NTRK gene fusions in common cancer types and technical issues regarding the complexity of fusion patterns, effectively screening patients for TRK inhibitor treatment in routine clinical practice is challenging. Different detection methods including immunohistochemistry, fluorescence in situ hybridization, reverse transcription‐polymerase chain reaction, and (DNA and/or RNA‐based) next‐generation sequencing have pros and cons. As such, recommending suitable tests for individual patients and ensuring the quality of tests is essential. Moreover, at present, there is a lack of systematic review for the clinical efficacy and development status of first‐ and second‐generation TRK inhibitors. To resolve the above issues, our expert group has reached a consensus regarding the diagnosis and treatment of NTRK gene fusion solid tumors, aiming to standardize clinical practice with the goal of benefiting patients with NTRK gene fusions treated with TRK inhibitors.

Real-world challenges in undertaking NTRK fusion testing in non-small cell lung cancer

“…While nucleic acid-based sequencing, in particular NGS, is the diagnostic of choice, pan-TRK IHC has shown to have high sensitivity and specificity particularly for NTRK 1 and NTRK 2 fusions in NSCLC ( 9 , 10 ), in addition to being cheap, widely accessible and quick. Screening with IHC is in line with international recommendations ( 11 - 13 ), and can be particularly useful in cancers with low prevalence of NTRK gene fusions and in laboratories where molecular sequencing methods are not readily available or NTRK testing is not part of routine workflow. Currently, two monoclonal antibodies are used for detecting specific proteins include EPR17341 (Ventana ® and Abcam ® ; used in this study) and A7H6R (Cell Signaling ® ) with comparable performance ( 14 ).…”

Selective type II TRK inhibitors overcome xDFG mutation mediated acquired resistance to the second-generation inhibitors selitrectinib and repotrectinib

“…The prevalence of NTRK fusions can reach 90% or higher in these rare tumors, with the ETV6-NTRK3 fusion diagnosed most 6 , 62 , 63 , 64 , 65 , while NTRK fusions are found at low incidence (<5%) in a series of common cancer types, such as lung cancer, breast cancer, colorectal cancer, pancreatic cancer etc. 21 , 12 , 66 , 67 . In addition to NTRK fusions, other TRK aberrations have also been found in some tumors, including TRK point mutations 68 , 69 , 70 , 71 , 72 , splice variants 48 , 68 , 73 , 74 , 75 , and TRK overexpression 76 , 77 , 78 .…”

Uncommon/rare oncogenic drivers in non‐small cell lung cancer: Consensus and contention

“…Moreover, given the large population of NSCLC patients in China, it is of great significance to establish standardized methodologies for the detection of uncommon/rare oncogenic drivers. Currently, several domestic and international expert consensuses have provided recommendations for the detection of certain uncommon/rare oncogenic drivers [6,[9][10][11][12][13][14][17][18][19]. It should be noted that while these consensuses respectively focus on methodological recommendations for the detection of a specific gene, there are commonalities among them.…”

“…Ultimately, the expert consensus was made. Approximately 40% of non-small cell lung cancer (NSCLC) patients carry common epidermal growth factor receptor (EGFR) gene sensitizing mutations [1,2], while another 20%-30% of patients carry uncommon/rare oncogenic drivers that can be specifically targeted for treatment [3][4][5][6][7][8][9][10][11][12][13][14]. Uncommon/ rare oncogenic drivers have significant clinical value in the diagnosis and treatment of NSCLC, but many clinical questions still remain unanswered.…”