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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.

SUBMITTER: Bebb DG

PROVIDER: S-EPMC7903287 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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

Bebb D Gwyn DG Banerji Shantanu S Blais Normand N Desmeules Patrice P Gill Sharlene S Grin Andrea A Feilotter Harriet H Hansen Aaron R AR Hyrcza Martin M Krzyzanowska Monika M Melosky Barbara B Noujaim Jonathan J Purgina Bibiana B Ruether Dean D Simmons Christine E CE Soulieres Denis D Torlakovic Emina Emilia EE Tsao Ming-Sound MS

Current oncology (Toronto, Ont.) 20210115 1

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 (<i>NTRK)</i> gene fusions. These <i>NTRK</i> 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 ...[more]

PMID: 33467570

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Project description:BackgroundNeurotrophic tyrosine receptor kinase (NTRK) gene fusions are present across various tumor types with an estimated overall prevalence of less than 1%. Tropomyosin receptor kinase inhibitors (TRKis) block the constitutively activated tyrosine receptor kinase (TRK) fusion protein produced in cancers with NTRK gene fusions (NTRK+) from downstream signaling. Many treatment guidelines now include TRKis as first-line (1L) or subsequent treatment options for TRK fusion cancer.ObjectiveThis study aimed to assess treatment patterns subsequent to a finding of NTRK+ status among patients with TRK fusion cancer.Patients and methodsThis was a one-time, retrospective, multi-site patient chart abstraction by oncology practices in the USA from June to September 2020. US medical oncologists from the Oncology Provider Extended Network (OPEN) who had treated patients with NTRK+ advanced/metastatic solid tumors abstracted information into electronic case report forms (eCRFs) for adult patients with advanced/metastatic solid tumors and a NTRK+ tumor test result with a known fusion partner. Data abstracted into eCRFs by oncologists included demographic, clinical, and treatment characteristics of patients with advanced/metastatic TRK fusion solid tumors. Responses were summarized using descriptive statistics. Median treatment durations across the lines of therapy were estimated by Kaplan-Meier time to discontinuation.ResultsA total of 19 medical oncologists abstracted data from 110 patient charts. Median patient age at advanced/metastatic diagnosis was 62 years. The majority of patients were male (58.2%) and White (79.1%). Solid tumor types reported in at least 10% of the study cohort were lung (24.5%), cholangiocarcinoma (13.6%), pancreatic (10.9%), and colorectal (10.0%). Results for patients with hepatobiliary cancers (i.e., cholangiocarcinoma, pancreatic cancer, hepatocellular carcinoma) and colorectal cancer, and appendiceal cancer are also included. Median duration of 1L TRKi therapy was 16.8 months across all solid tumor types, whereas median duration of 1L was 5.6 months among patients receiving non-TRKi therapies (p = 0.017). Among the solid tumor types represented by at least 10% of the study population, median duration of 1L TRKi therapy was only reached in patients with pancreatic cancer (3.3 months). Median duration of TRKi in the second-line (2L) setting was 7.9 months overall, relative to 5.3 months among patients receiving non-TRKi therapies (p = 0.003). Across lung, cholangiocarcinoma, pancreatic, and colorectal cancers, the median durations of 2L TRKi therapy were 14.1, 6.0, 6.1, and 4.1 months, respectively.Conclusion and relevanceAmong patients with advanced/metastatic TRK fusion solid tumors, medical oncologists reported that approximately two-thirds initiated a TRKi during the study period. Treatment with a TRKi was longer in duration compared to non-TRKi treatment in 1L and 2L therapy. Additional research is needed to gain insight into the association between early TRKi therapy initiation and clinical outcomes in the real-world setting.

Project description:BackgroundFusions involving one of three tropomyosin receptor kinases (TRK) occur in diverse cancers in children and adults. We evaluated the efficacy and safety of larotrectinib, a highly selective TRK inhibitor, in adults and children who had tumors with these fusions.MethodsWe enrolled patients with consecutively and prospectively identified TRK fusion-positive cancers, detected by molecular profiling as routinely performed at each site, into one of three protocols: a phase 1 study involving adults, a phase 1-2 study involving children, or a phase 2 study involving adolescents and adults. The primary end point for the combined analysis was the overall response rate according to independent review. Secondary end points included duration of response, progression-free survival, and safety.ResultsA total of 55 patients, ranging in age from 4 months to 76 years, were enrolled and treated. Patients had 17 unique TRK fusion-positive tumor types. The overall response rate was 75% (95% confidence interval [CI], 61 to 85) according to independent review and 80% (95% CI, 67 to 90) according to investigator assessment. At 1 year, 71% of the responses were ongoing and 55% of the patients remained progression-free. The median duration of response and progression-free survival had not been reached. At a median follow-up of 9.4 months, 86% of the patients with a response (38 of 44 patients) were continuing treatment or had undergone surgery that was intended to be curative. Adverse events were predominantly of grade 1, and no adverse event of grade 3 or 4 that was considered by the investigators to be related to larotrectinib occurred in more than 5% of patients. No patient discontinued larotrectinib owing to drug-related adverse events.ConclusionsLarotrectinib had marked and durable antitumor activity in patients with TRK fusion-positive cancer, regardless of the age of the patient or of the tumor type. (Funded by Loxo Oncology and others; ClinicalTrials.gov numbers, NCT02122913 , NCT02637687 , and NCT02576431 .).

Dataset Information

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

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

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