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How selecting best therapy for metastatic NTRK fusion-positive non-small cell lung cancer?

ABSTRACT: The tropomyosin receptor kinase (TRK) family of receptor tyrosine kinases has become a focus of clinical interest because the NTRK genes (NTRK1-3) encoding them have been identified as oncogenic fusion genes in a wide range of different tumor types, including lung cancer. These NTRK gene fusions usually occur at a low frequency below 1%, in non-small cell lung cancer (NSCLC) in 0.1-0.2% of the cases and have been reported across a wide range of tumor types. The TRK fusion proteins encoded by such gene fusions have constitutively activated tyrosine kinase domains and constitute actionable targets for tyrosine kinase inhibitors (TKIs). The first generation TRK TKIs larotrectinib and entrectinib have been investigated in clinical phase I and II trials in solid tumors both in adult and pediatric patients and results have demonstrated high response rates that are durable and with generally good tolerability. This has led to approval of these TRK inhibitors by regulatory authorities in the USA, Europe and Japan as tumor agnostic treatment of advanced or recurrent NTRK fusion-positive cancers in adult and pediatric patients. With a focus on lung cancer, this review gives a background to NTRK fusion genes, presents clinical data for TRK inhibitors and discuss the issue of acquired resistance to TRK inhibition.

SUBMITTER: Ekman S

PROVIDER: S-EPMC7815373 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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How selecting best therapy for metastatic NTRK fusion-positive non-small cell lung cancer?

Ekman Simon S

Translational lung cancer research 20201201 6

The tropomyosin receptor kinase (TRK) family of receptor tyrosine kinases has become a focus of clinical interest because the NTRK genes (NTRK1-3) encoding them have been identified as oncogenic fusion genes in a wide range of different tumor types, including lung cancer. These NTRK gene fusions usually occur at a low frequency below 1%, in non-small cell lung cancer (NSCLC) in 0.1-0.2% of the cases and have been reported across a wide range of tumor types. The TRK fusion pr ...[more]

PMID: 33489816

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Project description:BackgroundPatient-reported outcomes (PROs) are increasingly relevant endpoints in clinical trials, contributing to our understanding of risk-benefit profiles, in addition to efficacy and safety data. We investigated the impact of entrectinib on patient-reported symptoms, functioning, and health-related quality of life.Patients and methodsSTARTRK-2 is a phase II basket study in patients with locally advanced/metastatic neurotrophic receptor tyrosine kinase 1/2/3 (NTRK1/2/3) and ROS proto-oncogene 1 (ROS1) fusion-positive solid tumours. PROs (prespecified secondary endpoint) were evaluated using the European Organization for Research and Treatment of Cancer quality-of-life questionnaire (QLQ-C30), lung cancer module (QLQ-LC13), and colorectal cancer module (QLQ-CR29), and the EuroQoL 5-Dimension 3-Level instruments, completed before cycle 1 day 1 and each subsequent 4-week cycle of entrectinib dosing, and the end of treatment. Adverse events and treatment-related symptoms were assessed in the safety analysis (SA)-PRO population. Tumour-related symptoms, functioning, and global health status were assessed in the efficacy analysis (EA)-PRO population. Data cut-offs: 31 October 2018 NTRK cohort; 01 May 2019 ROS1 cohort.ResultsSA-PRO populations comprised patients with NTRK fusion-positive solid tumours (N = 88) or ROS1 fusion-positive non-small-cell lung cancer (N = 180) who received one or more doses of entrectinib, completed PRO questionnaires on cycle 1 day 1 and answered one or more questions on-study. EA-PRO populations (N = 71) and (N = 145), respectively, comprised SA-PRO patients with measurable baseline disease. Moderate-to-high baseline global health status scores were maintained in EA-PRO populations during treatment. Role and physical functioning scores were moderate-to-high at baseline, with trends towards clinical improvement during treatment. Both cohorts reported low-to-moderate symptom burden at baseline, which was maintained or trended towards clinically meaningful improvement. Symptoms commonly associated with cancer treatment (e.g. nausea, fatigue) remained stable or improved during treatment. All SA-PRO patients experienced one or more adverse events, most frequently constipation or diarrhoea.ConclusionsPRO findings were consistent with the favourable safety profile of entrectinib, and further reinforce the positive benefit-risk profile of this treatment, indicating minimal overall treatment burden.

Project description:BackgroundRET fusions are oncogenic drivers in 1 to 2% of non-small-cell lung cancers (NSCLCs). In patients with RET fusion-positive NSCLC, the efficacy and safety of selective RET inhibition are unknown.MethodsWe enrolled patients with advanced RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated separately in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response) as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety.ResultsIn the first 105 consecutively enrolled patients with RET fusion-positive NSCLC who had previously received at least platinum-based chemotherapy, the percentage with an objective response was 64% (95% confidence interval [CI], 54 to 73). The median duration of response was 17.5 months (95% CI, 12.0 to could not be evaluated), and 63% of the responses were ongoing at a median follow-up of 12.1 months. Among 39 previously untreated patients, the percentage with an objective response was 85% (95% CI, 70 to 94), and 90% of the responses were ongoing at 6 months. Among 11 patients with measurable central nervous system metastasis at enrollment, the percentage with an objective intracranial response was 91% (95% CI, 59 to 100). The most common adverse events of grade 3 or higher were hypertension (in 14% of the patients), an increased alanine aminotransferase level (in 12%), an increased aspartate aminotransferase level (in 10%), hyponatremia (in 6%), and lymphopenia (in 6%). A total of 12 of 531 patients (2%) discontinued selpercatinib because of a drug-related adverse event.ConclusionsSelpercatinib had durable efficacy, including intracranial activity, with mainly low-grade toxic effects in patients with RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).

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How selecting best therapy for metastatic NTRK fusion-positive non-small cell lung cancer?

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How selecting best therapy for metastatic <i>NTRK</i> fusion-positive non-small cell lung cancer?

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