Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials

Summary

Background

The selective TRK inhibitor larotrectinib was approved for paediatric and adult patients with advanced TRK fusion-positive solid tumours based on a primary analysis set of 55 patients. The aim of our analysis was to explore the efficacy and long-term safety of larotrectinib in a larger population of patients with TRK fusion-positive solid tumours.

Methods

Patients were enrolled and treated in a phase 1 adult, a phase 1/2 paediatric, or a phase 2 adolescent and adult trial. Some eligibility criteria differed between these studies. For this pooled analysis, eligible patients were aged 1 month or older, with a locally advanced or metastatic non-CNS primary, TRK fusion-positive solid tumour, who had received standard therapy previously if available. This analysis set includes the 55 patients on which approval of larotrectinib was based. Larotrectinib was administered orally (capsule or liquid formulation), on a continuous 28-day schedule, to adults mostly at a dose of 100 mg twice daily, and to paediatric patients mostly at a dose of 100 mg/m² (maximum of 100 mg) twice daily. The primary endpoint was objective response as assessed by local investigators in an intention-to-treat analysis. Contributing trials are registered with ClinicalTrials.gov, NCT02122913 (active not recruiting), NCT02637687 (recruiting), and NCT02576431 (recruiting).

Findings

Between May 1, 2014, and Feb 19, 2019, 159 patients with TRK fusion-positive cancer were enrolled and treated with larotrectinib. Ages ranged from less than 1 month to 84 years. The proportion of patients with an objective response according to investigator assessment was 121 (79%, 95% CI 72–85) of 153 evaluable patients, with 24 (16%) having complete responses. In a safety population of 260 patients treated regardless of TRK fusion status, the most common grade 3 or 4 larotrectinib-related adverse events were increased alanine aminotransferase (eight [3%] of 260 patients), anaemia (six, 2%), and decreased neutrophil count (five [2%]). The most common larotrectinib-related serious adverse events were increased alanine aminotransferase (two [<1%] of 260 patients), increased aspartate aminotransferase (two [<1%]), and nausea (two [<1%]). No treatment-related deaths occurred.

Interpretation

These data confirm that TRK fusions define a unique molecular subgroup of advanced solid tumours for which larotrectinib is highly active. Safety data indicate that long-term administration of larotrectinib is feasible.

Funding

Bayer and Loxo Oncology.

Introduction

The tropomyosin receptor kinase family of proteins TRKA (high-affinity nerve growth factor receptor), TRKB (BDNF/NT-3 growth factors receptor), and TRKC (NT-3 growth factor receptor) are encoded by the neurotrophic receptor tyrosine kinase genes (NTRK1, NTRK2, and NTRK3, respectively). TRK fusions (fusions between one of the NTRK genes and a 5ʹ partner gene) arise from intrachromosomal or interchromosomal rearrangements that collectively lead to the expression of a chimeric oncoprotein characterised by ligand-independent kinase activation, which consequently drives oncogenesis.1, 2 TRK fusions are found in various adult and paediatric cancers. These cancers include rare tumours (eg, mammary analogue secretory carcinoma,³ secretory breast carcinoma,⁴ infantile fibrosarcoma,⁵ and cellular congenital mesoblastic nephroma⁶) in which TRK fusions are found in the majority of cases, and more common cancers (eg, lung, breast, and gastrointestinal carcinomas, melanomas, and sarcomas)⁷ in which TRK fusions are found at lower frequencies. TRK fusions can be identified by DNA-based or RNA-based next-generation sequencing, or other assays such as fluorescence in-situ hybridisation (FISH) or immunohistochemistry.1, 8

We previously reported⁹ the activity and safety of larotrectinib, a highly selective and potent TRK inhibitor, in the first 55 consecutively enrolled adult and paediatric patients with TRK fusion-positive cancer who were treated across one of three clinical trials (primary analysis set). In this analysis, the proportion of patients with response according to independent review was 41 (75%) of 55 patients and 44 (80%) of 55 patients by investigator assessment. Based on these data, larotrectinib became the first tyrosine kinase inhibitor to be granted approval by the US Food and Drug Administration (FDA) and the European Medicines Agency for a tumour-agnostic indication; specifically, the treatment of adult and paediatric patients with advanced solid tumours that harbour an NTRK gene fusion. The multikinase inhibitor entrectinib¹⁰ has similarly been approved by the US FDA and the Japanese Ministry of Health, Labour, and Welfare for the treatment of patients with NTRK fusion-positive disease in a tumour-agnostic manner, and TRK inhibitors targeting acquired on-target resistance are in development.11, 12

Research in context

Evidence before this study

We searched PubMed and major congress abstracts (including those from meetings of the American Society of Clinical Oncology and the American Association for Cancer Research) using the terms “TRK or NTRK”, “fusion or rearrangement”, “cancer” and “treatment”. We did not restrict our search by publication date or language. The results of this search showed that TRK inhibition with the first-generation TRK inhibitors larotrectinib or entrectinib was active in TRK fusion-positive cancers of various histologies. Both drugs had been approved by multiple regulatory agencies for the treatment of TRK fusion-positive cancers in both adult and paediatric populations. The next-generation TRK inhibitors selitrectinib or repotrectinib showed preliminary activity in small series that included patients with resistance to first-generation TRK inhibitors.

Added value of this study

In the initial analysis of the first 55 consecutively enrolled adult and paediatric patients with TRK fusion cancer who were treated with larotrectinib, the durability of benefit and long-term safety had not been fully characterised. This expanded efficacy analysis includes data on the durability of disease control in a combined efficacy population almost three times larger than previously reported. Additionally, our expanded safety analysis in 260 patients confirms the favourable tolerability profile of larotrectinib, including in patients with longer treatment durations.

Implications of all the available evidence

TRK fusions define a unique molecular subgroup of advanced solid tumours for which the activity of larotrectinib is highly durable. Long-term safety is favourable. Our findings underscore the need to test for TRK fusions in the clinic with assays that are best poised to identify these alterations.

At the time of the previous prespecified analysis for larotrectinib, the median duration of response and progression-free survival had not been reached. Furthermore, little representation of several common cancer types including lung, melanoma, colon, and breast cancer in the primary analysis set made interpretation of efficacy challenging in these tumour types. Finally, long-term safety was unknown. To address these limitations, we report an expanded pooled efficacy analysis of 159 patients with TRK fusion-positive cancer treated with larotrectinib, and a safety analysis of 260 patients who received larotrectinib regardless of TRK fusion status.