Larotrectinib: safe and effective in TRK fusion-positive tumours

Dr David Hyman (Memorial Sloan Kettering Cancer Center, New York, USA) reported an integrated analysis showing that the tropomyosin receptor kinase (TRK) inhibitor larotrectinib shows anti-tumour activity in tumours with NTRK gene fusions, agnostic of tumour type, including long-lasting objective responses and low toxicity [1].

Treatment with larotrectinib led to objective responses in 79% of 153 evaluable patients across 18 different tumour types. The overall response rate included complete responses in 24 (16%) patients. An additional 12% of patients had stable disease as best response, resulting in a clinical benefit rate of 91%. Invited discussant Dr Christian Dittrich (Vienna University School of Medicine, Austria) characterised the overall response rate as “sensational.” He noted that the complete responses included 3 pathologic complete responses in patients with infantile fibrosarcoma.

In a subset of 108 patients with confirmed responses, the median duration of response was 35.2 months. “These data confirm the marked tissue-agnostic efficacy and long durability of response in patients with  TRK fusion–positive cancer treated with larotrectinib,” the investigators concluded. “Larotrectinib continued to demonstrate a favourable long-term safety profile. Screening patients for  NTRK gene fusions should be actively considered.”

The integrated analysis comprised the primary and supplementary cohorts enrolled in an adult phase 1 trial, the phase 1/2 SCOUT paediatric trial, and the phase 2 adult/adolescent NAVIGATE trial. The most common tumour types were infantile fibrosarcoma (18%), thyroid cancer (16%), salivary gland cancer (13%), lung cancer (8%), and a variety of other soft-tissue sarcomas (23%).

The analysis cohort consisted of 52 paediatric patients and 107 adults; 35 patients received larotrectinib as frontline treatment, whereas 48 patients had received 1 prior systemic therapy, 34 had received 2, and 42 patients had receive 3 or more prior lines. The gene fusions translocated  NTRK1  in 64 cases, NTRK2  in 4 patients,  NTRK3  in 88 patients, and remained unconfirmed in 3 patients.

The 79% overall response rate in the integrated analysis was virtually identical to response rates observed in the primary (80%) and supplementary (79%) data sets. Among 12 evaluable patients with brain metastases, the overall response rate was 75% in the primary data set, while it was 83% in the supplementary data set. The median time to objective response was 1.8 months (0.9-6.1 months), and the median treatment duration was 8.0 months (0.03-47.2 months).

In addition to the 35.2-month median duration of response, landmark analyses showed that 75% of patients from the primary data set and 83% from the supplementary data set had responses lasting at least 12 months. The researchers observed a median progression-free survival of 28.3 months and a 12-month progression-free survival of 67%. Median overall survival was 44.4 months, and 12-month overall survival was 88%.

An expanded safety cohort of 260 patients treated with larotrectinib showed no new safety signals. The most common treatment-emergent adverse events (AEs, any grade) were fatigue (33%), increased alanine aminotransferase (ALT; 28%), cough (28%), constipation (27%), anaemia (27%), increased aspartate aminotransferase (AST; 27%), dizziness (25%), nausea (25%), vomiting (25%), diarrhoea (24%), and pyrexia (20%). The most common grade 3/4 treatment-emergent AE was anaemia (10%, all grade 3). No other grade 3/4 treatment-emergent AEs occurred in more than 5% of patients.

1. Hyman DM et al. ESMO Congress 2019. Abstract 445PD.

Posted on 26 November, 201918 March, 2024