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SNO 2020: Larotrectinib Holds Promise in CNS Metastases of TRK Fusion Cancers

The drug was highly active and well tolerated in patients harboring such metastases.


November 19, 2020—Houston, Texas—The tyrosine receptor kinase (TRK) inhibitor larotrectinib has been shown to hold promise in central nervous system (CNS) metastases of NTRK fusion cancers.


This outcome of subanalyses of an ongoing, randomized, open-label phase 1 trial and an ongoing, nonrandomized, parallel-group, open-label phase II trial was reported at the 2020 Society for Neuro-Oncology (SNO) Virtual Meeting.


Jyoti D Patel, MD, of the Robert H. Lurie Comprehensive Cancer Center and Feinberg School of Medicine, Northwestern University, Chicago, Illinois, reported data on patients with TRK fusion cancers with CNS metastases that were treated with larotrectinib.


Patients with solid tumors with CNS metastases at baseline that harbored an NTRK gene fusion and were enrolled in either of two clinical trials were identified. Response was assessed by the investigator per Response Evaluation Criteria in Solid Tumors v1.1.


As of July 2019, 14 patients with CNS metastases had been enrolled: lung cancer (n = 7), thyroid cancer (n = 4), melanoma (n = 2), and nonsecretory breast cancer (n = 1).

Median patient age was 53 (range, 25-76) years.


Including all sites of disease, the objective response rate was 71% (95% CI, 42%-92%):

  • 10 patients experienced a partial response

  • 2 patients exhibited stable disease

  • 2 patients exhibited progressive disease (lung and melanoma)

Of the 3 patients with measurable intracranial disease at baseline, the best intracranial response was 1 complete response, 1 partial response, and 1 stable disease.


The median duration of response for all patients was 14.8 (range, 1.9+ to 17.4+) months. Median progression-free survival was 9.9 (range, 1.4 to 19.3+) months.


Median overall survival was 27.8 (range, 1.4+ to 27.8) months. The treatment duration ranged from 1.4 to 25.0 months.


Overall, 6 patients continued treatment beyond progression, lasting from 0.1+ to 8.5 months. Treatment-emergent adverse events were mainly grades 1 and 2. Grade 3 treatment-emergent adverse events occurred in 7 patients (50%), with one case (myalgia) attributed to larotrectinib (7%). No grade 4 treatment-emergent adverse events were observed.


Dr. Patel explained that NTRK gene fusions occur in a range of tumor types, including those that have metastasized to the CNS. Larotrectinib is a highly selective FDA- and EMA-approved TRK inhibitor. It demonstrated an objective response rate of 79% across various cancers.1

The first trial in which Dr. Patel reviewed CNS metastases is a multicenter, open-label, phase I study of orally administered larotrectinib in adult subjects with advanced solid tumors that have progressed or are unresponsive to available therapies and for which no standard or available curative therapy exists.


The second trial that Dr. Patel’s team reviewed is a phase II basket study of larotrectinib in subjects with NTRK fusion–positive tumors. The primary objective is to evaluate larotrectinib for advanced, solid, NTRK fusion tumors of types 1 to 3 in children and adults.


Secondary objectives are to evaluate the efficacy and safety of larotrectinib in different NTRK fusion tumor types.


Dr. Patel concluded that larotrectinib was highly active and well tolerated in NTRK fusion cancers that had metastasized to the CNS. The results support testing for NTRK gene fusions across all cancers, including those that have metastasized to the CNS.


References

  1. Hong DS, DuBois SG, Kummar S, et al. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol. 2020;21(4):531-540. https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30856-3/fulltext

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