Efficacy of Larotrectinib inTRKFusion–Positive Cancers in Adults and Children

Abstract

BACKGROUND Fusions 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. METHODS We 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. RESULTS A 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. CONCLUSIONS Larotrectinib 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.)

Tropomyosin-Related Kinase Receptor and Neurotrophin Expression in Cutaneous Melanoma Is Associated with a Poor Prognosis and Decreased Survival

“…Recurrent TRK fusions involving the NTRK1/2/3 genes (which encode TrkA/B/C proteins, respectively) lead to overexpression of the chimeric protein, resulting in constitutive downstream signaling [45]. Our study suggests a strong role for the NTs NGF and BDNF, in addition to TRKs, in melanoma progression, likely through the activation of TRK receptors.…”

“…Recently, the TRK protein inhibitors entrectinib (ALKA-372–001 and STARTAK-1) [19] and larotrectinb (NCT02122913, NCT02637687, and NCT02576431) [45] were shown to be well tolerated and to exhibit marked and durable antitumor activity in patients with TRK fusion-positive cancer regardless of patient age or tumor type. Recurrent TRK fusions involving the NTRK1/2/3 genes (which encode TrkA/B/C proteins, respectively) lead to overexpression of the chimeric protein, resulting in constitutive downstream signaling [45].…”

Clinicopathologic Features of Non–Small-Cell Lung Cancer Harboring an NTRK Gene Fusion

“…TRK tyrosine kinase inhibitors have shown tremendous promise in NTRK fusion-positive solid tumors across cancer types 8,9 , following the paradigm now well-established for EGFR -mutant and ALK or ROS1 fusion-positive NSCLCs. Although NTRK fusions are rare in NSCLC, uncertainty remains about which patients should undergo testing for these alterations.…”

“…The objective response rate to larotrectinib across 55 adult and pediatric tumors with NTRK gene rearrangements was 75%. 8 Responses were seen across tumor types and NTRK gene partners. Among 4 NSCLC cases, RECIST responses were seen in 3, and the fourth had an approximately 20% reduction in tumor size.…”

Darmkrebs - Aktuelle Standards und Perspektiven in der Therapieführung

“…NTRK-Fusionen sind innerhalb von kolorektalen Karzinomen sehr seltene Veränderungen (0,2-0,5%), können aber mit NTRK Inhibitoren sehr gut behandelt werden [[15]].…”