Larotrectinib shows durable response in TRK fusion-positive cancers across age groups
The use of larotrectinib, a highly selective TRK (tropomyosin receptor kinase) inhibitor, improves overall response rate in patients with TRK fusion-positive cancers regardless of tumour types or patient’s age, according to a recent study.
“This is truly a magic bullet for our patients with TRK-positive cancer," according to study senior co-author Dr Leo Mascarenhas from the Children's Center for Cancer and Blood Diseases.
“Larotrectinib had marked and durable antitumour activity in patients with TRK fusion-positive cancer, regardless of the age of the patient or of the tumour type,” said Mascarenhas and co-authors.
The investigation included a series of three studies: phase 1 (adults), phase I-II (children), and phase II (adolescents and adults). Fifty-five patients (age range, 4 months to 76 years) with 17 unique TRK fusion-positive tumour types were enrolled, including salivary-gland tumour (22 percent), other soft-tissue sarcoma (20 percent), infantile fibrosarcoma (13 percent), thyroid tumour (9 percent), and colon tumour (7 percent). TRK fusions were identified using next-generation sequencing (n=50) and fluorescence in situ hybridization (n=5). Participants received oral larotrectinib 100 mg twice daily. [N Engl J Med 2018;378:731-739]
As of data cut-off, the overall response rate was 75 percent (95 percent confidence interval [CI], 61–85), with a complete response rate of 13 percent and a partial response rate of 62 percent, as assessed by an independent review committee according to RECIST*. About 13 percent of the patients had stable disease and 9 percent had progressive disease.
Similar results were observed by investigator’s assessment, with an overall response rate of 80 percent (95 percent CI, 67–90), a complete response rate of 16 percent, and a partial response rate of 64 percent. The rates of stable and progressive disease were 9 percent and 11 percent, respectively.
At a median follow-up of 9.4 months, 86 percent (38 out of 44) of the responding patients were still continuing treatment or had undergone curative surgery.
At 12 months, 71 percent (10 out of 44) of patients continued responding to larotrectinib and 55 percent (12 out of 55) remained progression-free.
The median duration of response and progression-free survival had not been reached after 8.3 months and 9.9 months of median follow-up, respectively.
Although 15 percent of the patients required dose reduction – of which four cases were due to increased alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level, two to dizziness, and two to decreased neutrophil count – none of the patients discontinued treatment due to a drug-related adverse event (AE).
Majority of the AEs were of grade 1 or 2. The most common AEs were anaemia (11 percent), higher ALT or AST level (7 percent), weight gain (7 percent), and lower neutrophil count (7 percent).
None of the grade 3 or 4 AEs were reported in more than 5 percent of the patients and none were considered to be treatment related.
“TRK fusions defined a unique molecular subgroup of advanced solid tumours in children and adults in whom larotrectinib was highly active. Durable responses were observed without regard to the age of the patient, tumour tissue, and fusion status,” noted the researchers. “The side-effect profile of larotrectinib suggests that long-term administration is feasible for patients. [However,] screening strategies that include assays with the ability to detect TRK fusions will be needed in order to identify patients who may benefit from larotrectinib.”
“Our data not only validated TRK fusions as therapeutic targets, but also showed the potential for larotrectinib as a therapeutic agent for TRK-fusion positive cancers,” said lead author Dr David Hong from the Department of Investigational Cancer Therapeutics, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, Houston, Texas, US.
*RECIST: Response Evaluation Criteria in Solid Tumors