Larotrectinib shows significant efficacy in NTRK + tumors of the salivary glands

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“Larotrectinib has demonstrated robust and long-lasting efficacy in patients with NTRK fusion of salivary gland tumors with different types of histology, ”said Xiuning Le, MD, PhD, assistant professor in the department of thoracic / head and neck medical oncology at the University of Texas MD Anderson Cancer Center in Houston. “These data underscore the clinical importance of identifying NTRK gene fusions in patients with salivary gland tumors, regardless of histology.”

NTRK gene fusions occur in about 5% of salivary gland tumors, including about 80% of secretory carcinomas.

Larotrectinib has been approved for the treatment of adult and pediatric patients with solid tumors harboring NTRK gene fusions, regardless of tumor type, without known acquired resistance mutations that are either metastatic or for which surgery is not recommended.2 In a number of clinical trials, the TRK inhibitor induced an objective response rate (ORR) of 75% (95% CI, 61% to 85%) in 206 adult and pediatric cancer patients TRK positive for fusion.

For analysis of patients with TRK fusion positive salivary gland tumors, the researchers looked at patients from the phase 2 NAVIGATE trial (NCT02576431) and a phase 1 trial (NCT02122913) of adult patients, all with advanced solid tumors. Twenty-four patients were treated with 100 mg larotrectinib twice daily, with the exception of one patient who received 150 mg twice daily.

The primary endpoint was investigator-assessed TRG according to RECIST v1.1, and secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival ( OS) and security.

The patients had a median age of 58.5 years (range: 28.0-78.0), 75% were men, and half had an ECOG performance index of 0. Almost all of the patients had undergone surgery ( 96%) and radiation therapy (83%), and half had received systemic treatment. Twenty-one percent of patients had received at least 2 prior systemic therapies.

Tumor histology was secretory carcinoma in 54%, adenocarcinoma in 21% and mucoepidermoid in 13%. In addition, 1 patient each had adenoid cystic carcinoma, sarcomatoid glandular carcinoma and not otherwise specified. All patients had an ETV6-NTR K3 gene fusion.

The ORR was 92% (95% CI: 73% to 99%), which consisted of complete responses in 13% and partial responses in 79%; progressive disease was reported in the remaining 8% of patients, 1 of whom had an NTRK3 G623R resistance mutation after previous treatment with entrectinib (Rozlytrek). Responses were observed in all histologies.

The duration of treatment ranged from 0.95 to 60.4+ months. Five of the 8 patients who progressed continued treatment beyond progression for 2.8 to 20.5+ months. The median time to response was 1.84 months (range 0.99 to 5.98). Le noted that early responses were “consistent with a powerful, effective, on target [tyrosine kinase inhibitor]. “

Not all median DOR, PFS, and OS were met on the data cutoff date (TABLE 1). The rate of DOR was 72% at 24 months and 60% at 36 months. The PFS rate was 78% at 24 months and 66% at 36 months. The ILI rate was 91% at 24 and 36 months.

Le noted that the treatment was generally well tolerated, even for long-term use. Treatment-related adverse events (AEs) were mostly grade 1 or 2. No Grade 4 events or treatment discontinuation due to treatment-related AEs were reported in the study.

The most common treatment-related AEs were increased alanine aminotransferase (ALT), dizziness, increased aspartate aminotransferase (AST), fatigue, constipation, nausea, myalgia and spasms. muscle. Treatment-related Grade 3 AEs included increased ALT in 3 patients, increased AST in 2, dizziness in 1, and abnormal liver function in 1.

THE REFERENCES
1. Le X, Baik C, Bauman J, et al. Efficacy and safety of larotrectinib in patients with advanced salivary gland cancer by TRK fusion. Presented at the 10th American Head & Neck Society International Conference on Head and Neck Cancer; July 22-25, 2021; virtual. Abstract S030.
2. The FDA approves larotrectinib for solid tumors with NTRK gene fusion. FDA. Updated December 14, 2018. Accessed August 24, 2021. https://bit.ly/3BaseOq


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