Larotrectinib in TRK Fusion–Positive Cancers in Adults and Children
In a study reported in The New England Journal of Medicine, Drilon et al found that the oral tropomyosin receptor kinase (TRK) inhibitor larotrectinib produced a high response rate and enduring responses in patients with TRK fusion–positive cancers. These fusions have been found to lead to oncogene addiction and may be implicated in up to 1% of all solid cancers.
Study Details
The study involved consecutive enrollment of prospectively identified patients with TRK fusion–positive cancers between March 2015 and February 2017 into a phase I study involving adults, a phase I/II study involving children, and a phase II study involving adolescents and adults. The primary endpoint for the combined analysis was overall response rate using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 on independent review.
Adolescents, adults, and children with body surface area ≥ 1 m2 received a dose of 100 mg twice daily, whereas children with a body surface area < 1 m2 received 100 mg/m2 twice daily. A liquid formulation was available for patients unable to swallow capsules. Treatment continued until disease progression, withdrawal from the study, or unacceptable toxicity.
A total of 55 patients aged 4 months to 76 years were enrolled and treated. Patients had 17 unique TRK fusion–positive tumor types.
Responses
At the primary data cutoff of July 2017, the overall response rate was 75% on independent radiology review committee assessment, including complete response in 7 patients (13%) and partial response in 34 (62%); an additional 7 patients (13%) had stable disease. Five patients (9%) had progressive disease and two (4%) could not be evaluated due to early withdrawal for clinical deterioration. On investigator assessment, the response rate was 80%, including complete response in 16% and partial response in 64%. Responses were observed irrespective of tumor type, patient age, or TRK fusion characteristics.
Median time to response was 1.8 months. At 6 months, 83% of responses were ongoing and 73% of patients were progression-free. At 1 year, 71% of responses were ongoing and 55% of patients remained progression-free. Median duration of response and progression-free survival were not reached. At median follow-up of 9.4 months, 86% of patients with response continued on treatment or had undergone curative surgery.
Adverse Events
The most common adverse events of any grade were increased alanine transaminase (ALT) or aspartate transaminase (AST) in 42%, fatigue (36%), and vomiting (33%). The most common grade 3 adverse events (no grade 4 events were observed) were anemia (11%), increased ALT or AST (7%), increased body weight (7%), and decreased neutrophils (7%). Increased ALT or AST (5%) was the only treatment-related grade 3 adverse event occurring in > 2% of patients. No patient discontinued larotrectinib due to a drug-related adverse event.
The investigators concluded, “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.”
The study was funded by Loxo Oncology, National Institutes of Health grants, Cancer Prevention and Research Institute of Texas, National Center for Advancing Translational Sciences, and Alex’s Lemonade Stand Foundation.
Alexander Drilon, MD, and David M. Hyman, MD, of Memorial Sloan Kettering Cancer Center; Theodore W. Laetsch, MD, of The University of Texas Southwestern Medical Center; and David S. Hong, MD, of The University of Texas MD Anderson Cancer Center, contributed equally to The New England Journal of Medicine article.
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