The FDA has granted an accelerated approval to larotrectinib (Vitrakvi) for use in adult and pediatric patients with solid tumors that have an <em>NTRK</em> gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment.
The FDA has granted an accelerated approval to larotrectinib (Vitrakvi) for use in adult and pediatric patients with solid tumors that have anNTRKgene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment.
The FDA based its decision on findings from 3 clinical trials. Results published in theNew England Journal of Medicine(NEJM) in February 2018 showed larotrectinib induced an objective response rate of 75% (95% CI, 61-85) by independent review and 80% (95% CI, 67-90) by investigator assessment in 55 evaluable patients. Per the independent assessment, there were 7 (13%) complete responses, 34 (62%) partial responses, and 7 (13%) patients with stable disease.
At 1 year, 71% of responses were ongoing. More than half (55%) of patients remained progression-free at 1 year. The median duration of response had not been reached after a median follow-up of 8.3 months. The same was true for median progression-free survival after a median follow-up of 9.9 months.
The FDA reviewed data from 55 adult and pediatric patients withTRKfusionpositive cancers enrolled across a phase I adult trial, the phase II NAVIGATE trial, and the phase I/II SCOUT pediatric trial. The data cutoff for theNEJMfindings was July 17, 2017.
The breakdown by tumor type included salivary gland tumor (n = 12), other soft-tissue sarcoma (n = 11), infantile fibrosarcoma (n = 7), thyroid tumor (n = 5), colon cancer (n = 4), lung cancer (n = 4), melanoma (n = 4), GIST (n = 3), cholangiocarcinoma (n = 2), appendix tumor (n = 1), breast cancer (n = 1), and pancreatic cancer (n = 1).
The median patient age was 45 years (range, 0.3-76.0), with 56% of patients ≥40 years of age. A third of patients (35%) had received ≥3 prior systemic chemotherapies. Twenty-four patients had an ECOG performance status of 0, 27 had a status of 1, and 4 had a status of 2.
The most common all-grade treatment-related adverse events (TRAEs) were increased ALT/AST level (38%), dizziness (25%), fatigue (16%), nausea (16%), constipation (16%), vomiting (11%), increased body weight (11%), anemia (9%), decreased neutrophil count (9%), and diarrhea (5%).
Grade 3 TRAEs included increased ALT/AST level (5%), anemia (2%), decreased neutrophil count (2%), nausea (2%), and dizziness (2%). There were no grade 4/5 TRAEs. Dose reductions were required in 8 of the 55 patients.
TRKgene fusions are genetic alterations that appear across a wide range of tumorsincluding breast and colorectal cancer, infantile fibrosarcoma, lung cancer, melanoma, and various sarcomas—and lead to uncontrolled TRK signaling and tumor growth. Such fusions are rare, but they are expressed in dozens of adult and pediatric tumor types. To date, researchers have identified more than 50 different partner genes that fuse with 1 of 3 TRK genes (NTRK 1, 2, and 3).
Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusionpositive cancers in adults and children.N Engl J Med. 2018; 378:731-739. doi: 10.1056/NEJMoa1714448.