Theodore W. Laetsch, MD
Larotrectinib induced an “unprecedented” objective response rate of 93% in pediatric patients with TRK
fusion–positive solid tumors, according to findings from a phase I/II study published in The Lancet Oncology.1
Twenty-four patients were enrolled in this multicenter, open-label, study conducted at 8 sites in the United States from December 2015 to April 2017. Patients were aged from 1 month to 21 years and had been diagnosed with locally advanced or metastatic solid tumors or CNS tumors that had relapsed, progressed, or were nonresponsive to available therapies, regardless of TRK
fusion status. Seventeen patients had tumors harboring TRK
fusions and 7 did not.
Twenty-two patients were evaluable for response, 15 of whom harbored TRK
fusions. Fourteen patients (93%; 95% CI, 68-100), all with TRK
fusions, had an objective response by investigator review. There were 4 complete responses (CRs) and 10 partial responses (PRs). One patient had an initial partial response that became stable disease at a subsequent assessment.
Independent radiology review confirmed objective responses in 14 (93%) patients with 2 CRs and 12 PRs. All 7 patients without documented TRK fusions had progressive disease as best response.
“Every patient with a TRK fusion–positive solid tumor treated on this study had their tumor shrink,” lead author Theodore W. Laetsch, MD, leader of the Experimental Therapeutics Program in the Gill Center for Cancer and Blood Disorders at Children’s Health, Dallas, Texas, said in a statement. “The nearly universal response rate seen with larotrectinib is unprecedented.”
In this dose-escalation phase of the study, 9 patients were positive for NTRK1
, 1 for NTRK2,
and 7 for NTRK3
fusions. Patients had primary diagnoses of infantile fibrosarcoma (n = 8), other soft tissue sarcomas (n = 7), papillary thyroid cancer (n = 2), and other (n = 7). Eleven (65%) of 17 patients with TRK
fusion cancers had locally advanced disease, including 2 (12%) with infantile fibrosarcoma who were enrolled without previous systemic therapy.
Patients received larotrectinib orally twice daily in 28-day cycles of continuous dosing. Cohort 1 used a dosing nomogram that assigned doses on the basis of both age and bodyweight to achieve an area under the curve (AUC) equivalent to an adult dose of 100 mg twice daily. Cohort 2 used a dosing nomogram based on the same modeling predicted to achieve an AUC equivalent to an adult dose of 150 mg twice daily.
Depending on age, patients in cohort 1 were assigned doses ranging from 17% to 96% of the body surface area (BSA)-adjusted recommended adult phase II dose of 100 mg twice daily, while those in cohort 2 were assigned doses ranging from 30% to 208% of the same BSA-adjusted adult dose.
After review of data from cohorts 1 and 2, the protocol was amended on Sept 12, 2016, assigning patients enrolled to cohort 3 to a dose of 100 mg/m2
twice daily regardless of age, equating to a maximum of 173% of the recommended adult phase 2 dose.
Of the 17 patients with TRK
fusions, 1 patient discontinued treatment, 14 remained on treatment, and 2 underwent surgery with curative intent after a median of 8.2 months (IQR, 5.2-9.5). The median duration of response was not reached.
The maximum-tolerated dose was not reached. Following analysis of safety, pharmacokinetics, and objective responses at the completion of enrollment to cohort 3, researchers established 100 mg/m2
twice daily, with a maximum of 100 mg per dose, as the recommended phase II dose in pediatric patients based on pharmacokinetic parameters similar to those reported in adults treated with 100 mg per dose.
All enrolled patients were evaluable for safety. Three (75%) of 4 patients in cohort 1 and 2 (18%) of 11 in cohort 2 received an intrapatient dose escalation 1 to 4 times each. In cohort 3, 1 patient with a TRK fusion-negative neuroblastoma had a grade 3 dose-limiting ALT elevation. This patient had not undergone intrapatient dose escalation and discontinued therapy because of this adverse event (AE). No other patient had a dose-limiting toxicity or discontinued larotrectinib for AEs.
Twenty-one (88%) of 24 patients experienced AEs, but only 4 (17%) of those were grade 3 treatment-related AEs. No grade 3 treatment-related AE occurred in more than 1 patient, and there were no grade 4/5 AEs attributed to larotrectinib. There were no larotrectinib-related deaths or deaths on treatment.
There were 2 larotrectinib-related serious AEs, 1 grade 3 nausea and 1 grade 3 ejection fraction decrease. The grade 3 ejection fraction decrease occurred during the patient's 28-day follow-up period off larotrectinib after discontinuation for progressive disease.