Larotrectinib Exceeds 90% Response Rate in TRK+ Pediatric Cancers

Larotrectinib induced an “unprecedented” objective response rate of 93% in patients with TRK fusion–positive solid tumors.

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.

Writing in an accompanying editorial, Lucas Moreno, MD, PhD, Clinical Trials Unit, Hospital Infantil Universitario Niño Jesús, Madrid, Spain, called the study a “major breakthrough.” He wrote that the treatment produced durable, clinically meaningful responses without compromising quality of life, and the treatment facilitated nonmutilating surgeries for previously inoperable patients.2

“In conclusion, this phase I trial showed short-term safety and encouraging activity of larotrectinib in pediatric patients with solid tumors harboring NTRK fusions, and is an exemplary study design in terms of biological rationale, rapid accrual, and inclusion of pediatric age cohorts, which maximizes its chances of success and paves the way for development of other targeted agents in childhood cancers,” wrote Moreno.

In March 2018, Loxo and Bayer completed a rolling submission of a new drug application (NDA) to the FDA for the treatment of adult and pediatric patients with locally advanced or metastatic solid tumors harboring an NTRK gene fusion.

The application is supported by findings that were published in the New England Journal of Medicine in February 2018, in which 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 adult patients.3 Per the independent assessment, there were 7 (13%) complete responses, 34 (62%) partial responses, and 5 (9%) 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.


  1. Laetsch TW, DuBois SG, Mascarenhas L, et al. Larotrectinib for pediatric solid tumors harboring NTRK gene fusions: phase 1 results from a multicenter, open-label, phase 1/2 study [published online March 20, 2018]. Lancet Oncol. doi: 10.1016/S1470-2045(18)30119-0.
  2. Moreno L. An active drug for TRK-positive pediatric solid tumors [published online March 20, 2018]. Lancet Oncol. doi: 10.1016/S1470-2045(18)30191-8.
  3. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion—positive cancers in adults and children. N Engl J Med. 2018; 378:731-739. doi: 10.1056/NEJMoa1714448.