According to findings from a phase I/II study published in <em>The Lancet Oncology</em>, there was an “unprecedented” objective response rate of 93% with larotrectinib in patients with TRK fusion–positive solid tumors.
Theodore W. Laetsch, MD
According to findings from a phase I/II study published inThe Lancet Oncology, there was an “unprecedented” objective response rate of 93% with larotrectinib in patients with TRK fusionpositive solid tumors.1
From December 2015 to April 2017, a multicenter, open-label, study enrolled 24 patients from 8 sites in the United States. The ages of patients ranged from 1 month to 21 years and all patients enrolled were 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 while 7 did not.
Of these patients, 22 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). An initial partial response in one patient became stable disease at a subsequent assessment.
Objective responses in 14 (93%) patients with 2 CRs and 12 PRs was confirmed by an independent radiology review. All of the 7 patients without documented TRK fusions had progressive disease as best response.
“Every patient with a TRK fusionpositive solid tumor treated on this study had their tumor shrink. The nearly universal response rate seen with larotrectinib is unprecedented," said 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.
Nine patients were positive for NTRK1, 1 for NTRK2, and 7 for NTRK3 fusions in the dose-escalation phase. Patients had primary diagnoses of infantile fibrosarcoma (n = 8), other soft tissue sarcomas (n = 7), papillary thyroid cancer (n = 2), and other (n = 7). Also, 11 (65%) of the 17 patients with TRKfusion cancers had locally advanced disease, including 2 (12%) with infantile fibrosarcoma who were enrolled without previous systemic therapy.
Larotrectinib was given orally twice a day in 28-day cycles of continuous dosing. Cohort 1 used a dosing nomogram that assigned doses by 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 modeling expected to achieve an AUC equivalent to an adult dose of 150 mg twice daily.
Patients in cohort 1 were assigned, depending on age, doses ranging from 17% to 96% of the body surface area (BSA)-adjusted recommended adult phase II dose of 100 mg twice daily. Patients in cohort 2 were assigned doses ranging from 30% to 208% of the same BSA-adjusted adult dose.
After reviewing the findings from these cohorts, 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. This equated to a maximum of 173% of the recommended adult phase 2 dose.
Based on review of the 17 patients with TRK fusions, Investigators found that 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). However, the median duration of response was not reached.
The maximum-tolerated dose was also not reached. After analysis of the safety, pharmacokinetics, and objective responses at the completion of enrollment to cohort 3, it was established that 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 patients in this study 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 did not receive intrapatient dose escalation and discontinued therapy because of this adverse event (AE). No other patients were noted with a dose-limiting toxicity or discontinued larotrectinib due to AEs.
AEs were experienced in 21 (88%) of 24 patients, but only 4 (17%) 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. Review also found there were no larotrectinib-related deaths or deaths on treatment.
Only 2 larotrectinib-related AEs were serious, including 1 grade 3 nausea and 1 grade 3 ejection fraction decrease. The grade 3 ejection fraction decrease happened during the 28-day follow-up period when the patient was off larotrectinib after discontinuation for progressive disease.
Lucas Moreno, MD, PhD, Clinical Trials Unit, Hospital Infantil Universitario Niño Jesús, Madrid, Spain, called the study a “major breakthrough," in an accompanying editorial. He said the treatment produced durable, clinically meaningful responses without compromising quality of life, and 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,” said Moreno in the editorial.
Loxo and Bayer completed a rolling submission, in March 2018, of a new drug application (NDA) to the FDA for the treatment of adult and pediatric patients with locally advanced or metastatic solid tumors that harbored an NTRK gene fusion.
Findings published in the New England Journal of Medicine in February 2018 supported the application. Findings found 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.3There were 7 (13%) complete responses, 34 (62%) partial responses, and 5 (9%) patients with stable disease found in the independent assessment.
At the 1 year mark, 71% of responses in patients were still ongoing. Over half (55%) of the patients were still progression-free at 1 year. The median duration of response was not reached after a median follow-up of 8.3 months. This was also true for median progression-free survival after a median follow-up of 9.9 months.