Larotrectinib Effective in TRK+ Pediatric Cancers and CNS Tumors

Wayne Kuznar
Published: Friday, Jun 07, 2019

Cornelis M. van Tilburg, MD, PhD

Cornelis M. van Tilburg, MD, PhD

The efficacy of larotrectinib (Vitrakvi) is supported in distinct patient populations with TRK fusion cancer—specifically pediatric patients and adult or pediatric patients with brain metastases or primary central nervous system (CNS) tumors, according to analyses presented at the 2019 ASCO Annual Meeting.1,2

In one analysis, treatment with larotrectinib at either 100 mg or 150 mg twice daily resulted in an overall response rate (ORR) of 94% in pediatric patients with TRK fusion cancers, and responses were durable. In addition, larotrectinib was well tolerated in the pediatric cancer population, said Cornelis M. van Tilburg, MD, PhD.

Larotrectinib is FDA approved for the treatment of patients with solid tumors harboring NTRK fusions, and exhibits high potency against TRKA, TRKB, and TRKC. TRK fusions are oncogenic drivers.

At the data cutoff of July 30, 2018, 12 (35%) experienced a complete response (CR) to larotrectinib, 18 (59%) had a partial response (PR), and 2 (6%) had stable disease. Median time to response was about 1.8 months. Thirty-three patients (87%) remained on treatment or underwent surgery with curative intent.

At a median follow-up of 8.9 months, the median duration of response was not reached. Eighty-four percent of the responders had an estimated duration of response ≥1 year.

At a median follow-up for progression-free survival (PFS) of 10.7 months, the median PFS was not reached. Moreover, the median duration of follow-up of 12.3 months for overall survival (OS), the median OS was not reached.

The study findings expand on those from an earlier dataset of 17 pediatric patients, which showed encouraging antitumor activity with larotrectinib, a first-in-class and selective TRK inhibitor. Based on the recent findings, routing testing for NTRK fusions in pediatric patients is warranted, said van Tilburg, pediatric oncologist, Heidelberg University Hospital and German Cancer Research Center.

“In the event of a fusion, the kinase domain of NTRK is activated, and will activate downstream signaling pathways, like AKT and ERK,” he said.

The data presented at the 2019 ASCO Annual Meeting were from a subset of 38 children and adolescents (<18 years old) with non-CNS TRK fusion cancer who were enrolled in 2 larotrectinib clinical trials (NCT02637687 and NCT02576431).

Larotrectinib was administered until complete surgical resection, disease progression, withdrawal, or unacceptable toxicity. Three patients received the adult equivalence dose of 100 mg twice daily, 6 received 150 mg twice daily, and 29 received 100 mg/m2 twice daily (with a maximum dose of 100 mg twice daily).

The 38 patients came primarily from the phase I/II SCOUT study (n = 35), with 3 obtained from the phase II NAVIGATE study.

Twenty females and 18 males were included. The median age of patients overall was 2.3 years, with a range of 0.1 to 14.0 years. Fourteen (37%) were <1 year. Tumor types were infantile fibrosarcoma in 47%, other soft tissue sarcoma in 42%, thyroid in 5%, melanoma in 3%, and congenital mesoblastic nephroma in 3%.

TRK fusions involved NTRK1 (47%), NTRK2 (5%), and NTRK3 (47%). Prior treatments included surgery in 61%, radiotherapy in 11%, and systemic therapy in 68%. Sixteen percent received ≥3 lines of prior systemic therapy. At enrollment, 50% of the patients had locally advanced fusion cancer and 50% had metastatic disease.

The most common grade 3/4 treatment-emergent adverse events were neutropenia (n = 15), increase in weight (n = 9) pyrexia (n = 4), anemia (n = 4), and pain in extremity (n = 4).

Efficacy in CNS tumors

In a separate clinical trial presented here, larotrectinib also proved to be highly active against TRK fusion-positive cancers that involved the CNS. In 24 patients with intracranial disease—18 with primary CNS tumors and 6 with nonprimary CNS tumors and brain metastases—from 3 clinical trials (a phase I study [n = 1], the SCOUT study [pediatric phase I/II [n = 12], and the NAVIGATE phase II basket trial [n = 11]), treatment with larotrectinib at 100 mg or 100 mg/m2 induced responses in 3 of 5 (60%) evaluable patients with TRK fusion–positive solid tumor with brain metastases and 5 of 14 (36%) evaluable patients with TRK fusion–positive primary CNS tumors.

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