Abstract PR07: A pediatric phase 1 study of larotrectinib, a highly selective inhibitor of the tropomyosin receptor kinase (TRK) family: An updated analysis
Authors: Turpin Brian , Albert Catherine M. , Mascarenhas Leo , Federman Noah , Nagasubramanian Ramamoorthy , Reynolds Mark , Smith Steven , Cruickshank Scott , Cox Michael C. , Pappo Alberto S. , Hawkins Douglas S. , DuBois Steven G. , Laetsch Theodore W. 
Published: February 2019

Abstract
Background: NTRK gene fusions occur in a broad range of pediatric and adult malignancies at low frequencies, but are present in the vast majority of infantile fibrosarcomas. Larotrectinib is the first selective small-molecule inhibitor of TRKA, B, and C in clinical development. Larotrectinib has demonstrated a high response rate and a favorable safety profile in children and adults with TRK-fusion positive cancers. Here we report an updated analysis from the pediatric phase 1 study of larotrectinib.
Methods: This multicenter, rolling 6 phase 1 study enrolled pediatric patients with refractory solid or CNS tumors. Patients with locally advanced infantile fibrosarcoma who would require disfiguring surgery or limb amputation to achieve a complete surgical resection were also eligible. Measurable or evaluable disease by RECIST v1.1/RANO was required. Patients were dosed orally BID on a continuous 28-day schedule either by capsule or oral solution. Pharmacokinetic (PK)-directed intra-subject dose escalation was permitted, with exposures targeting the adult recommended phase 2 dose (RP2D) of 100 mg BID. The primary objective was to define the maximum tolerated dose (MTD) / RP2D; secondary objectives included pharmacokinetics (PK) and efficacy using RECIST v1.1/RANO.
Results: As of July 17, 2017, 24 patients (17 with TRK fusions, 7 without TRK fusions) with a median age of 4.5 years (range 1 month-18 years) were enrolled. Patients had diverse TRK fusions (9 NTRK1, 1 NTRK2, and 7 NTRK3) in heterogeneous tumor diagnoses (8 infantile fibrosarcoma (IFS), 7 other sarcoma, and 2 papillary thyroid cancer). Patients were treated on 3 dose levels: 100 mg BID (DL1, n=4) and 150 mg BID (DL2, n=11) adult equivalent doses by SimCyp modeling, and 100 mg/m2/dose BID with a cap of 100 mg/dose (DL3, n=9). The RP2D was determined to be 100 mg/m2 (capped at 100 mg) BID based on PK, safety and efficacy. No MTD was defined. The most common AEs attributed to larotrectinib were increased AST, vomiting, and neutropenia. No grade 4/5 AEs were attributed to larotrectinib. Both capsule and solution formulations delivered similar dose-dependent PK. AUC0-24 at the RP2D was comparable to the adult RP2D across the pediatric age spectrum (&lt;2, 2-11, and 12-18 years). No responses were seen in patients (n=7) without TRK fusions (all had PD as best response). Among patients with TRK fusions and measureable disease by RECIST (n=15), the investigator-assessed confirmed objective response rate was 93% (67% PR, 27% CR). 1 patient (7%) had SD with tumor shrinkage. All patients with TRK fusions (n=17) had a reduction in tumor burden regardless of histology or specific TRK fusion. With median follow-up of 6.5 (range 1.5+ to 12.5+) months, 14 patients with TRK fusions remain on treatment. Three patients have discontinued therapy, including two patients with responses that led to surgical resection; both had negative margins (R0 surgery) and one had a pathologic complete response. These patients remain on study and off larotrectinib without recurrence. Only one case of acquired resistance has been observed, which involved a TRKC G623R mutation.
Conclusions: Larotrectinib demonstrated broad histology-independent efficacy in pediatric patients harboring TRK fusions and a favorable tolerability profile. A pediatric RP2D of 100 mg/m2/dose BID with a cap of 100 mg/dose has been defined. Blinded central review of responses and a minimum of 6 months of follow-up for all patients will be presented.
Citation Format: Brian Turpin, Catherine M. Albert, Leo Mascarenhas, Noah Federman, Ramamoorthy Nagasubramanian, Mark Reynolds, Steven Smith, Scott Cruickshank, Michael C. Cox, Alberto S. Pappo, Douglas S. Hawkins, Steven G. DuBois, Theodore W. Laetsch. A pediatric phase 1 study of larotrectinib, a highly selective inhibitor of the tropomyosin receptor kinase (TRK) family: An updated analysis [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr PR07.