Larotrectinib Achieves Over 90% Response in Pediatric Solid Tumors

Brian Turpin, DO

The novel pan-TRK inhibitor larotrectinib (LOXO-101) achieved a 93% response rate in pediatric patients with TRK fusion—positive solid tumors, according to findings from the phase I SCOUT trial presented at the AACR Special Conference on Pediatric Cancer.

The 93% (95% CI, 68-100) overall response rate (ORR) was determined by an independent review committee and included a complete response (CR) rate of 13% and a partial response (PR) rate of 80%. An additional 7% of patients had stable disease and no patients had progressive disease.

“Targeted therapy success stories in pediatric oncology are uncommon, and larotrectinib has invigorated the pediatric oncology community,” Brian Turpin, DO, the presenting SCOUT principal investigator and assistant professor in the division of oncology at Cincinnati Children’s Hospital, said in a statement.

“Larotrectinib’s near universal response rate and compelling durability of response in pediatric patients with TRK fusion cancers is likely to be practice changing. Furthermore, the first-ever TRK inhibitor response in a TRK fusion glioblastoma patient highlights the potential for larotrectinib in TRK fusion central nervous system tumors,” added Turpin.

The results from the SCOUT trial presented at the AACR meeting included 24 pediatric patients with solid tumors, 17 of whom had TRK fusion—positive cancers. Cancers in the TRK fusion–positive cohort included infantile fibrosarcoma (n = 8), soft tissue sarcoma (n = 7), and papillary thyroid cancer (n =2). In the non–TRK fusion group, 5 patients had CNS disease, 1 patient had osteosarcoma, and 1 patient had neuroblastoma.

Across the study population, 5 patients were aged <1 year, 2 patients were aged 1-2 years, 10 patients were aged 2-12 years, and 7 patients were aged >12 years. The median age was 4.5 years (range, 0.1-18.3). The population was evenly split between males and females.

Forty-six percent of patients had locally advanced disease, 33% had metastatic disease, and 21% had CNS involvement. Patients were evenly divided among 0 prior therapies (n = 7), 1 to 2 prior therapies (n = 9), and 3 or more prior therapies (n = 8).

Four patients received the starting dose of 100 mg twice daily (adult equivalent dose [AED]), 11 patients received 150 mg twice daily (AED), and 9 patients received 100 mg/m² twice daily (capped at 100 mg). There was no maximum-tolerated dose defined, with the recommended phase II dose being 100 mg/m² twice daily (max 100 mg).

At the July 17, 2017, data cutoff date, 94% of the TRK-positive population continued to receive larotrectinib or had received surgery with curative intent. Twelve patients had been followed for at least 6 months, and 4 patients had been followed for more than 12 months.

Per investigator assessment, the ORR in TRK-positive patients was also 93% (95% CI, 68-100), including a CR rate of 27%. Seven percent of patients had stable disease and no patients had progressive disease.

There were no responses per investigator assessment among the 7 patients with tumors not harboring TRK fusions.

Larotrectinib was considered to be well tolerated with a safety profile consistent with previously presented results. The majority of adverse events (AEs) were grade 1 among the 9 patients receiving the recommended phase II dose: 3 patients with increased AST; 2 patients each with nausea, increased ALT, leukopenia, anemia, and constipation; and 1 patient each with neutropenia, vomiting, hypoalbuminemia, blood creatinine increased, and fatigue.

Also among patients receiving the recommended phase II dose, 1 patient each had grade 2 increased AST, neutropenia, vomiting, increased blood alkaline phosphatase, and hyperkalemia. There were 3 cases of grade 3 AEs in this population: neutropenia, nausea, and increased ALT. No grade 4 AEs were reported.

TRK fusions occur when 1 of the NTRK genes (NTRK1, NTRK2, NTRK3) becomes abnormally connected to an unrelated gene, such as TV6, LMNA, or TPM3. The fusion leads to uncontrolled TRK signaling, which can result in cancer.

In November 2017, Bayer and Loxo Oncology entered into a partnership to develop and market larotrectinib (LOXO-101) and LOXO-195 in the United States and worldwide. LOXO-195 is an investigational next-generation, selective TRK inhibitor capable of addressing potential mechanisms of acquired resistance that may emerge in patients receiving larotrectinib or multikinase inhibitors with anti-TRK activity.

“We are grateful to the children and families who have enabled the development of larotrectinib through their participation in clinical trials,” Josh Bilenker, MD, chief executive officer of Loxo Oncology, said in a press release.

The phase II portion of the SCOUT trial is now enrolling globally.

Turpin B, Albert CM, Mascarenhas L, et al. A pediatric phase 1 study of larotrectinib, a highly selective inhibitor of the tropomyosin receptor kinase (TRK) family: an updated analysis. Presented at: American Association for Cancer Research (AACR) Special Conference on Pediatric Cancer Research; December 3-6, 2017; Atlanta, Georgia.