Larotrectinib Demonstrates 93% Response Rate in Pediatric Patients With Solid Tumors


According to findings from the phase I SCOUT trial, the novel pan-TRK inhibitor larotrectinib (LOXO-101)&nbsp;achieved a 93% response rate in pediatric patients with <em>TRK</em>&nbsp;fusion&ndash;positive solid tumors.

Brian Turpin, DO

Brian Turpin, DO

According to findings from the phase I SCOUT trial, the novel pan-TRK inhibitor larotrectinib (LOXO-101) achieved a 93% response rate in pediatric patients withTRKfusion—positive solid tumors.

As determined by an independent review committee, the 93% (95% CI, 68-100) overall response rate (ORR) 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.

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

&ldquo;Larotrectinib&rsquo;s near universal response rate and compelling durability of response in pediatric patients withTRKfusion cancers is likely to be practice changing. Furthermore, the first-ever TRK inhibitor response in a TRKfusion glioblastoma patient highlights the potential for larotrectinib in TRK fusion central nervous system tumors,&rdquo; added Turpin.

The results from the SCOUT trial presented at the AACR meeting included 24 pediatric patients with solid tumors, 17 of whom hadTRKfusion—positive cancers. Cancers in the TRK fusion&ndash;positive cohort included infantile fibrosarcoma (n = 8), soft tissue sarcoma (n = 7), and papillary thyroid cancer (n =2). In the non&ndash;TRKfusion 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/m2twice daily (capped at 100 mg). There was no maximum-tolerated dose defined, with the recommended phase II dose being 100 mg/m2twice 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 inTRK-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 theNTRKgenes (NTRK1, NTRK2,&nbsp;NTRK3) becomes abnormally connected to an unrelated gene, such asTV6, LMNA,&nbsp;orTPM3. 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.

&ldquo;We are grateful to the children and families who have enabled the development of larotrectinib through their participation in clinical trials,&rdquo; 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.

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