Larotrectinib Rolling NDA Submission Initiated for TRK+ Cancers

Loxo Oncology has initiated a rolling submission of data for a NDA to the FDA for the novel pan-TRK inhibitor larotrectinib (LOXO-101) as a treatment for adult and pediatric patients with TRK fusion-positive advanced solid tumors.

Josh Bilenker, MD

Loxo Oncology has initiated a rolling submission of data for a new drug application (NDA) to the FDA for the novel pan-TRK inhibitor larotrectinib (LOXO-101) as a treatment for adult and pediatric patients with TRK fusion-positive advanced solid tumors.

The rolling submission of data was permitted under a breakthrough therapy designation received by larotrectinib in July 2016. If approved, larotrectinib would be indicated for the treatment of unresectable or metastatic solid tumors with NTRK-fusion proteins in adult and pediatric patients who require systemic therapy and who have either progressed following prior treatment or who have no acceptable alternative treatments. The company hopes to complete the NDA submission in early 2018.

"The initiation of the NDA submission for larotrectinib is an important milestone for Loxo Oncology and a step towards the goal of treating cancer based on the genetic signature of a tumor rather than its location in the body," Josh Bilenker, MD, chief executive officer of Loxo Oncology, said in a statement. "We are proud of the strong data underlying our application in both adult and pediatric patients and will continue to work expeditiously to complete the submission and bring this potential new medicine to patients with TRK fusion cancers."

TRK gene fusions are genetic alterations that appear across a wide range of tumors—including breast and colorectal cancer, infantile fibrosarcoma, lung cancer, melanoma, and various sarcomas—and lead to uncontrolled TRK signaling and tumor growth. Such fusions are rare, but they are expressed in dozens of adult and pediatric of tumor types. To date, researchers have identified more than 50 different partner genes that fuse with 1 of 3 TRK genes (NTRK 1, 2, and 3).

“Research has generated great interest in TRK as a potential target for cancer treatment because while TRK fusions occur rarely, they present broadly in various rare adult and pediatric tumors,” said Carsten Brunn, president of Bayer Pharmaceuticals for the Americas Region, which is jointly developing larotrectinib with Loxo Oncology.

Larotrectinib has shown strong results in clinical trials so far. The agent was associated with a 93% (95% CI, 68%-100%) overall response rate (ORR) in pediatric patients in the phase I SCOUT trial1 and a 76% response rate in adult and pediatric patients with a range of TRK fusion—positive solid tumors in data presented at the 2017 ASCO Annual Meeting.2

The SCOUT trial included 24 pediatric patients, median age was 4.5 years (range, 0.1-18.3), with solid tumors, 17 with TRK fusion—positive cancers. Forty-six percent of patients had locally advanced disease, 33% had metastatic disease, and 21% had CNS involvement. Cancers in the TRK fusion–positive cohort included infantile fibrosarcoma, soft tissue sarcoma, and papillary thyroid cancer.

First presented at the 2017 AACR Special Conference on Pediatric Cancer,1 the 93% ORR was determined by an independent review committee in 17 patients with TRK fusion cancers. The 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. At the July 17, 2017, data cutoff, 94% of the TRK-positive population continued to receive larotrectinib or had received surgery with curative intent. None of 7 patients without the TRK fusion responded to larotrectinib.

Larotrectinib was well tolerated with a safety profile consistent with previously presented results for pediatric patients. Most adverse events (AEs) were grade 1 among the 9 patients receiving the recommended phase II dose of 100 mg/m2 twice daily: 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.

The phase II portion of the SCOUT trial is now enrolling globally (NCT02637687).

In the results reported at ASCO,2 55 TRK fusion—positive adult and pediatric patients with advanced solid tumors representing 17 unique cancer types were enrolled across 3 phase I/II clinical trials. Patients were assigned to 100 mg larotrectinib twice daily. The median age of patients was 45 years (range, 0.3-76.0), with 56% of patients ≥40 years of age. A third of patients (31%) had received ≥3 prior systemic chemotherapies.

ORR was 76% (95% CI, 62%-87%) based on investigator assessment for 50 patients for whom confirmatory response data were available. Included in that result was a PR in 64% of patients and a complete response in 12%. Five additional patients, who had not undergone confirmatory scans, all had at least a PR. Among those with a PR, 2 patients were downstaged and taken forward to potentially curative surgery with pathologic CR.

Investigators did not notice a trend toward better results in one tumor type versus another with larotrectinib. Additionally, outcomes appeared similar regardless of the age of patients or the type of NTRK alteration (1,2, or 3) or fusion partner.

At a median follow-up of 7.7 months, the median progression-free survival had not yet been reached. At 12 months, 63% of patients treated with larotrectinib remained alive and progression free.

Most AEs with larotrectinib were grade 1 or 2. There were no grade 4 AEs and the most common treatment-related grade 3 events were increased ALT (4%), anemia (3%), and nausea (2%). The most common treatment-emergent grade 3 AEs were anemia (9%), fatigue (5%), increased ALT (4%), and increased AST (3%).

Once the rolling submission is complete, the FDA will assign a review timeline within 60 days. After this point, under a priority review, the FDA would render a decision within 6 months. A standard review would require 10 months.


  1. 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.
  2. Hyman DM, Laetsch TW, Kummar S, et al. The efficacy of larotrectinib (LOXO-101), a selective tropomyosin receptor kinase (TRK) inhibitor, in adult and pediatric TRK fusion cancers. J Clin Oncol. 2017;35 (suppl; abstr LBA2501).