Larotrectinib FDA Submission Completed for TRK Fusion Cancer

A rolling new drug application has been completed for larotrectinib (LOXO-101) for the treatment of adult and pediatric patients with locally advanced or metastatic solid tumors harboring an NTRK gene fusion.

Scott Fields, MD

A rolling new drug application (NDA) has been completed for larotrectinib (LOXO-101) for the treatment of adult and pediatric patients with locally advanced or metastatic solid tumors harboring an NTRK gene fusion.

Loxo, which is codeveloping the pan-TRK inhibitor with Bayer, reported in December 2017 that the NDA had been initiated. The rolling submission followed a breakthrough therapy designation granted by the FDA in July 2016. Bayer plans to file a marketing authorization application in the European Union later this year.

“This NDA submission in the US marks an important milestone in bringing us one step closer to providing larotrectinib as a potential treatment option for patients with TRK fusion cancer,” Scott Fields, MD, Bayer's senior vice president and head of Oncology Development at Bayer's Pharmaceutical Division, said in a statement. “NTRK gene fusions, while rare, are present in various pediatric and adult cancers. We are committed to working with the FDA and the oncology community to bring larotrectinib to patients as soon as possible.”

In results published in the New England Journal of Medicine (NEJM) in February 2018, larotrectinib induced an objective response rate 75% (95% CI, 61-85) by independent review and 80% (95% CI, 67-90) by investigator assessment in 55 evaluable patients. Per the independent assessment, there were 7 (13%) complete responses, 34 (62%) partial responses, and 5 (9%) patients with stable disease.1

At 1 year, 71% of responses were ongoing. More than half (55%) of patients remained progression-free at 1 year. The median duration of response had not been reached after a median follow-up of 8.3 months. The same was true for median progression-free survival after a median follow-up of 9.9 months.

The NEJM data included an additional 3 months of patient follow-up to data presented at the 2017 ASCO Annual Meeting.2 The data presented at ASCO came from the first 55 consecutively enrolled adult and pediatric patients with TRK fusion cancers from across a phase I adult trial, the phase II NAVIGATE trial, and the phase I/II SCOUT pediatric trial. The data cutoff for the NEJM findings was July 17, 2017.

TRK fusion—positive adult and pediatric patients with advanced solid tumors representing 17 unique cancer types were enrolled across the 3 phase I/II clinical trials. The breakdown by tumor type included salivary gland tumor (n = 12), other soft-tissue sarcoma (n = 11), infantile fibrosarcoma (n = 7), thyroid tumor (n = 5), colon cancer (n = 4), lung cancer (n = 4), melanoma (n = 4), GIST (n = 3), cholangiocarcinoma (n = 2), appendix tumor (n = 1), breast cancer (n = 1), and pancreatic cancer (n = 1).

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 (35%) had received ≥3 prior systemic chemotherapies. Twenty-four patients had an ECOG performance status of 0, 27 had a status of 1, and 4 had a status of 2. Patients were assigned to 100 mg of larotrectinib twice daily.

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.

Most patients (93%) experienced grade 1 or 2 adverse events (AEs). There were no grade 4 AEs related to treatment and the most common treatment-related grade 3 AEs were increased ALT or AST (5%), anemia (2%), decreased neutrophil count (2%), nausea (2%), and dizziness (2%).

The most common grade 3 AEs (≥5%) regardless of attribution were anemia (11%), increased ALT or AST (7%), decreased neutrophil count (7%), and increased body weight (7%).

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 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).


  1. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion—positive cancers in adults and children. N Engl J Med. 2018; 378:731-739. doi: 10.1056/NEJMoa1714448.
  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).