New Drug Application Completed for Larotrectinib for Solid Tumors Harboring NTRK Gene Fusion

The new drug application for larotrectinib (LOXO-101) for treatment of patients with locally advanced or metastatic solid tumors that harbor an NTRK gene fusion has been completed. 

Scott Fields, MD

The new drug application (NDA) for larotrectinib (LOXO-101) for treatment of patients with locally advanced or metastatic solid tumors that harbor an NTRK gene fusion has been completed. The codelveloper of the pan-TRK inhibitor with Bayer, Loxo, released a report in December 2017 announcing the initiation of the NDA. 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. 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," Scott Fields, MD, Bayer's senior vice president and head of Oncology Development at Bayer's Pharmaceutical Division, said in a statement.

TheNew England Journal of Medicine (NEJM) published results in February 2018, demonstrating that larotrectinib induced an objective response rate of 75% (95% CI, 61-85) by independent review and 80% (95% CI, 67-90) by investigator assessment in 55 evaluable patients. The independent assessment found that 7 (13%) patients had complete responses, 34 (62%) had partial responses, and 5 (9%) had stable disease.1

Responses still ongoing after 1 year totaled 71%, and 55% of the patients were still progression-free at 1 year. Median duration of response was not reached at the median follow-up of 8.3 months. This was also true for median progression-free survival after a 9.9 month median follow-up.

An additional 3 months of patient follow-up was included byNEJMwith the data presented at the 2017 ASCO Annual Meeting.2This data, shared at ASCO, came from the first 55 consecutively enrolled adult and pediatric patients with TRK fusion cancers from across three trials: a phase I adult trial, the phase II NAVIGATE trial, and the phase I/II SCOUT pediatric trial. There was a data cutoff date of July 17, 2017, for these findings.

TRK fusion—positive adult and pediatric patients with advanced solid tumors represented 17 unique cancer types. These patients were enrolled across the 3 different phase I/II clinical trials. Tumor type was broken down by 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 patients' had a median age of 45 years (range, 0.3-76.0), with 56% of patients ≥40 years of age. A group of 35% of patients had received ≥3 prior systemic chemotherapies. Also, 24 patients demonstrated an ECOG performance status of 0, while 27 had a status of 1, and 4 had a status of 2. Patients in the trials were assigned to 100 mg of larotrectinib twice daily.

There was no significant difference in one tumor type versus another with larotrectinib. Outcomes also appeared to be similar regardless of the patient's age or type of NTRK alteration (1, 2, or 3) or fusion partner.

Overall, 93% of the patients experienced grade 1 or 2 adverse events (AEs). Grade 4 AEs did not occur within this treatment. The most common grade 3 AEs related to treatment were increased ALT or AST (5%), anemia (2%), decreased neutrophil count (2%), nausea (2%), and dizziness (2%). The most common grade 3 AEs (≥5%) discovered in this trial, regardless of attribution, included anemia (11%), increased ALT or AST (7%), decreased neutrophil count (7%), and increased body weight (7%).

TRK gene fusions are genetic alterations appearing across a range of tumors. These included breast and colorectal cancer, infantile fibrosarcoma, lung cancer, melanoma, and various sarcomas, leading to uncontrolled TRK signaling and tumor growth. These fusions are considered rare, but they have been expressed in many adult and pediatric tumor types. Researchers have identified more than 50 different partner genes, to date, 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.[Published online June 20, 2016.]Nat Med.doi:10.1038/nm.4118.
  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).