Larotrectinib Approved in Europe for NTRK+ Tumors

The European Commission has approved larotrectinib for the treatment of certain adult and pediatric patients with solid tumors who have an NTRK gene fusion without a known acquired resistance mutation.

Jesus Garcia-Foncillas, MD, PhD

The European Commission has approved larotrectinib (Vitrakvi) for the treatment of adult and pediatric patients with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment.1

The approval is based on data from patients enrolled across a phase I trial (LOXO-TRK-14001) in adult patients, the phase II NAVIGATE trial in adult and adolescent patients, and the phase I/II SCOUT pediatric trial. The data group included 102 patients, 93 from the pooled primary analysis population and 9 additional patients with primary CNS tumors.

The overall response rate (ORR) with the TRK inhibitor larotrectinib was 72% (95% CI, 62-81) in the primary pooled analysis population, comprising a 16% complete response (CR) rate and 55% partial response (PR) rate. When including the primary CNS patients in the analysis, the ORR was 67% (95% CI, 57-76), comprising a 15% CR and 51% PR.

The median duration of response for the pooled primary analysis was not yet reached. Available data showed responses ranging from 1.6+ to 38.7+ months. Seventy-five percent of patients had a ≥12-month duration of response.

“With this first-ever tumor-agnostic approval in the EU, physicians in Europe now have the option to replace less tailored treatment approaches with a precision oncology treatment exclusively designed to treat tumors that have an NTRK gene fusion—a rare cancer which affects both children and adults and occurs in varying frequencies across various tumor types,” Jesus Garcia-Foncillas, MD, PhD, director of the University Cancer Institute and the Department of Oncology at the University Hospital “Fundacion Jimenez Diaz” and professor of oncology at the Autonomous University of Madrid, said in a press release.

“Existing therapies commonly used to treat TRK fusion cancer patients such as chemotherapy or immuno-oncology therapies have shown limited efficacy, and may have significant side effects. With Vitrakvi, we have seen rapid, robust and durable responses with a consistent and manageable safety profile in patients with TRK fusion cancer, regardless of the age of the patient or where in the body the tumor is located,” added Garcia-Foncillas.

Larotrectinib was approved in the United States in November 2018 for this indication, based on pooled results2 from the first 55 evaluable patients in the same 3 clinical trials in the EU application. Larotrectinib induced an ORR of 75% (95% CI, 61-85) by independent review and 80% (95% CI, 67-90) by investigator assessment. Per the independent assessment, there were 7 (13%) complete responses, 34 (62%) partial responses, and 7 (13%) patients with stable disease (SD).

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.

In the 3 pivotal studies, adult patients received oral larotrectinib at 100 mg orally twice daily and pediatric patients (aged ≤18 years) were treated with larotrectinib at 100 mg/m2 up to a maximum of 100 mg orally twice daily. Treatment was received until disease progression or unacceptable toxicity.

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 patient age 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.

The ORR by tumor type was salivary gland tumor (83%), other soft-tissue sarcoma (91%), infantile fibrosarcoma (100%), thyroid tumor (100%), colon cancer (25%), lung cancer (75%), melanoma (50%), GIST (100%), cholangiocarcinoma (best response, SD), appendix tumor (best response, SD), breast cancer (progressive disease), and pancreatic cancer (best response, SD).

The most common all-grade treatment-related adverse events (TRAEs) were increased ALT/AST level (38%), dizziness (25%), fatigue (16%), nausea (16%), constipation (16%), vomiting (11%), increased body weight (11%), anemia (9%), decreased neutrophil count (9%), and diarrhea (5%).

Grade 3 TRAEs included increased ALT/AST level (5%), anemia (2%), decreased neutrophil count (2%), nausea (2%), and dizziness (2%). There were no grade 4/5 TRAEs. Dose reductions were required in 8 of the 55 patients.

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. Vitrakvi (larotrectinib) receives first tumor-agnostic approval in EU. Bayer. Published online September 23, 2019. Accessed September 23, 2019.
  2. 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.