NICE Cites Uncertainty in Deciding Against Larotrectinib in NTRK Fusion+ Solid Tumors

The National Institute for Health and Care Excellence does not recommend larotrectinib for the treatment of advanced NTRK fusion–positive solid tumors in adults and children without satisfactory treatment options.

The National Institute for Health and Care Excellence (NICE) has announced that it does not recommend larotrectinib (Vitrakvi) for the treatment of advanced NTRK fusion—positive solid tumors in adults and children without satisfactory treatment options.1

The agency noted that these guidelines are not intended to affect treatment with the agent that started before the guidelines were issued, according to the appraisal consultation document.

Although clinical evidence has indicated that treatment with larotrectinib can shrink NTRK fusion­­—positive tumors, NICE stated in its appraisal consultation document that just how effective the agent is remains unclear, as the agent has yet to be compared with other treatments in a clinical trial. Furthermore, the agency cited that the question of whether larotrectinib shows activity in every type of NTRK fusion—positive tumor is still unanswered, to date.

Larotrectinib costs £5,000 ($6506.02) per 100-mL vial of 20 mg/mL oral solution, according to the appraisal consultation document. The recommended dose of the agent in adults is 100 mg twice daily, until either disease progression or unacceptable toxicity. In children, dosing is informed based on body surface area.

“The cost-effectiveness estimates for larotrectinib are very uncertain because of limitations in the data, such as the substantial uncertainty about how long people would live after their disease gets worse,” the agency noted in the document. Further data could potentially address some of these gaps in the available clinical evidence for the agent, NICE added.

“However, larotrectinib does not have the potential to be a cost-effective use of NHS resources at its current price so it is not recommended for routine commissioning, or through the Cancer Drugs Fund,” the agency stated.

No current standard treatment exists for patients with solid tumors who harbor NTRK gene fusions. As such, treatment decisions are often informed by where the cancer originates within the body. Because larotrectinib is a histology-independent agent, it can target these fusions regardless of where the cancer starts.

In November 2018, larotrectinib was granted an accelerated approval from the FDA for use in adult and pediatric patients with solid tumors that have a NTRK 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.

The approval was based on data from 3 multicenter, open-label, single-arm clinical trials: LOXO-TRK-14001 (NCT02122913), SCOUT (NCT02637687), and NAVIGATE (NCT02576431).

In 55 evaluable patients, larotrectinib was found to induce an overall response rate (ORR) of 75% (95% CI, 61%-85%) per independent review and 80% (95% CI, 67%-90%) via investigator assessment, according to data published in the New England Journal of Medicine in February 2018.2 Furthermore, 13% (n =7) of patients experienced a complete response (CR) with the agent, 62% (n = 34) had a partial response, and 13% (n = 7) had stable disease.

At a median follow-up of 8.3 months, the median duration not response (DOR) had not been reached. At a median follow-up of 9.9 months, median progression-free survival (PFS) had also not been reached. At 1 year, investigators reported that the majority of responses (71%) were ongoing, and more than half of patients (55%) remained free of disease progression.

In updated data from the integrated analysis of the 3 trials presented at the 2019 ESMO Congress, larotrectinib induced an ORR of 79% of 153 evaluable patients across several tumor types (95% CI, 72%-85%).3 CRs were observed in 16% (n = 24) of patients and partial responses noted in 63% (n = 97) of patients. With an additional 12% of patients achieving stable disease at best response, the clinical benefit rate with the agent was 91%.

Furthermore, in the primary cohort of 55 patients, the median DOR with larotrectinib in 44 patients with CRs or PRS at a median follow-up of 26 months was 35.2 months (95% CI, 21.2-not evaluable [NE]). Median PFS in the primary cohort was 25.8 months (95% CI, 9.9-NE); 27 patients experienced disease progression.


  1. Appraisal consultation document: Larotrectinib for treating NTRK fusion-positive solid tumors. National Institute for Health and Care Excellence. Posted January 17, 2020. Accessed January 17, 2020.
  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(8):731-739. doi: 10.1056/NEJMoa1714448.
  3. Hyman DM, van Tilburg CM, Albert CM, et al. Durability of response with larotrectinib in adult and pediatric patients with TRK fusion cancer. Ann Oncol. 2019;30(suppl 5; abstr 445PD). doi: 10.1093/annonc/mdz244.007.