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New HTA Decisions in England
August 2020
Drug name
ROZLYTREK® (entrectinib)
Decision date
Therapeutic area
Therapeutic sub area
Recommended with restrictions (CDF)
Entrectinib is recommended for use within the Cancer Drugs Fund as an option for treating neurotrophic tyrosine receptor kinase (NTRK) fusion-positive solid tumours in adults and children 12 years and older.
Decision Detail
Only if: the disease is locally advanced or metastatic or surgery could cause severe health problems and; they have not had an NTRK inhibitor before and; they have no satisfactory treatment options. It is recommended only if the conditions in the managed access agreement for entrectinib are followed. There is a managed access agreement (simple discount patient access scheme) and a commercial access agreement for entrectinib.
The key clinical evidence comes from a pooled analysis of results for 54 adults from 3 clinical trials (ALKA, STARTRK 1 and STARTRK 2) in its original submission. STARTRK 2 is an ongoing phase 2 basket trial for people aged 18 years and over with advanced or metastatic solid tumours that have an NTRK, ROS1 or ALK gene fusion. Both ALKA and STARTRK 1 are ongoing phase 1 ascending dose and dose escalation studies. The children's data were collected in the STARTRK NG trial, a dose escalation and expansion study evaluating the effect of entrectinib in children, adolescent and young adults aged 2 to 22 years. The committee noted the small patient numbers from each of the trials making up the pooled analysis, and that the trials were single arm and did not include a control group. The pooled analysis of 66 people across 13 tumour types showed a clinically relevant overall response rate across tumour types (exact results are confidential and cannot be reported here). However, there was considerable uncertainty about the extent to which the response translated into clinically meaningful survival benefits. At the most recent data-cut, median follow up was short and the survival data were immature. Also, the number of patients with specific cancers was very small so there was uncertainty in the robustness of all survival data. The committee saw that there was no direct evidence of entrectinib's effectiveness compared with established management. It concluded that entrectinib could be clinically effective, but the limited data for each of the tumour types, the immature survival data and the lack of trial data directly comparing entrectinib with established management meant the size of this benefit was difficult to measure. The committee concluded that there was uncertainty about entrectinib's clinical effectiveness for tumour types that were not included in the clinical trials. Until further data are reported, the clinical benefit of using entrectinib in the NHS cannot be confirmed. The company's revised base case after the technical engagement stage gave a deterministic ICER of £49,358 per quality-adjusted life year (QALY) gained for entrectinib compared with established management. This included entrectinib's confidential simple discount but list prices for all other treatments. Based on the available evidence, the committee concluded that entrectinib (with the discount agreed in the commercial arrangement) had plausible potential for cost effectiveness if it met the end-of-life criteria. However, it also concluded that the ICER range on which it was basing its decision was associated with substantial uncertainty, particularly in the survival estimates and in modelling a population that was not generalisable to NHS clinical practice. The committee agreed this uncertainty needed to be accounted for in making its judgement about entrectinib's acceptability as an effective use of NHS resources. It acknowledged the ongoing NHS developments and that the company had asked that entrectinib was considered only for use within the Cancer Drugs Fund. The committee concluded that entrectinib could not be recommended for routine use in the NHS. Collecting more data on entrectinib would help to address some of the uncertainty in the evidence. Entrectinib has the potential to be cost effective given the company's commercial offer as part of a managed access agreement and using the diagnostic testing costs provided by NHS England. Therefore, entrectinib is recommended for use in the Cancer Drugs Fund.