Trifluridine–tipiracil for treating metastatic gastric cancer or gastro-oesophageal junction adenocarcinoma after 2 or more treatments

3.1 The initial symptoms of gastric cancer are vague and similar to other stomach conditions, but for advanced disease they may include lack of appetite, weight loss, fluid in the abdomen and blood in the stool. The clinical experts estimated that life expectancy after 2 previous treatments is between 2 and 4 months in current practice. They explained that there is no standard treatment for previously treated metastatic gastric cancer but in clinical practice in the NHS in England, treatment is usually in line with the European Society for Medical Oncology (ESMO) guideline for gastric cancer. The clinical experts advised that paclitaxel is generally used after 1 treatment, and irinotecan may be used after 2 treatments but for most people it is not appropriate because of the risk of side effects. They estimated that third-line chemotherapy is used in about 10% of people, with most people having best supportive care alone. The committee was aware that the ESMO guideline had recently been updated to recommend trifluridine–tipiracil as a third-line treatment option for people with an Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1. The committee noted that there was no patient expert submission for this appraisal, but the clinical experts explained that maintaining health-related quality of life is very important to people with metastatic gastric cancer. They advised that an oral treatment such as trifluridine–tipiracil would be preferred because it does not need many hospital visits, allowing people to spend more time at home. The committee concluded that there is an unmet need for third-line treatment options for gastric cancer.

3.2 The company submitted cost-effectiveness analyses comparing trifluridine–tipiracil and best supportive care with placebo and best supportive care. It advised that there is a lack of evidence to support the use of third-line chemotherapy and that its expert advice suggested this is usually restricted to clinical trials. The committee recalled that third-line chemotherapy is appropriate but is used in only a small proportion of people in current practice, with most people having best supportive care alone (see section 3.1). The clinical experts explained that although there is no clear definition of best supportive care, it usually includes treatments to control symptoms such as pain. The committee concluded that the most appropriate comparator is best supportive care.

3.3 The clinical evidence for trifluridine–tipiracil came from TAGS, a phase 3 randomised controlled trial. It compared trifluridine–tipiracil and best supportive care with placebo and best supportive care in 507 adults with metastatic gastric cancer (including 29% with gastro-oesophageal junction cancer) who had had at least 2 treatments for advanced disease, and who had an ECOG performance score of 0 or 1. The committee was aware of several issues that may impact the generalisability of the full intention-to-treat analysis from TAGS to the NHS in England:

3.4 The EAG advised that the committee's preferred third-line, European subgroup (see section 3.3) had imbalances in patient characteristics between the 2 arms of the TAGS trial. Some of these could favour survival after treatment with trifluridine–tipiracil and some could favour survival after treatment with placebo (the exact numbers are confidential and cannot be reported here). The company accepted that any subgroup analysis may be at risk of imbalances in characteristics, but it felt there were no imbalances in verified prognostic factors in this analysis. After the second meeting, the committee requested additional analyses to adjust the third-line data for imbalances in:

3.5 The company included a partitioned survival cost-effectiveness model in its evidence submission. The model comprised 3 health states representing progression-free disease, progressed disease and death. Health-state occupancy over time was informed by survival functions from TAGS data. The EAG advised that the model was generally clear and appropriate. The committee concluded that the company's model was suitable for decision making.

3.6 In TAGS, the most common side effects included nausea, anaemia, decreased appetite, vomiting, diarrhoea, fatigue, neutropenia, asthenia and thrombocytopenia. Anaemia was considerably more common in the trifluridine–tipiracil group than the placebo group (45% compared with 19%). Neutropenia was also more common (53% compared with 4%). The company included adverse events such as neutropenia in the model to capture their effect on health-related quality of life. The committee noted that in the summary of product characteristics for trifluridine–tipiracil, neutropenia was one of the most common side effects that led to treatment being stopped, delayed or interrupted. It concluded that neutropenia may affect health-related quality of life.

3.7 The company extrapolated overall survival in both treatment arms using an accelerated failure time model, which included a dependent variable to capture the effect of treatment. This approach assumes that the relative treatment effect is constant over time. In its base-case analysis the company used a log-normal function that was applied for the entire duration of the model. The EAG explained that the Kaplan−Meier estimates from the intention-to-treat population, new analyses at consultation and analyses in the committee's preferred population (the third-line, European subgroup) all showed that trifluridine–tipiracil survival either crossed or almost converged with best supportive care survival. This indicates that the treatment effect was not constant over time. The committee heard that because of this, the EAG preferred separate functions that were fitted independently to each treatment arm. This had little difference in statistical fit compared with the dependent models. The company maintained its preference for the dependent model in its base-case analysis but acc