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

There is an unmet need for third-line treatment options for gastric cancer

3.1 The initial symptoms of gastric cancer are vague and similar to other stomach conditions, but for advanced disease 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 therapy 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 this population and an oral treatment such as trifluridine–tipiracil would help 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.

The most appropriate comparator is best supportive care

3.2 The company submitted cost-effectiveness analyses comparing trifluridine–tipiracil and best supportive care against placebo and best supportive care. It advised that there is 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 it is used in only a small proportion of people in current practice, with most people having best supportive care alone (see section 3.1). It noted that there were no cost-effectiveness analyses comparing trifluridine–tipiracil with third-line chemotherapy. 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.

The TAGS trial's subgroup of people in Europe who have not had ramucirumab is the most relevant population for decision making

3.3 The clinical evidence for trifluridine–tipiracil came from TAGS, a phase III randomised controlled trial. It compared trifluridine–tipiracil and best supportive care against 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. 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:

The company preferred to use data from a TAGS subgroup of people from Europe who had not had ramucirumab, because this is more generalisable to the treatment pathway and population in the NHS in England. The company highlighted that its preferred subgroup included fewer people from Japan and fewer people who had 3 or more previous treatments than the full intention-to-treat population (exact data is confidential and cannot be reported here). The committee recognised that the company's preferred subgroup may be more representative of the population in the NHS in England. However, it noted that this subgroup still included a higher proportion of people from Japan than would be expected in England, and that data from patients from Japan may be less generalisable to NHS practice. The committee understood that trifluridine–tipiracil improved overall survival compared with placebo and best supportive care in the full intention-to-treat population and all subgroup analyses (see table 1). The committee concluded that the TAGS subgroup of people from Europe who had not had ramucirumab was the most relevant to the NHS in England.

Table 1 Overall-survival results from TAGS

The company's economic model is suitable for decision making

3.4 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 curves from TAGS data. The ERG advised that the model was generally clear and appropriate. The committee concluded that the company's model was suitable for decision making.

The model should use overall-survival curves that are fitted independently to each trial arm

3.5 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. In its base-case analysis the company used a lognormal curve that was applied for the entire duration of the model. This approach assumes that the relative treatment effect is constant over time. The ERG explained that the Kaplan-Meier data from the intention-to-treat population and the committee's preferred population (the Europe subgroup who had not had ramucirumab) showed that the treatment curves crossed or almost converged. This indicates that the treatment effect was not constant over time. Because of this, the ERG preferred separate curves fitted independently to each treatment arm. It noted that 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 accepted that other approaches may also be valid. The committee concluded that the model should use survival curves fitted independently to each trial arm to extrapolate overall survival.

A full lognormal survival curve is the most plausible

3.6 The company used a lognormal curve to extrapolate overall survival for the entire duration of the model in its base-case analysis. The clinical experts predicted that 20% to 25% of people survive to 6 months in current practice, which reduces to 10% to 15% at 1 year. The committee noted exploratory analyses that modelled overall survival using the relatively mature Kaplan-Meier data for the first 12 or 18 months of the model, then applied a parametric curve to extrapolate beyond each timepoint. The ERG advised that using the Kaplan-Meier data was problematic because the timepoint when the observed data was replaced by the parametric curve was arbitrary. It was also necessary to use the available parametric curves, based on the full duration of trial data rather than the end portion alone, to extrapolate beyond each timepoint. The ERG explained that its preferred method for extrapolating the overall survival was a parametric model used for the entire time horizon. The committee concluded that a full lognormal curve was most plausible, and should be considered for decision making.

The company's utility values mapped from TAGS EORTC QLQ-30 data are acceptable for decision-making

3.7 The company's base-case utility values were 0.764 for the progression-free health state and 0.652 for progressed disease. These values came from TAGS data on EORTC QLQ-C30. This is a disease-specific measure, mapped onto the generic EQ-5D-3L scale using an algorithm from a small Greek study that included people with non-metastatic gastric cancer. The committee was aware that at the clarification stage, the company did not provide cost-effectiveness results using alternative mapping studies from Versteegh et al. (2012) or Longworth et al. (2014). The company clarified that this was because neither study was in gastric cancer and 1 study did not use the UK value set. The committee noted that the company's preferred utility values were higher than those used in NICE's technology appraisal guidance on ramucirumab for treating advanced gastric cancer or gastro–oesophageal junction adenocarcinoma previously treated with chemotherapy, particularly for progressed disease (0.652 compared with 0.587). The utility values in that appraisal were based on EQ-5D data from a trial (RAINBOW) and included people with metastatic disease after 1 previous treatment. The company did not consider those utility values appropriate because they did not account for correlation between utility scores for the same patient over time. The committee noted that the preferred utility values in the ramucirumab appraisal included data from multiple timepoints for the progression-free health state but not for progressed disease. The clinical experts advised that, in their opinion, the most appropriate data source would be the population from the TAGS trial who had at least 2 previous treatments and no previous ramucirumab and had good performance status. The committee concluded that the company's mapped utility values from TAGS were acceptable for decision making.

Trifluridine–tipiracil is not considered to be a life-extending treatment at the end of life

3.8 The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The committee recalled the poor prognosis for people with gastric cancer who have had previous treatments (see section 3.1). The committee noted that using its preferred assumptions (see section 3.10) the mean survival in the best supportive care arm of the model was 6.5 months. Therefore it concluded that the short life expectancy criterion was met. The committee understood that the mean survival gain in the company's base case was 2.7 months, equivalent to a 44% increase compared with best supportive care. However, it noted that in its preferred analysis (see section 3.10) the overall survival gain from the model was only 1.7 months. This is equivalent to a 26% increase compared with best supportive care. The committee referred to the NICE methods guide and considered whether the extension-to-life criterion could be met with an overall survival gain of less than 3 months, given the mature survival data and the poor prognosis for people with metastatic gastric cancer. It was aware of 1 previous technology appraisal that applied the extension-to-life criterion despite an overall survival gain of 2.4 months, because the disease has a poor prognosis and the survival data were robust (see NICE's technology appraisal guidance on paclitaxel as albumin-bound nanoparticles with gemcitabine for untreated metastatic pancreatic cancer). The clinical experts explained that an overall-survival benefit of 2 months is clinically meaningful, particularly if this could be achieved while maintaining good quality of life, because it would allow patients to benefit from a longer time free of worsening symptoms. The committee agreed that, in line with the NICE methods guide, the criterion requiring a 3-month survival gain should only be relaxed in exceptional circumstances, rather than routinely. The mean modelled survival gain for trifluridine–tipiracil using the committee's preferred analysis (1.7 months) was lower than the gain in the paclitaxel appraisal, and considerably lower than 3 months. Based on the evidence presented, the committee was not convinced that trifluridine–tipiracil provided an adequate survival benefit. It concluded that trifluridine–tipiracil did not meet the extension-to-life criterion, and therefore could not be considered a life-extending treatment at the end of life.

The most plausible incremental cost-effectiveness ratio (ICER) is substantially higher than £30,000 per quality-adjusted life year (QALY) gained

3.9 The company's base-case ICER for trifluridine–tipiracil compared with best supportive care was £45,164 per QALY gained, including the commercial discount for trifluridine–tipiracil. The committee noted that the company's cost-effectiveness estimates for its probabilistic sensitivity analysis showed a wide range of incremental QALYs (and ICERs). The company's cost-effectiveness acceptability curve suggested that the probability of trifluridine–tipiracil being cost effective at a threshold of £50,000 per QALY gained was 64%. However, this did not include all of the committee's preferred assumptions, which were:

The committee understood that after taking into account all of its preferred assumptions, the most plausible ICER was £68,061 per QALY gained. It understood that using data for the full intention-to-treat population rather than the European subgroup and using survival curves with a dependent variable for the treatment effect reduced the ICER. However, it noted that the resulting ICERs were still much higher than £30,000 per QALY gained. The committee also understood that using utility values from ramucirumab and using the observed survival data to model the first 12 or 18 months of survival increased the ICER.

Trifluridine–tipiracil could not be recommended for routine use in the NHS

3.10 The committee concluded that all ICERs, including the most plausible ICER based on its preferred assumptions, were substantially higher than £30,000 per QALY gained. Therefore, trifluridine–tipiracil could not be recommended for routine use in the NHS.

Trifluridine–tipiracil does not meet the criteria to be considered for inclusion in the Cancer Drugs Fund

3.11 Having concluded that trifluridine–tipiracil could not be recommended for routine use, the committee then considered whether it could be recommended for treating gastric cancer within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum).

The committee concluded that trifluridine–tipiracil does not meet the criteria to be considered for inclusion in the Cancer Drugs Fund.

Trifluridine–tipiracil is not innovative and all benefits are captured in the model

3.12 The committee recalled the poor prognosis for people with metastatic gastric cancer and that there is an unmet need for third-line treatment options (see section 3.1). The committee understood that the company considered trifluridine–tipiracil to be innovative because it provides an alternative oral treatment option that increases overall survival. It also noted that the utility values in the company's analysis did not include the health-related quality of life of carers of people with gastric cancer. The committee recalled that trifluridine–tipiracil was clinically effective compared with best supportive care (see section 3.3), but noted that it had not seen evidence of additional benefits that were not captured in the model. It concluded that trifluridine–tipiracil is not innovative, and all relevant benefits had been captured in the cost-effectiveness estimates.

There are no equalities issues relevant to the recommendation

3.13 The committee understood that no equalities issues were raised during scoping and technical engagement. It also noted that no potential equality issues were identified in the company submission. The committee concluded there were no equalities issues relevant to the recommendation.