Trifluridinetipiracil for previously treated metastatic colorectal cancer

Evidence-based recommendations on trifluridinetipiracil (Lonsurf) for previously treated metastatic colorectal cancer in adults.

# Recommendations
Trifluridinetipiracil is recommended, within its marketing authorisation, as an option for treating metastatic colorectal cancer, that is:
in adults who have had previous treatment with available therapies including fluoropyrimidine-, oxaliplatin- or irinotecan-based chemotherapies, anti-vascular endothelial growth factor (VEGF) agents and anti-epidermal growth factor receptor (EGFR) agents, or when these therapies are not suitable, and
-nly when the company provides trifluridinetipiracil with the discount agreed in the patient access scheme.# The technology
Description of the technology
Trifluridinetipiracil (Lonsurf, Servier Laboratories) combines 2 drugs: a nucleoside analogue (trifluridine) and a thymidine phosphorylase inhibitor (tipiracil). Trifluridine is taken into the DNA of tumour cells and inhibits tumour growth. Tipiracil slows the breakdown of trifluridine to prolong this action.
Marketing authorisation
'The treatment of adult patients with metastatic colorectal cancer (CRC) who have been previously treated with, or are not considered candidates for, available therapies including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF  agents, and anti-EGFR  agents.'
Adverse reactions
The most frequently seen adverse drug reactions are neutropenia, nausea, fatigue, anaemia and leukopenia. For full details of adverse reactions and contraindications, see the summary of product characteristics.
Recommended dose and schedule
The recommended starting dose of trifluridinetipiracil in adults is 35 mg/m2/dose administered orally twice daily on days 1 to 5 and days 8 to 12 of each 28day cycle for as long as there is a benefit or until there is unacceptable toxicity. Each dose must not exceed 80 mg.
Price
The list price of a 20tablet pack of 15 mg trifluridinetipiracil is 500, and that of 20 mg trifluridinetipiracil is 667. Each dose is also available in 60tablet packs at pro rata prices.
The average cost per patient per cycle of treatment is estimated at 2,032 based on the list price.
The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of trifluridinetipiracil, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Evidence
The appraisal committee (section 6) considered evidence submitted by Servier Laboratories and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.# Committee discussion
The appraisal committee reviewed the data available on the clinical and cost effectiveness of trifluridinetipiracil, having considered evidence on the nature of metastatic colorectal cancer and the value placed on the benefits of trifluridinetipiracil by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.

# Patients' perspective
The patient experts stated that, after multiple lines of treatment, metastatic colorectal cancer is more likely to be resistant to other drugs. Therefore, another treatment option, especially one that is taken orally and offers some survival benefit, gives people hope. The committee recognised that patients value options in treatment, and that trifluridinetipiracil would be welcomed by patients and their families.

# Position in the treatment pathway
The committee noted that NICE's clinical guideline on colorectal cancer: diagnosis and management recommends FOLFOX (folinic acid plus fluorouracil plus oxaliplatin) or XELOX (capecitabine plus oxaliplatin) as first-line treatments, and single-agent irinotecan or FOLFIRI (folinic acid plus fluorouracil plus irinotecan) as second-line treatments (single-agent irinotecan is recommended only after FOLFOX). The committee was aware that there is no positive NICE guidance on third- or subsequent-line treatments.
The committee noted that trifluridinetipiracil has a marketing authorisation for 'adult patients with metastatic colorectal cancer (CRC) who have been previously treated with, or are not considered candidates for, available therapies including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF  agents, and anti-EGFR  agents'. It understood that the company proposed that trifluridinetipiracil would be used as a third- or subsequent-line treatment. The clinical experts agreed that this was the point at which they would mainly offer trifluridinetipiracil. The committee discussed the meaning of 'not considered candidates for available therapies', noting that there was no evidence from clinical trials for this population. It heard from the clinical experts that this refers to people who, in clinical practice, would not be considered fit enough to have the therapies recommended by NICE first and second line. However, the committee understood that this is a very small group. The clinical experts noted that trifluridinetipiracil was available in some centres in the UK as part of a 'named patient programme'. In this, over 95% of people had had 2 or more therapies before having trifluridinetipiracil. The committee agreed that, in clinical practice, trifluridinetipiracil would mainly be used in people who have previously had 2 or more therapies when there are no further treatment options.

# Clinical effectiveness
The committee considered the 2 clinical trials presented by the company; Yoshino et al. (2012), and RECOURSE. Both trials were double-blind randomised controlled trials comparing trifluridinetipiracil with placebo in adults with metastatic colorectal cancer who had had 2 or more regimens of standard chemotherapy, and in whom fluoropyrimidine, irinotecan and oxaliplatin had stopped working or were unsuitable. The primary endpoint was overall survival in both trials. The committee agreed that both trials were relevant to the decision problem and suitable for assessing the clinical effectiveness of trifluridinetipiracil.

## Generalisability of trial results
The committee was aware that both trials provided evidence for people who had previously had 2 or more therapies, but not for those in whom available therapies were not suitable. The committee recalled that only a few people would not be considered fit enough to have the therapies recommended by NICE first and second line (see section 4.3). Furthermore, it heard from the clinical experts that trifluridinetipiracil was unlikely to replace those therapies. The committee agreed that the evidence could be generalised to people in whom available therapies are not suitable.
The committee was aware that in RECOURSE, but not in Yoshino et al. (2012), patients must have had bevacizumab before enrolling in the trial; patients with KRAS wild-type tumours also must have had cetuximab or panitumumab. The committee noted that none of these therapies were recommended by NICE, or funded by the Cancer Drugs Fund, for previously treated metastatic colorectal cancer. Therefore, people in England are unlikely to have had bevacizumab, cetuximab or panitumumab before trifluridinetipiracil. The company considered that there was no biological reason for the effect of trifluridinetipiracil to differ in people who do or do not have biological therapies. The committee noted that 22% of patients in Yoshino et al. did not have bevacizumab. In this group, the hazard ratio for overall survival was 0.37 (95% confidence interval  0.16 to 0.86) compared with 0.63 (95% CI 0.42 to 0.95) in those who did have bevacizumab; there was no statistically significant interaction between the 2 groups. However, the committee considered these results were inconclusive because it was unclear whether previous treatments had differed between the 2 groups in a way that affected survival outcomes. The committee heard from the clinical experts that effectiveness would be expected to diminish with each additional line of treatment. In addition, the clinical experts questioned whether bevacizumab increases survival; therefore, the long-term benefit of previous bevacizumab treatment was unclear. The committee concluded that trifluridinetipiracil would be similarly effective in people who have or have not had bevacizumab, and that the results of the trials were generalisable to NHS patients in England who have not had bevacizumab.

## Meta-analysis of trials
The committee considered the company's meta-analysis of Yoshino et al. (2012) and RECOURSE, noting that the company 'naively' pooled the efficacy data from the 2 trials. The committee heard from the ERG that the trials had similar designs, and that patients in both trials had similar disease characteristics at baseline. Also, the pooled results mirrored the individual trials. During the committee meeting, the company confirmed that the results were almost the same whether the meta-analysis was or was not stratified (adjusted) by trial. The committee noted the ERG's comments in the meeting that the naive pooling of data was unlikely to be biased. Given the similarity between the 2 trials and the consistency between the results, the committee concluded that the company's original meta-analysis provided valid results.

## Results
The committee discussed the results of the trials, noting that the survival data were 'mature'; that is most patients had died by the end of the follow-up period (Yoshino et al.; 72.8%; RECOURSE: 89.0%). Compared with placebo, trifluridinetipiracil increased median overall survival by 2.4 months in Yoshino et al. (2012) and by 2.0 months in RECOURSE. The company's meta-analysis of Yoshino et al. and RECOURSE showed that trifluridinetipiracil led to a statistically significant increase in overall survival (hazard ratio  0.67, 95% CI 0.58 to 0.78) and progression-free survival (HR 0.46, 95% CI 0.40 to 0.53). The committee heard from the clinical and patient experts that, for an end-of-line treatment, even small extensions to life are important. Also, people at this stage of the disease would be unlikely to tolerate treatments with severe adverse effects. According to the experts, trifluridinetipiracil offers the advantage of being an oral treatment with minimal adverse effects. The committee concluded that the survival benefit of trifluridinetipiracil, although relatively small, was clinically meaningful.

## Adverse events
The committee noted that, in clinical trials, trifluridinetipiracil was associated with a higher incidence of adverse events than placebo (Yoshino et al.; 96.5% compared with 70.2%; RECOURSE: 85.7% compared with 54.7%). It heard that patients considered the safety profile of trifluridinetipiracil to be acceptable. The clinical experts also stated that trifluridinetipiracil was well tolerated by people who took part in the named patient programme, and caused less fatigue than regorafenib (whose NICE technology appraisal was terminated), which may also be used at the same stage in the treatment pathway as trifluridinetipiracil. The committee concluded that trifluridinetipiracil had an acceptable burden of adverse events.

# Cost effectiveness

## Survival modelling
To model overall survival and progression-free survival, the company fitted independent models for each treatment group (trifluridinetipiracil or placebo); in this method, the treatment effects do not need to meet the proportional hazards assumption. The ERG, however, preferred a single model with a covariate (predictor) for the treatment group because it noted that the log-cumulative hazard plots for overall survival and for progression-free survival indicated that the proportional hazards assumption would hold. The committee was aware that the pooled data for overall survival and progression-free survival were very mature (86% and 89% respectively). This meant that the choice of the model was unlikely to influence the results greatly; when the ERG chose a different model, this had a negligible impact on the incremental cost-effectiveness ratio (ICER). Moreover, the committee did not consider the log-cumulative hazard plots for progression-free survival to strongly indicate that the proportional hazards assumption would hold. Because of this, the committee concluded that modelling each treatment group independently was reasonable and more appropriate than including the treatment group as a predictor in the model.

## Body surface area
The committee was aware that the dose of trifluridinetipiracil, and hence its cost, is based on body surface area. To model the dose that people would receive, the company estimated the distribution of body surface area from patients in RECOURSE. It grouped patients based on their body surface area, then fitted the log-normal distribution to these data. The ERG considered that using the actual (observed) data on body surface area from RECOURSE was more reasonable. The committee noted that the average body surface area in RECOURSE was 1.78 m2, which was lower than the average body surface area among the UK general population. The committee did not consider that a value from the general population was a relevant comparison because people with advanced colorectal cancer would likely be smaller than the general population, as confirmed by the clinical experts. The committee recognised that the modelling of body surface area should minimally influence the cost of treatment because trifluridinetipiracil is taken orally and patients are grouped into dosing groups. This means that patients with slightly different body surface areas may be in the same dosing group and have the same dose. The committee did not consider there was a need to use parametric methods (notably, a reason to extrapolate) to estimate body surface area, preferring to use the data from the trial for decision-making.

## Health-related quality of life
The committee noted that neither the clinical trials (Yoshino et al.  and RECOURSE) nor the named patient programme provided data on health-related quality of life. To estimate health-related quality of life in the model, the company averaged utility values from the CORRECT trial, which evaluated regorafenib for previously treated metastatic colorectal cancer, and the evidence submission for NICE's technology appraisal guidance on cetuximab for the first-line treatment of metastatic colorectal cancer. The committee understood that the company considered these 2 sources reflected utility values at both ends of the range. The ERG was concerned about using the submission for NICE's technology appraisal guidance on cetuximab to source utility values because the pre-progression utility value from that submission was derived using the Health Utilities Index Mark 3 instrument, which was not in line with the NICE reference case, and it was not ultimately used in the model for that appraisal. Furthermore, the post-progression utility value was derived from people with KRAS wild-type metastatic colorectal cancer that was refractory to chemotherapy, and the ERG could not verify its original source. Because of this, the ERG preferred using CORRECT only to source utility values. The committee heard from the clinical experts that the population in CORRECT reasonably reflected people who would have trifluridinetipiracil. The committee concluded that, to apply utility values, using the average value from 2 sources is methodologically worse than using data collected from clinical trials, or than using CORRECT alone.

## Cost-effectiveness results
The committee considered the cost-effectiveness results including the patient access scheme discount. It noted that the deterministic ICER from the company's base case revised in response to a request for clarification from the ERG was 42,674 per quality-adjusted life year (QALY) gained for trifluridinetipiracil compared with best supportive care. The ERG estimated a probabilistic ICER of 52,695 per QALY gained based on clinical data from RECOURSE only, but also presented an ICER based on the pooled dataset, which was 49,392 per QALY gained. The committee was aware that the ERG's ICER of 49,392 per QALY gained used the utility values from CORRECT (see section 4.12), and the data on body surface area seen in RECOURSE (see section 4.11), both of which it preferred. This ICER, however, did not reflect the use of independent models for each treatment group to model survival, but the committee recalled that this modification individually had a negligible impact on the ICER (see section 4.10). Therefore, the committee concluded that the ERG's ICER of 49,392 per QALY gained most closely mirrored its preferred analysis.

# End-of-life considerations
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods.
The committee discussed whether trifluridinetipiracil is indicated for patients with a short life expectancy, normally less than 24 months. It agreed that the best estimate of expected survival using current standard of care was observed in the control group of the trials. In RECOURSE, the median overall survival in the placebo group was 5.2 months. The mean overall survival estimated by the company's model for people who had placebo was 7.9 months using the pooled dataset including patients from Yoshino et al. (2012) and RECOURSE. The committee concluded that trifluridinetipiracil for third- or subsequent-line treatment of metastatic colorectal cancer meets the criterion for short life expectancy.
The committee considered the survival benefit of trifluridinetipiracil in the context of the end-of-life criteria:
It noted that the ERG's modified base case, using pooled data from Yoshino et al. (2012) and RECOURSE, estimated that trifluridinetipiracil would extend mean overall survival by 3.2 months compared with best supportive care; this estimate was based on extrapolating survival beyond the follow-up period and up to the end of the time horizon. The committee recognised that the modelled estimate of 3.2 months was based on mature data in the trials, suggesting that this estimate was fairly robust.
The ERG highlighted the difference in restricted mean overall survival of 2.4 months, which was based on the conservative and unrealistic assumption that all remaining patients died just after the trial ended.
The committee recognised that people in clinical practice may derive a greater survival advantage than patients in the trials because they will not have had all the therapies that the trial patients would have had, although it was aware that there were no conclusive data on this (see section 4.5).The committee considered that it should view the survival benefit with trifluridinetipiracil in the context of the life expectancy of this population. It agreed that potentially adding an average of 3.2 months to a particularly short life expectancy of 7.9 months would represent a clinically meaningful benefit. The committee appreciated that trifluridinetipiracil represents a well-tolerated treatment that would help extend life by even a relatively short time, while maintaining a reasonably good quality of life at a late stage in the treatment pathway when there are no further options left. The committee concluded that trifluridinetipiracil, as a third- or subsequent-line treatment for metastatic colorectal cancer, met the criterion for extending life.
Having concluded that trifluridinetipiracil meets the end-of-life criteria for the third-line treatment of metastatic colorectal cancer, and that the most plausible ICER was 49,392 per QALY gained, the committee concluded that it could recommend trifluridinetipiracil as a cost-effective use of NHS resources for adults who have had previous treatment with available therapies including fluoropyrimidine-, oxaliplatin- or irinotecan-based chemotherapies, anti-vascular endothelial growth factor (VEGF) agents and anti-epidermal growth factor receptor (EGFR) agents, or when these therapies are not suitable, and only when the company provides trifluridinetipiracil with the discount agreed in the patient access scheme.

# Pharmaceutical Price Regulation Scheme 2014
The committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014 and, in particular, the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.

# Summary of appraisal committee's key conclusions
TA405
Appraisal title: Trifluridinetipiracil for previously treated metastatic colorectal cancer
Section
Key conclusion
The committee concluded that it could recommend trifluridinetipiracil as a cost-effective use of NHS resources for treating metastatic colorectal cancer, that is:
in adults who have had previous treatment with available therapies including fluoropyrimidine-, oxaliplatin- or irinotecan-based chemotherapies, anti-vascular endothelial growth factor (VEGF) agents and anti-epidermal growth factor receptor (EGFR) agents, or when these therapies are not suitable, and
-nly when the company provides trifluridinetipiracil with the discount agreed in the patient access scheme.
The committee concluded that the evidence review group's (ERG) incremental cost-effectiveness ratio (ICER) of 49,392 per quality-adjusted life year (QALY) gained most closely mirrored its preferred analysis.
The committee concluded that trifluridinetipiracil, as a third- or subsequent-line treatment for metastatic colorectal cancer, met the criterion for extending life.
Current practice
Clinical need of patients, including the availability of alternative treatments
The committee recognised that patients value options in treatment, and that trifluridinetipiracil would be welcomed by patients and their families.
The committee was aware that there is no positive NICE guidance on third- or subsequent-line treatments.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The patient experts stated that, after multiple lines of treatment, metastatic colorectal cancer is more likely to be resistant to other drugs. Therefore, another treatment option, especially one that is taken orally and offers some survival benefit, gives people hope.
According to the experts, trifluridinetipiracil offers the advantage of being an oral treatment with minimal adverse effects.
What is the position of the treatment in the pathway of care for the condition?
The committee agreed that trifluridinetipiracil would mainly be used in people who have previously had 2 or more therapies when there are no further treatment options.
Adverse reactions
The committee heard that patients considered the safety profile of trifluridinetipiracil to be acceptable.
The clinical experts stated that trifluridinetipiracil was well tolerated by people who took part in the named patient programme, and caused less fatigue than regorafenib.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The company presented 2 clinical trials: Yoshino et al. (2012), and RECOURSE. Both trials were double-blind randomised controlled trials comparing trifluridinetipiracil with placebo.
The committee agreed that both trials were relevant to the decision problem and suitable for assessing the clinical effectiveness of trifluridinetipiracil.
Relevance to general clinical practice in the NHS
The committee was aware that, before enrolling in RECOURSE, patients must have had bevacizumab, which is not available in England. It concluded that trifluridinetipiracil would be similarly effective in people who have or have not had bevacizumab, and that the results of the trials were generalisable to NHS patients in England who have not had bevacizumab.
Uncertainties generated by the evidence
The committee noted that the survival data were 'mature'; that is, most patients had died by the end of the follow-up period.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
There are no clinically relevant subgroups for which there is evidence of differential effectiveness.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
Compared with placebo, trifluridinetipiracil increased median overall survival by 2.4 months in Yoshino et al. (2012) and by 2.0 months in RECOURSE. The company's meta-analysis of Yoshino et al. and RECOURSE showed that trifluridinetipiracil led to a statistically significant increase in overall survival (hazard ratio  0.67, 95% CI 0.58 to 0.78) and progression-free survival (HR 0.46, 95% CI 0.40 to 0.53).
Evidence for cost effectiveness
Availability and nature of evidence
The company developed a de novo, partitioned-survival model to assess the cost effectiveness of trifluridinetipiracil for previously treated metastatic colorectal cancer.
Uncertainties around and plausibility of assumptions and inputs in the economic model
To model survival, the company fitted independent models for each treatment group (trifluridinetipiracil or placebo). The ERG preferred a single model with a covariate (predictor) for the treatment group. The committee was aware that the pooled data for overall survival and progression-free survival were very mature, which meant that the choice of the model was unlikely to influence the results greatly.
The company estimated the distribution of body surface area in the model from patients in RECOURSE using parametric methods. The ERG considered that using the actual (observed) data on body surface area from the trial was more reasonable. The committee did not consider there was a need to use parametric methods to estimate body surface area, preferring to use the data from the trial.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The committee noted that neither the clinical trials (Yoshino et al.  and RECOURSE) nor the named patient programme provided data on health-related quality of life. To estimate health-related quality of life in the model, the company averaged utility values from the CORRECT trial, which evaluated regorafenib for previously treated metastatic colorectal cancer, and the evidence submission for NICE's technology appraisal guidance on cetuximab for the first-line treatment of metastatic colorectal cancer. The ERG preferred using CORRECT only. The committee concluded that using the average value from 2 sources is methodologically worse than using CORRECT alone.
Are there specific groups of people for whom the technology is particularly cost effective?
There are no specific groups of people for whom the technology is particularly cost effective.
What are the key drivers of cost effectiveness?
There were no specific conclusions about the key drivers of cost effectiveness.
Most likely cost-effectiveness estimate (given as an ICER)
The committee concluded that the ERG's ICER of 49,392 per QALY gained most closely mirrored its preferred analysis.
Additional factors taken into account
Patient access schemes (PPRS)
The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of trifluridinetipiracil, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence.
The committee concluded that the Pharmaceutical Price Regulation Scheme (PPRS) payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.
End-of-life considerations
The committee concluded that trifluridinetipiracil for third- or subsequent-line treatment of metastatic colorectal cancer meets the criterion for short life expectancy.
For the criterion for life extension, the committee agreed that potentially adding an average of 3.2 months to a particularly short life expectancy of 7.9 months would represent a clinically meaningful benefit. The committee appreciated that trifluridinetipiracil represents a well-tolerated treatment that would help extend life by even a relatively short time, while maintaining a reasonably good quality of life at a late stage in the treatment pathway when people have no further options left. The committee concluded that trifluridinetipiracil, as a third- or subsequent-line treatment for metastatic colorectal cancer, met the criterion for extending life.
Equalities considerations and social value judgements
No potential equality issues were identified during the appraisal.