Technology appraisal guidance Published: 21 March 2018

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Regorafenib for previously treated advanced hepatocellular carcinoma Technology appraisal guidance Published: March 2018 NICE All rights reserved. Subject to Notice of
Regorafenib for previously treated advanced hepatocellular carcinoma Technology appraisal guidance Published: March 2018 NICE All rights reserved. Subject to Notice of rights ( Your responsibility The recommendations in this guidance represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, health professionals are expected to take this guidance fully into account, alongside the individual needs, preferences and values of their patients. The application of the recommendations in this guidance are at the discretion of health professionals and their individual patients and do not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian. Commissioners and/or providers have a responsibility to provide the funding required to enable the guidance to be applied when individual health professionals and their patients wish to use it, in accordance with the NHS Constitution. They should do so in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Commissioners and providers have a responsibility to promote an environmentally sustainable health and care system and should assess and reduce the environmental impact of implementing NICE recommendations wherever possible. Page 2 of Contents 1 Recommendations Information about regorafenib Committee discussion... 6 Unmet need... 6 Treatment pathway... 6 Clinical evidence... 7 The company's economic model... 9 Overall survival extrapolation in the economic model Time-to-treatment discontinuation in the economic model Costs in the economic model Utility values in the economic model The company's updated economic analysis The ERG's updated exploratory economic analyses The updated most plausible ICER after consultation End of life Cancer Drugs Fund Innovation Conclusion Appraisal committee members and NICE project team Appraisal committee members NICE project team Page 3 of 1 Recommendations 1.1 Regorafenib is not recommended for treating advanced unresectable hepatocellular carcinoma in adults who have had sorafenib. 1.2 This recommendation is not intended to affect treatment with regorafenib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations In the NHS, advanced unresectable hepatocellular carcinoma is mostly treated with sorafenib. For people who cannot tolerate sorafenib, or whose disease progresses with sorafenib, the only current option is best supportive care. Regorafenib is a possible treatment option after sorafenib instead of best supportive care, in line with its marketing authorisation. Clinical trial evidence in people with advanced hepatocellular carcinoma who have already had sorafenib, have an Eastern Cooperative Oncology Group (ECOG) performance status score of either 0 or 1, and Child-Pugh grade A liver impairment shows that people having regorafenib live longer than people having best supportive care. However, the survival benefit with regorafenib is unclear in people who cannot tolerate sorafenib, have a poorer ECOG performance status or more severe liver disease. These people were not included in the trial so it is uncertain whether the results of the trial would translate into similar benefits in the NHS. The company responded to the committee's preferred assumptions after consultation and submitted a further model incorporating these assumptions for overall survival extrapolation, full dose and pooled resource use surveys. Regorafenib meets NICE's criteria to be considered a life-extending treatment at the end of life. The most plausible cost-effectiveness estimates are higher than those NICE normally considers an acceptable use of NHS resources for end-of-life treatments. Therefore regorafenib cannot be recommended for routine use in the NHS. Regorafenib is not recommended through the Cancer Drugs Fund because the uncertainties in the clinical and cost effectiveness cannot be resolved by data collection in the Cancer Drugs Fund, and regorafenib does not have plausible potential to be cost effective. Page 4 of 2 Information about regorafenib Marketing authorisation Regorafenib (Stivarga, Bayer) is indicated as 'monotherapy for the treatment of adult patients with hepatocellular carcinoma who have been previously treated with sorafenib'. 'Regorafenib is not recommended for patients with severe hepatic impairment (Child-Pugh grade C) because it has not been studied in this population'. Dosage in the marketing authorisation 160 mg (4 40 mg tablets) orally once daily for 3 weeks followed by 1 week off therapy. A 4-week period is considered a treatment cycle. Price The list price per treatment cycle for 160 mg of regorafenib is 3, (excluding VAT; British national formulary online [accessed October 2017]). The company has agreed a patient access scheme with the Department of Health. If regorafenib had been recommended, this scheme would provide a simple discount to the list price of regorafenib 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 would not constitute an excessive administrative burden on the NHS. Page 5 of 3 Committee discussion The appraisal committee (section 4) considered evidence submitted by Bayer and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence. Unmet need People with advanced hepatocellular carcinoma would welcome a new treatment option 3.1 Advanced unresectable hepatocellular carcinoma is often diagnosed late in life and has a poor survival prognosis. It is a debilitating condition with many distressing symptoms. The clinical and patient experts noted that people with advanced unresectable hepatocellular carcinoma have limited treatment options and will have been through many unsuccessful treatments in a long treatment pathway. They noted that improving quality of life and even small extensions to length of life are of considerable importance to this patient group. The committee agreed that people with advanced unresectable hepatocellular carcinoma who have already had sorafenib have an unmet clinical need, and would welcome other treatment options. Treatment pathway Regorafenib is a potential option for advanced unresectable hepatocellular carcinoma after sorafenib 3.2 If surgical or locoregional treatments fail or are unsuitable, systemic therapy with sorafenib is the only active treatment option available for people with hepatocellular carcinoma. NICE technology appraisal guidance on sorafenib recommends it as an option for treating advanced hepatocellular carcinoma only in people with Child-Pugh grade A liver impairment. During the appraisal of sorafenib, the committee noted that people need both adequate liver function and performance status to have sorafenib in clinical practice in England, and that treatment should be restricted to people with Child-Pugh grade A liver function and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. The clinical expert explained that best supportive care or clinical trials are the only options for people whose disease progresses despite taking sorafenib, or who cannot tolerate it. There are no second-line therapies Page 6 of available and a palliative care approach is taken for these patients. The committee noted that regorafenib offers a potential second-line treatment option for people who cannot tolerate, or whose disease progresses on, sorafenib. Clinical evidence Regorafenib is more clinically effective e than best supportive care in the clinical trial population 3.3 The company's clinical evidence came from 1 trial. RESORCE (n=573) was an international, phase III, multicentre, randomised, double-blind, placebocontrolled trial comparing regorafenib (plus best supportive care) with placebo (plus best supportive care). The trial included people whose disease had progressed on sorafenib, who had either 160 mg regorafenib orally once daily for weeks 1 to 3 of each 4-week treatment cycle or best supportive care. Up to 2 regorafenib dose reductions because of toxicity were allowed (from 160 mg to 120 mg to 80 mg). The primary outcome was overall survival, with secondary outcomes including progression-free survival. The committee noted that the results showed a small and statistically significant median overall survival gain of 2.8 months for regorafenib (10.6 months; 95% confidence interval [CI] 9.1 to 12.1) compared with best supportive care (7.8 months; 95% CI 6.3 to 8.8). The committee noted that the hazard ratio for overall survival for regorafenib compared with best supportive care was 0.63 (95% CI 0.50 to 0.79) and that regorafenib offered an important survival benefit for people with advanced hepatocellular carcinoma. Median progression-free survival was statistically significantly better for regorafenib (3.1 months, 95% CI 2.8 to 4.2) than for best supportive care (1.5 months, 95% CI 1.4 to 1.6). The committee noted that the hazard ratio for progression-free survival for regorafenib compared with best supportive care was 0.46 (95% CI 0.37 to 0.56), which represented a clinically relevant reduced risk of progression for the regorafenib group. It also heard that quality-of-life scores were generally similar across treatment arms with different measures, including EQ-5D. Scores were slightly worse for regorafenib than for best supportive care but these differences did not pass the 'minimally important difference' threshold established in the literature. The committee noted that there were only 5 clinical trial centres in the UK, with 20 patients randomised to treatment in 4 of the centres. The ERG noted that RESORCE was a high-quality randomised controlled trial, with a low risk of selection, Page 7 of performance, attrition and reporting bias. Therefore, the committee concluded that regorafenib offers an important gain in progression-free and overall survival compared with best supportive care. The generalisability of the population included in the RESORCE trial to clinical practice in England is uncertain 3.4 RESORCE included people with advanced unresectable hepatocellular carcinoma who: previously had sorafenib mostly had Child-Pugh grade A liver impairment had an ECOG performance status score of either 0 or 1. The committee noted that regorafenib's marketing authorisation is broader than the trial population, because the trial did not include people who: had Child-Pugh grade B liver impairment had an ECOG performance status of 2 or more cannot tolerate sorafenib. The clinical expert noted that RESORCE included a highly selective population who could tolerate sorafenib well and also highlighted that post-trial studies investigating survival outcomes for sorafenib, which included patients outside of the strict trial criteria, showed lower survival than predicted in the main sorafenib trial. The clinical expert stated that the toxicity and efficacy of regorafenib in people who could not tolerate sorafenib, with Child-Pugh grade B liver impairment and with an ECOG performance status of 2 or more was unknown. The committee therefore concluded that benefits could not be extrapolated outside the trial population because of the uncertainty in survival benefit for people not included in RESORCE but covered by the broader marketing authorisation for regorafenib. An audit of sorafenib use shows differences between the RESORCE trial population and the population in clinical practice in England 3.5 A 2017 audit of sorafenib use in the UK by King et al. found that sorafenib is used in patients who have an ECOG performance status of 2 or more and Page 8 of Child-Pugh grade B liver impairment (% and 16% of the audit population respectively). The committee noted that sorafenib is recommended as an option for treating advanced hepatocellular carcinoma only for people with Child-Pugh grade A liver impairment, but that people progressing on sorafenib are likely to have further deterioration in liver impairment (Child-Pugh status) and ECOG performance status. The clinical expert explained that because sorafenib and regorafenib are both tyrosine kinase inhibitors with similar mechanisms of action, people who cannot tolerate sorafenib may also be unable to tolerate regorafenib (although there are no data to support this at this time). Therefore, an estimated 30% to 50% of the population whose disease progressed on sorafenib would be eligible for regorafenib. The committee also noted that all patients had a treatment-related adverse event, and that qualityof-life values were only maintained rather than improved with regorafenib treatment. The committee acknowledged comments received during consultation that use of regorafenib should be restricted based on the eligibility criteria in the RESORCE trial. It concluded that given the lack of evidence in people with an ECOG performance status of 2 or more, with Child-Pugh B liver impairment and who cannot tolerate sorafenib, there is considerable uncertainty in the efficacy of regorafenib in populations not included in RESORCE but covered by its marketing authorisation. The company's economic model The model structure is appropriate for decision-making 3.6 The company used a partitioned survival model with 3 health states (progression free, progressed disease and death). The committee, however, noted the uncertainty in the model about people covered by the marketing authorisation for regorafenib who were excluded from RESORCE. The committee understood that all efficacy and clinical parameters in the model were derived using patient-level data from RESORCE. The committee noted that data for progression-free survival from RESORCE represented a full pattern of progression, so no extrapolation was needed and the progressionfree survival curve was taken directly from the observed trial Kaplan Meier data. The committee accepted that standard parametric curve fitting was done using patient-level data from RESORCE for overall survival. Page 9 of The company submitted a model suitable for decision-making 3.7 After consultation, the company submitted a further model using the committee's preferred assumptions, specifically: extrapolating overall survival using a Weibull distribution using the full dose of 160 mg per cycle resource use estimates from pooled 2015 and 2007 surveys full extrapolation of time-to-treatment discontinuation. This model originally contained errors, which resulted in the company submitting several iterations of the economic model and response to consultation. The committee noted this divergence from NICE processes but accepted the company's model as suitable for decision-making. Overall survival extrapolation in the economic model The Weibull distribution is most appropriate for extrapolating overall survival 3.8 In the company's original base case, a dependent lognormal curve was used to model overall survival. The ERG disagreed with this choice of curve and the fitting of dependent models because the lognormal function is an accelerated failure time model. The ERG also considered the choice of the lognormal curve to be inappropriate, based on its clinical expert's advice that the modelpredicted sustained difference in overall survival between the regorafenib and best supportive care curves beyond 35 cycles was unrealistic in a population with progressed hepatocellular carcinoma. The committee heard from the clinical expert that the 5-year survival suggested by the lognormal curve was implausible because the modelled population was elderly, with advanced disease refractory to most previous treatments. The ERG noted that the NICE reference case places most significance on clinical plausibility and preferred the Weibull curve based on clinical opinion and goodness-of-fit to observed data. The Cancer Drugs Fund clinical lead highlighted a recent study reporting mature follow-up data on patients having sorafenib (plus other treatments) in specialist centres. This showed relatively high 5-year survival rates of 5% to 8%, suggesting that some people may have indolent disease. The committee noted that this study included a sorafenib population and that the population having Page 10 of regorafenib are likely to have lower 5-year survival rates because they are further along the treatment pathway. The committee concluded that the company's preferred dependent lognormal curves were overly optimistic and technically incorrect. It preferred the use of independent Weibull curves, but recognised that these were associated with significant uncertainty. 3.9 The committee considered that the Weibull distribution remained the most appropriate choice for extrapolating overall survival because no new evidence was provided during consultation. However, in its updated analyses, the company extrapolated overall survival with independently fitted Gompertz and exponential distributions, as well as the Weibull distribution. The company noted that the ERG's clinical expert also considered the Gompertz and exponential extrapolations to be clinically plausible, so it provided costeffectiveness results for these 3 distributions individually combined with its updated assumptions. The ERG explained that its preference for the Weibull distribution was not based only on clinical opinion of its plausibility, but also on goodness-of-fit to the observed data and the empirical hazards. The committee noted that based on the empirical hazards (particularly in the best supportive care arm), an exponential curve was not appropriate and that the Akaike information criterion/bayesian information criterion for Weibull fit better than Gompertz by more than 5 points. The company provided no further information to support the use of an exponential or Gompertz curve. The committee reiterated that the Weibull was the most appropriate distribution for extrapolating overall survival, in preference to the Gompertz and exponential curves. Time-to-treatment discontinuation in the economic model Treatment discontinuation in RESORCE may not represent NHS clinical practice 3.10 The committee noted that the number of people continuing treatment with regorafenib despite disease progression was high in RESORCE and that time-totreatment discontinuation did not equate to time to progression. The clinical expert explained that this did not represent clinical practice in England because 80% of patients would stop treatment on progression. They highlighted that the number of people continuing treatment despite disease progression and the efficacy of treatment in these patients was uncertain. The committee concluded Page 11 of that the rate of treatment discontinuation in RESORCE is unlikely to represent NHS clinical practice. Including the survival benefits but excluding the costs of post-progression treatment is unreasonable 3.11 The company agreed that most people will discontinue treatment if their disease progresses, and accepted that people would have less treatment in practice than in RESORCE. The company did a new survey which investigated post-progression treatment, and found that 8 of the 9 respondents would stop treatment at progression. In response to consultation, the company presented a scenario whereby an area under the log-logistic time-to-treatment discontinuation curve was applied adjusting for
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