Cabozantinib for previously treated advanced hepatocellular carcinoma

3.1 Hepatocellular carcinoma (HCC) is often diagnosed at an advanced stage. Symptoms of HCC include weakness, deep fatigue, nausea, abdominal pain, ascites, and hepatic encephalopathy. Patient experts described how the physical symptoms of HCC can affect everyday life, making basic functions like eating, speaking, writing and even staying awake difficult. Aside from physical symptoms, people with HCC often experience depression from the poor prognosis. The patient experts explained that people with advanced HCC live with uncertainty, hopelessness and often stigma and isolation because of the perception of liver cancer. They described how the physical symptoms and the psychological impact of HCC can also have a considerable impact on the quality of life of families and carers. The committee concluded that HCC has a substantial impact on the quality of life of people with the condition, and their families and carers.

3.2 The company proposed that cabozantinib would be used in the same position as regorafenib in the treatment pathway. That is, as a second-line or third-line systemic therapy after progression on or intolerance to sorafenib. The NICE technology appraisal guidance on regorafenib for previously treated advanced HCC recommends it only for people who have Child–Pugh grade A liver impairment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The company positioned cabozantinib at the same position and in the same population as regorafenib. This is because the clinical trial evidence is relatively limited for cabozantinib in people with advanced HCC with more severe liver disease or a poorer performance status. The clinical experts agreed with the company's proposed positioning of cabozantinib and explained that in clinical practice atezolizumab plus bevacizumab, lenvatinib and sorafenib are used as first-line systemic therapies. After first-line atezolizumab plus bevacizumab, lenvatinib and sorafenib can be used second line, with regorafenib available as a third-line option if someone has previously had sorafenib. For those treated with sorafenib first line, regorafenib can be used second line. So, the committee concluded that the company's proposed positioning in the treatment pathway was appropriate, and regorafenib was the relevant comparator.

3.3 The patient and clinical experts said that if people's disease has progressed on sorafenib, or if they cannot tolerate it, there are limited treatment options. Only regorafenib is available. They said a new treatment option would be welcomed. Clinical experts also said that cabozantinib may be an option for a broader group of people than regorafenib, which was only evaluated in a sorafenib-tolerant population. They explained that regorafenib is generally only used if sorafenib was tolerated, whereas cabozantinib could be used for people who could not tolerate sorafenib. The committee concluded that cabozantinib would offer a new treatment for people with limited options.

3.4 The clinical effectiveness evidence was based on CELESTIAL, a randomised, double-blind trial that compared cabozantinib plus best supportive care with placebo plus best supportive care. CELESTIAL included people with HCC who had had 1 or 2 treatments already, and who had had sorafenib (whether they tolerated it or not). People also had to have an ECOG performance status of 0 or 1 and Child–Pugh grade A. The primary outcome was overall survival. Secondary outcomes included progression-free survival and objective response rate. At a median follow up of 22.9 months, the median overall survival in the cabozantinib arm was 10.2 months, compared with 8.0 months in the placebo arm (hazard ratio 0.76, 95% confidence interval [CI] 0.63 to 0.92). The median progression-free survival was 5.2 months, compared with 1.9 months in the placebo arm (hazard ratio 0.44, 95% CI 0.36 to 0.52). The committee concluded that cabozantinib was clinically effective compared with placebo.

3.5 Because there was no direct head-to-head evidence for cabozantinib compared with regorafenib, the company provided a series of indirect treatment comparisons. The indirect treatment comparisons used the Bucher approach and matching-adjusted indirect comparison (MAIC). Data for cabozantinib was from the CELESTIAL trial. Data for regorafenib was from the RESORCE trial, a randomised, double-blind trial of regorafenib plus best supportive care compared with placebo plus best supportive care. The relative treatment effect of cabozantinib compared with regorafenib was estimated for overall survival and progression-free survival. The company acknowledged that population differences between the CELESTIAL and RESORCE trials introduced bias into the Bucher analysis, so it had to do the MAICs. The ERG agreed and said that the Bucher approach does not provide robust results because of the observed cross-trial differences. So, the committee discussion focused on the 3 MAIC approaches presented by the company:

3.6 The committee noted that the anchored MAICs showed a non-statistically significant progression-free survival benefit for cabozantinib and a non-statistically significant overall survival benefit for regorafenib. The anchored MAIC analysis with constant hazard ratios produced hazard ratios of 1.09 (95% CI 0.73 to 1.62) for overall survival and 0.80 (95% CI 0.55 to 1.15) for progression-free survival. The anchored MAIC analysis with time-varying hazard ratios produced time-varying hazard ratios of:

3.7 The company's model assumed equivalent healthcare management costs in the progression-free health state for cabozantinib and regorafenib. This was based on the company's clinical expert opinion, which was that clinicians are experienced in handling generic tyrosine kinase inhibitor toxicities, and that cabozantinib's tolerability issues can be managed. The ERG preferred to include additional monitoring costs, based on the views of its clinical advisers that cabozantinib has a comparatively worse toxicity profile than regorafenib. This was supported by the comparison of safety outcomes from the MAICs. Only the odds ratio for diarrhoea was statistically significant in favour of regorafenib but the point estimate odds ratios for hypertension, elevated aspartate transaminase, fatigue and palmar-plantar erythrodysaesthesia syndrome were also above 1 (in favour of regorafenib). The odds ratio for elevated bilirubin was in favour of cabozantinib but was not statistically significant. The ERG provided an alternative scenario that included the cost of 0.5 additional oncologist visits per month (0.46 visits per 28‑day model cycle).

3.8 The ERG commented that in the CELESTIAL trial there was a potentially clinically meaningful difference in favour of placebo for health-related quality of life when measured using the EQ‑5D. The company acknowledged that the EQ‑5D data from RESORCE does not suggest a significant difference between regorafenib and placebo. But it said that the EQ‑5D questionnaire in RESORCE was completed on the first day of each treatment cycle, when someone had not had treatment for a week. This may have affected responses. Clinical experts said that the toxicity profiles for regorafenib and cabozantinib seem broadly consistent. The committee concluded that it was uncertain if cabozantinib would result in additional monitoring costs compared with regorafenib, but it would consider both the company's and ERG's scenarios in its decision making.

3.9 The company's base case analyses assumed that packs of treatment can be split so that every tablet prescribed is taken, so they did not include wastage costs. This assumption advantages the cabozantinib group because the relative dose intensity is much lower for cabozantinib than for regorafenib (61% compared with 90%, respectively). The ERG noted that there may be some wastage because people can progress or die before completing a pack of treatment. The ERG provided an alternative scenario consistent with previous appraisals in HCC, in which the costs of 7 days' worth of treatment in both treatment groups (adjusted for relative dose intensity) was included. A clinical expert said that dose adjustments are usually made quickly; normally after 2 weeks of treatment, so wastage is likely to be minimised. The committee noted that including drug wastage costs as per the ERG's scenario was not a key driver of cost effectiveness but was likely to reflect clinical practice.

3.10 The committee agreed that its preferred approach to modelling would:

3.11 The committee also accepted the ERG analyses, which included corrections of minor errors, a general population mortality constraint and age-adjusted utilities. Using the committee's preferred assumptions and including the confidential discounts for cabozantinib and regorafenib, cabozantinib was associated with fewer quality-adjusted life years (QALYs) and overall lower costs than regorafenib in all scenarios. The scenario using the anchored MAIC with constant hazard ratios and equivalent healthcare management costs in the progression-free health state produced the most favourable results. The scenario using the anchored MAIC with time-varying hazard ratios and the cost of 0.5 additional oncologist visits per month for cabozantinib produced the least favourable results. The committee acknowledged that the true costs and QALYs were likely to be in between the 2 scenarios. The exact savings, net health benefits and incremental cost-effectiveness ratios (ICERs) are commercial in confidence and cannot be reported here. The committee was aware that, when an ICER is estimated for a technology that is less effective and less costly than its comparator, the commonly assumed decision rule of accepting ICERs below a given threshold is reversed. So, the higher the ICER, the more cost effective a treatment is. The committee considered the limited treatment options after sorafenib, particularly for people unable to tolerate it. It took the net health benefits and the ICERs into account. It noted that the QALY losses were sufficiently small for the anchored MAICs (less than 0.1, or roughly equivalent to 1 month in perfect health) and the south-west quadrant ICERs per QALY lost were high enough to consider cabozantinib a cost-effective use of NHS resources. The exact QALYs are commercial in confidence and cannot be reported here. The committee concluded that cabozantinib can be considered cost effective for treating advanced HCC in people who have previously had sorafenib.

3.12 The patient expert said that liver disease and liver cancer disproportionally affect the poorest in society, and many people with liver cancer come from disadvantaged backgrounds. Differences in prevalence and patient population cannot usually be resolved in a technology appraisal, although the committee can consider whether a specific equality issue has a significant impact on access to treatments it recommends. The committee concluded that this was not the case for its recommendations about cabozantinib.

3.13 The committee acknowledged the need for more treatment options in advanced HCC. It took account of the commercial discounts for cabozantinib and regorafenib. In the committee's preferred analyses, cabozantinib was considered a cost-effective use of NHS resources compared with regorafenib. So, cabozantinib is recommended as a treatment option for people with advanced HCC who have had sorafenib and who have Child–Pugh grade A liver impairment and an ECOG performance status of 0 or 1.