Cabozantinib with nivolumab for untreated advanced renal cell carcinoma

Patient experts explained that advanced renal cell carcinoma is life changing. They explained how renal cell carcinoma affects people's lives, starting from the shock and despair of initial diagnosis. It is difficult for people with renal cell carcinoma to continue with daily life even after successful treatment, because of the fear of recurrence. Patient experts said that people with advanced renal cell carcinoma are frequently hospitalised, may have to take early retirement and have uncertainty about the future. Commonly there is a significant psychological impact. Patient experts explained that current treatment options are associated with toxicity, which can result in needing to take time off work. There is inconsistency in which treatment options are available across the country, and for some people there are no treatment options at all. Patient experts feel there is a need for more treatment options and support. The committee understood that advanced renal cell carcinoma substantially affects people's quality of life.

Treatment decisions for advanced renal cell carcinoma are often guided by risk status. Renal cell carcinoma is usually grouped into 2 categories: favourable-risk, or intermediate- and poor-risk, as defined by the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. All-risk includes all these risk statuses. Treatments for all risk groups include sunitinib, pazopanib or tivozanib. For intermediate- or poor-risk cancer, cabozantinib, nivolumab plus ipilimumab, pembrolizumab plus lenvatinib or avelumab plus axitinib (only available through the Cancer Drugs Fund) are also available. All treatments recommended for routine commissioning were included as comparators. Avelumab plus axitinib was not considered to be a relevant comparator because it is only available through the Cancer Drugs Fund. Clinical expert opinion confirmed that these treatments are all used at first line for untreated advanced renal cell carcinoma. The NHS England clinical lead for Cancer Drugs Fund (from here, the Cancer Drugs Fund lead) explained that the renal cell carcinoma treatment pathway changes all the time. Currently about 500 people per year have nivolumab plus ipilimumab, and about 600 people per year have pembrolizumab plus lenvatinib. They explained that people also have sunitinib, pazopanib, tivozanib and cabozantinib. Clinical experts explained that if recommended, cabozantinib plus nivolumab would likely displace nivolumab plus ipilimumab and pembrolizumab plus lenvatinib. Clinical experts and the Cancer Drugs Fund lead explained that combination treatments were the most appropriate comparators because they are most likely to be replaced by cabozantinib plus nivolumab. The committee concluded that in the all-risk and favourable-risk group, comparators are limited to sunitinib, pazopanib or tivozanib. But, the most appropriate comparators for the intermediate- or poor-risk subgroup were likely to be nivolumab plus ipilimumab and pembrolizumab plus lenvatinib.

The main source of evidence for cabozantinib plus nivolumab for renal cell carcinoma was CheckMate 9ER, a single-blind randomised controlled trial comparing cabozantinib plus nivolumab with sunitinib. There were 651 people from all risk groups enrolled in the trial, which had a final median follow up of 44 months. Cabozantinib plus nivolumab had a median overall survival of 49.48 months compared with 35.52 months for sunitinib (hazard ratio 0.7 [95% confidence interval (CI) 0.56 to 0.87]). Median progression-free survival was 16.6 months compared with 8.4 months for sunitinib (hazard ratio 0.59 [95% CI 0.49 to 0.71]). The evidence suggested that cabozantinib plus nivolumab slows progression and lengthens life for people with renal cell carcinoma when compared with sunitinib. There are no further data cuts planned for CheckMate 9ER. The committee concluded that CheckMate 9ER suggests that cabozantinib plus nivolumab is clinically effective compared with sunitinib when assessed across all risk groups.

The EAG explained there may be differences in cabozantinib plus nivolumab's effectiveness compared with sunitinib in the favourable-risk or intermediate- and poor-risk subgroups. CheckMate 9ER stratified people by risk score. About three quarters were in the intermediate- and poor-risk subgroup and one quarter in the favourable-risk subgroup. Clinical experts explained that about 80% of people with renal cell carcinoma in the UK have intermediate- or poor-risk cancer, and that this distribution is also seen globally. For the favourable-risk subgroup, median overall survival had not been reached with cabozantinib plus nivolumab and was 47.6 months for sunitinib (hazard ratio 1.07 [95% CI 0.63 to 1.79]). Median progression-free survival was 21.4 months for cabozantinib plus nivolumab compared with 13.9 months for sunitinib (hazard ratio 0.72 [95% CI 0.49 to 1.05]). When considering the intermediate- and poor-risk subgroup, cabozantinib plus nivolumab had a median overall survival of 49.5 months compared with 29.2 months for sunitinib (hazard ratio: 0.65 [95% CI 0.51 to 0.83]) and a median progression-free survival of 15.6 months compared with 7.1 months for sunitinib (hazard ratio 0.56 [95% CI 0.46 to 0.69]). The committee discussed how, while the effect was numerically better in the intermediate- and poor-risk subgroup compared with the favourable-risk subgroup, these differences were not conclusive. The company reiterated that cabozantinib plus nivolumab is best assessed in an all-risk population. The company explained that, while cabozantinib plus nivolumab appears to have a different relative effect in the different subgroups, the trial was not powered to detect a statistical difference between the treatments in the subgroups. So, any comparison of treatment effects across subgroups should be interpreted with caution. The committee explained that some other clinical trials for renal cell carcinoma have also shown numerical differences in treatment effect between risk subgroups. It also explained how risk subgroups have been considered in previous NICE recommendations and how the treatment pathway differs by risk subgroup, with different treatments available dependent on risk status. The committee concluded that cabozantinib plus nivolumab appears to slow progression compared with sunitinib in both the favourable-risk subgroup and the intermediate- and poor-risk subgroup. The committee noted that, even if a treatment has the same relative effect across risk groups, the overall benefit might be different between risk groups because of a different underlying prognosis. The committee thought there was no compelling evidence that the relative treatment effect was different in different risk groups. The committee explained that another analysis applying the all-risk effect to each risk subgroup might reduce uncertainty. The committee concluded that, in general, investigating subgroups by risk status was appropriate, and necessary to compare cabozantinib plus nivolumab with the most appropriate comparators and account for underlying differences between subgroups.