Avelumab with axitinib for untreated advanced renal cell carcinoma

3.1 First-line treatment options in clinical practice for people with advanced renal cell carcinoma include pazopanib, sunitinib, tivozanib and, for people with disease classified as intermediate or poor risk, cabozantinib. Nivolumab with ipilimumab and pembrolizumab with axitinib cannot be comparators in this appraisal because they are not established clinical practice. Nivolumab with ipilimumab is recommended through the Cancer Drugs Fund (and so is not routinely commissioned) and pembrolizumab with axitinib is being appraised by NICE. Later-line treatments include axitinib alone, nivolumab, cabozantinib, lenvatinib with everolimus, and everolimus alone.

3.2 The Cancer Drugs Fund clinical lead and the clinical experts explained that, if people were to have first-line treatment with avelumab (a checkpoint inhibitor) plus axitinib (a tyrosine kinase inhibitor), they would not be eligible in the NHS for nivolumab (another checkpoint inhibitor) or axitinib monotherapy later in the treatment pathway. The committee noted that any disease model should reflect this, but the current model does not. The clinical experts also explained that they would value being able to offer the most effective treatments at first line. The Cancer Drugs Fund clinical lead and the clinical experts stated that, if patients have avelumab plus axitinib first line, there would be interest from patients and clinicians in using current first-line treatments such as sunitinib in the second-line setting. The committee concluded that patients and clinicians should have the opportunity to choose between the most effective treatment options as early in the pathway as possible, and that the modelled treatment pathway should reflect both the costs and benefits of NHS care.

3.3 The companies presented evidence from JAVELIN Renal 101, a phase 3 randomised controlled trial of avelumab plus axitinib (442 patients) compared with sunitinib (444 patients) in advanced renal cell carcinoma. The original primary objective was to show the superiority of avelumab plus axitinib in prolonging progression-free survival in all patients in the trial. However, the investigators amended the protocol during the trial. The primary objective was changed to show superiority either on progression-free or overall survival in a subpopulation (that is, people with PD‑L1 positive tumours). The companies stated that this had changed because results from other trials suggested that avelumab plus axitinib may improve overall survival in the PD‑L1 subpopulation, and it improved effectiveness compared with the subpopulation whose tumours do not express PD‑L1. However, the European Medicines Agency ultimately granted the licence for the whole population. The clinical experts explained that NHS clinicians do not measure PD‑L1 in renal cell carcinoma. The committee was satisfied that it could take the results of the main population into account in its decision making.

3.4 The companies explained that the first interim analysis of JAVELIN Renal 101 showed a benefit for progression-free survival of avelumab plus axitinib over sunitinib, and that the companies continued the trial to evaluate overall survival. The companies submitted 2 data cuts from the trial: interim analysis 1 (June 2018) and interim analysis 2 (January 2019). The committee noted that avelumab plus axitinib was more effective in improving progression-free survival compared with sunitinib at the first interim analysis (hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.56 to 0.84). The committee also noted that the results for overall survival from JAVELIN Renal 101 were immature (fewer than half of the 535 deaths needed for the planned final analysis had occurred at the January 2019 data cut) and the results showed a hazard ratio of 0.80 (95% CI 0.62 to 1.03). The clinical experts explained that people are likely to live longer if they take avelumab plus axitinib, which combines an immune-oncology drug (avelumab) and a tyrosine kinase inhibitor (axitinib), than if they take only a tyrosine kinase inhibitor (sunitinib). The committee concluded that avelumab plus axitinib prolongs progression-free survival compared with sunitinib. However, it added that the companies' immature data meant that uncertainty remained about whether avelumab plus axitinib prolongs overall survival compared with sunitinib and, if so, by how much

3.5 Given the absence of mature trial data for overall survival, the committee considered whether there were other data to inform effectiveness over time:

3.6 The committee highlighted that a weight-based dose for avelumab was used in JAVELIN Renal 101, whereas the licence specifies a fixed dose. The companies explained that they derived the fixed dose using pharmacokinetic and pharmacodynamic data, and taking into account similar approaches used historically. The Cancer Drugs Fund clinical lead advised that this approach was taken with other drugs for this disease area. The committee was aware that it could appraise drugs only within their marketing authorisation. It accepted that the licensed fixed dose would have similar effectiveness to the weight-based dose, and concluded that it would use the licensed dose in making decisions.

3.7 The committee noted that most patients in JAVELIN Renal 101 had clear-cell disease, but in NHS practice some have non-clear-cell disease. The clinical experts stated that there is no evidence that the results in people with cancers characterised by clear-cell histology would be generalisable (or not) to people with disease characterised by non-clear-cell histology. Therefore, there might be an argument to limit avelumab plus axitinib to people with clear-cell disease only. However, the clinical experts noted, and the committee agreed, that the situation is similar with other first-line treatments for advanced renal cell carcinoma. The committee agreed that this was an area in need of further research. It suggested that data should be collated by histology in the Cancer Drugs Fund, to monitor whether there is a difference in effectiveness.

3.8 There are no head-to-head trials of avelumab plus axitinib compared with tivozanib, pazopanib or cabozantinib. The companies therefore indirectly compared avelumab plus axitinib with these comparators by network meta-analyses for progression-free and overall survival. The companies constructed networks for:

3.9 There were several issues with using the network meta-analyses to compare avelumab plus axitinib with tivozanib:

3.10 The companies stated that some of the trial results in the networks appeared to violate the assumption of proportional hazards. They therefore did 2 sets of network meta-analyses. One set was a standard Bayesian network meta-analysis, which assumed proportional hazards. The output of this was a hazard ratio for avelumab plus axitinib compared with each comparator in the scope. In the other set, the companies did not assume proportional hazards. Instead, parametric curves were fitted to data from each treatment arm of each trial in the network to estimate time-varying treatment effects. This generated estimates of the probabilities of progression-free and overall survival at 1, 2 and 10 years for each treatment in the model. The companies chose the latter approach for their base case. The ERG was satisfied with the methods and rationale for both approaches. It noted that it was useful to see both approaches, as 1 generates a hazard ratio and the other a parametric curve over time. However, the ERG outlined that the concerns it had already highlighted with the network meta-analysis (see section 3.9) applied to both approaches. The committee concluded that methodological concerns and the immature data informing the model made these results uncertain.

3.11 The companies used a partitioned-survival economic model that included 3 health states: pre-progression, post-progression and death. Patients could have first-line treatment with avelumab plus axitinib, sunitinib, pazopanib or tivozanib. The population with intermediate and poor risk could have avelumab plus axitinib or cabozantinib. If disease progressed, patients could move on to several other subsequent treatments, depending on which treatment they had first line. The committee concluded that the model type was appropriate and consistent with the approach used in other appraisals for renal cell carcinoma.

3.12 In JAVELIN Renal 101, people in both treatment arms could have nivolumab after disease progression on first-line treatment. The committee noted that this differed from NHS practice in which only people having sunitinib would be eligible to have second-line nivolumab or axitinib in NHS practice. The committee appreciated that the results of JAVELIN Renal 101 reflected the effect of treatments offered second line and beyond (see section 3.1). The companies stated that this had biased the trial results against avelumab plus axitinib because a substantially higher proportion of patients had nivolumab in the sunitinib arm than in the avelumab plus axitinib arm. The companies also claimed that the proportion of patients in the trial having nivolumab after disease progression on sunitinib was higher than would be expected in NHS practice. To explore the effect of this, the companies adjusted the trial results using the rank preserving structural failure time method. The committee noted that the companies did not provide details of this method or the assumptions needed for it. Also, they did not justify their choice of this method over others. The committee was aware that, in the NHS, some patients would be expected to have nivolumab after sunitinib, whereas no patients would be expected to have nivolumab after avelumab plus axitinib. Therefore, the companies' adjustment was not appropriate. The committee concluded that it would have preferred to see the companies adjusting for any life-extending follow-on treatments offered in the trial that would not form part of a routine NHS treatment pathway, using an appropriate adjustment method.

3.13 The companies applied the costs of subsequent treatments using a one-off cost, which depended on the treatment offered first line. For avelumab plus axitinib, and for sunitinib, the treatment patients had in the model was estimated from the subsequent treatments given in the relevant treatment arm in JAVELIN Renal 101. All other first-line treatments in the model were assumed to be the same as sunitinib. The committee recognised that it was important to know all the treatments offered in the trial that are proven to extend life, but are not routinely commissioned in the NHS. However, the companies' model accounted only for the subsequent treatments taken by more than 10 people in either treatment arm of JAVELIN Renal 101. These treatments were cabozantinib, everolimus, axitinib, sunitinib, nivolumab, lenvatinib plus everolimus, and pazopanib. The companies confirmed that the trial had included some treatments that are not available in the NHS, such as durvalumab. As discussed (see section 3.12), a small proportion of patients in the model having avelumab plus axitinib went on to have other checkpoint inhibitors or axitinib after progression. The committee noted that although this likely had little effect on the cost-effectiveness estimates, given the small proportion of patients, it did not reflect clinical practice in England. The committee agreed that it would have liked to have seen base-case modelling that adjusted the trial data to reflect both the effects and costs of subsequent treatments offered in NHS practice.

3.14 In the economic model, the companies used parametric distributions to extrapolate the data on overall survival from JAVELIN Renal 101. The committee noted several uncertainties with modelled overall survival:

3.15 The companies based the cost-effectiveness estimates on the results from the June 2018 data cut, even though they had presented clinical results using the January 2019 data cut. The companies stated that this was because the first data cut was:

3.16 In the economic model, the companies originally assumed that clinicians stop treatment with avelumab plus axitinib after 2 years of treatment, whether or not a patient's disease has progressed. After this, and despite stopping treatment, the companies assumed that:

3.17 Related to the stopping rule, the companies assumed that two-thirds of patients who stopped treatment would have a treatment benefit over their lifetimes, and one-third would have waning of the treatment effect (that is, over 2 years, the effect of treatment would decrease to that of the comparator). The ERG presented scenarios exploring the effect of removing the treatment waning effect (that is, all patients maintained a full treatment effect in the absence of treatment). However, the committee was not clear how the ERG had implemented removing the treatment waning effect and the stopping rule (see section 3.15). The committee concluded that there was no evidence to support what proportion of patients would have a long-term treatment effect after stopping treatment. Therefore, the modelling should have accounted for a range of potential options, including the potential for no patients to have a long-term treatment effect after stopping treatment. At the second meeting, the committee was aware that the companies had removed the stopping rule, so the model now excluded treatment waning (that is, because treatment now continued in the model, there was no need to apply assumptions around what happens to the treatment effect after stopping treatment at a set time period, rather than for adverse events or progression). The committee agreed this was appropriate.

3.18 The cost-effectiveness results are commercial in confidence and cannot be reported here. The committee agreed that some of the original assumptions in the companies' base-case model were implausible. The committee went on to review the exploratory scenarios presented by the ERG, some (but not all) of which had used some of the committee's preferred assumptions:

3.19 Having concluded that avelumab plus axitinib could not be recommended for routine use, the committee then considered whether it could be recommended for treating advanced renal cell carcinoma within the Cancer Drugs Fund. It 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 noted that the key uncertainties were:

3.20 Based on the considerations in section 3.19, the committee considered that it could recommend avelumab plus axitinib for use in the Cancer Drugs Fund. The committee agreed that, at the end of the period in the Cancer Drugs Fund, when the guidance is reviewed, the updated model should include these preferred assumptions (unless new evidence indicates otherwise):

3.21 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. It recognised that the companies did not submit evidence to support avelumab plus axitinib as an end-of-life therapy. It noted that the lower confidence interval boundary of median overall survival exceeded 24 months. The committee noted the comments from the companies in their submission that, in pivotal trials of the NICE-recommended first-line monotherapies for acute renal cell carcinoma (sunitinib, pazopanib, tivozanib and cabozantinib), median overall survival ranged from 21.8 to 30.3 months. As such, avelumab plus axitinib does not meet the criteria for consideration as a life-extending treatment at the end of life for patients with acute renal cell carcinoma with favourable- to poor-risk status. The committee concluded that avelumab plus axitinib does not meet the criteria for end of life.

3.22 The clinical experts stated they considered avelumab plus axitinib to be innovative because it is the first combination of a checkpoint inhibitor plus a tyrosine kinase inhibitor licensed for use in patients with untreated advanced renal cell carcinoma. The committee considered that this does not make the treatment innovative. It also concluded that the associated benefits of treatment are likely captured in the quality-adjusted life year calculations.