The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of nintedanib plus docetaxel, having considered evidence on the nature of non‑small‑cell lung cancer and the value placed on the benefits of nintedanib plus docetaxel by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.
The Committee heard from the clinical and patient experts about the nature of locally advanced, metastatic and locally recurrent non‑small‑cell lung cancer that has progressed after chemotherapy. The Committee heard that the symptoms from non‑small‑cell lung cancer can be debilitating, and many symptoms such as breathlessness are difficult to manage. It understood that the prognosis for patients with non‑small‑cell lung cancer is poor, and heard from the clinical and patient experts that only about half of people with non‑small‑cell lung cancer that has progressed after chemotherapy have good general health, and very few of these people have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 (fully active) or 1 (restricted in strenuous activity, but ambulatory). The Committee also heard that treatment options currently available to people whose disease has progressed after chemotherapy are limited to docetaxel and erlotinib, neither of which has a substantial impact on survival. The clinical and patient experts emphasised that any extension to survival and improvement in quality of life are important for people with non‑small‑cell‑lung cancer and their families. The Committee recognised the importance of having effective and tolerable treatment options for people with non‑small‑cell lung cancer that has progressed after chemotherapy.
The Committee considered the clinical pathway for people with non‑small‑cell lung cancer. The Committee was aware that the presence of epidermal growth factor receptor (EGFR)‑tyrosine kinase (TK) mutation in the tumour influences prognosis and determines treatment choice in first‑ and second‑line settings. It understood that most EGFR‑TK mutation positive non‑small‑cell lung cancer is treated with an EGFR‑TK inhibitor as first‑line treatment (in line with NICE's technology appraisal guidance on gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer and erlotinib for the first-line treatment of locally advanced or metastatic EGFR-TK mutation-positive non-small-cell lung cancer), followed by either erlotinib (in line with NICE's technology appraisal guidance on erlotinib for the treatment of non-small-cell lung cancer [now replaced by NICE's technology appraisal guidance on erlotinib and gefitinib for treating non-small-cell lung cancer that has progressed after prior chemotherapy]) or docetaxel (in line with NICE's guideline on lung cancer [now replaced by NICE's guideline on lung cancer: diagnosis and management]) if the disease has progressed after chemotherapy. It also understood that EGFR‑TK negative mutation non‑small‑cell lung cancer is treated with either pemetrexed (in line with NICE's technology appraisal guidance on pemetrexed for the first-line treatment of non-small-cell lung cancer) or docetaxel (in line with NICE's guideline on lung cancer [now replaced by NICE's guideline on lung cancer: diagnosis and management]) followed by either docetaxel or erlotinib (in line with NICE's technology appraisal guidance on erlotinib for the treatment of non-small-cell lung cancer [now replaced by NICE's technology appraisal guidance on erlotinib and gefitinib for treating non-small-cell lung cancer that has progressed after prior chemotherapy]) if disease has progressed after chemotherapy. The Committee was aware that the mechanism of action of nintedanib is independent of EGFR‑TK mutation status, and therefore noted that either erlotinib or docetaxel might, in principle, be considered as comparators to nintedanib. The Committee heard from the clinical expert that, until recently, erlotinib and docetaxel were considered to be equally effective but that erlotinib has a more favourable side‑effect profile. However, the clinical expert explained that clinical practice has changed since the publication of NICE's technology appraisal guidance on erlotinib for the treatment of non-small-cell lung cancer (now replaced by NICE's technology appraisal guidance on erlotinib and gefitinib for treating non-small-cell lung cancer that has progressed after prior chemotherapy): now, people considered to be fit (ECOG performance score of 0 or 1) are offered docetaxel as a second‑line treatment, while those with poor fitness (an ECOG status of 2) are offered erlotinib. The Committee was aware that the marketing authorisation for nintedanib specifies giving it with docetaxel, and agreed that most people likely to be offered nintedanib have similar patient characteristics to those offered docetaxel, such as ECOG performance status of 0 or 1 and having had first‑line treatment. The clinical expert explained that, in clinical practice, patients might stay on nintedanib plus docetaxel even after disease progression if symptoms are controlled. However, the Committee was aware that this differed from the protocol of the LUME‑Lung 1 trial on which the clinical evidence is based, and agreed with a comment from NHS England received during consultation stating that nintedanib treatment should be stopped at disease progression. The Committee also agreed that most people treated with erlotinib second line would differ from people treated with nintedanib plus docetaxel in terms of ECOG performance status and first‑line treatments. The Committee concluded that docetaxel alone was the only appropriate comparator to nintedanib plus docetaxel, and that it would not need to consider any comparison of nintedanib plus docetaxel with erlotinib.
The Committee considered the clinical‑effectiveness data from the LUME‑Lung 1 trial comparing nintedanib plus docetaxel with docetaxel alone, which formed the basis of the clinical‑effectiveness evidence in the company's submission. The Committee noted that the LUME‑Lung 1 trial was a good quality trial, that patients remained on treatment until disease progression, that the study remained unblinded between analysing the primary outcome of progression‑free survival and the secondary outcome of overall survival, and that treatment crossover was not permitted. The Committee discussed the Evidence Review Group (ERG)'s concerns about the generalisability of the results to clinical practice in England (see section 3.27). The Committee was aware that patients with cavitary or necrotic tumours were more likely to have squamous cell lung cancer rather than adenocarcinoma, and are not included in this appraisal. The Committee also heard from the clinical expert that patients with adenocarcinoma are generally not treated with anticoagulants other than low molecular weight heparin, and would only receive 75 mg aspirin per day, meaning that these exclusion criteria were unlikely to affect the generalisability of the trial. The Committee noted the ERG's concerns and the clinical expert comments that the population in the trial was generally younger than those seen in clinical practice, where the average age is over 65 years. The Committee noted comments received in consultation stating that the marketing authorisation for nintedanib is in combination with docetaxel. It also noted that, because patients must be able to tolerate docetaxel treatment, the population to be treated with nintedanib is younger and fitter than all people with non‑small‑cell lung cancer waiting for second‑line therapy who are seen in clinical practice in England, and is therefore similar to the trial population. The Committee agreed that the trial was not generalisable to all patients with adenocarcinoma whose disease had progressed after chemotherapy or for patients with an ECOG score of 2, but it was generalisable to patients offered docetaxel monotherapy as second‑line treatment, such as those with an ECOG status of 0 and 1. The Committee also discussed the ERG's concerns about the LUME‑Lung 1 trial protocol allowing unlimited docetaxel treatment, with the maximum number of docetaxel cycles being 41 cycles. The clinical expert explained that, in clinical practice in England, patients would generally have 4 cycles of docetaxel, because a higher number of cycles would produce unacceptable adverse effects, although rarely some may have up to 6 cycles. The Committee concluded that the results from the LUME‑Lung 1 trial were relevant and generalisable to most, but not all, patients in routine clinical practice in England.
The Committee considered the results of the LUME‑Lung 1 trial. It noted that the company presented results for the overall trial population (n=1,314) and also for a subgroup (658 of the total trial population) with adenocarcinoma, which had not been a pre‑specified subgroup. However, nintedanib plus docetaxel has a marketing authorisation only for treating adenocarcinoma, and not for other histological subtypes. The Committee, however, accepted that adenocarcinoma constituted most cases of non‑squamous carcinoma, a pre‑specified subgroup in the LUME‑Lung 1 trial (658 of 759 patients). The Committee would have preferred adenocarcinoma to have been a stratification factor. However, it accepted that the efficacy data from the subgroup with adenocarcinoma were the most relevant for decision‑making because this was the population that was specified in the marketing authorisation for nintedanib.
The Committee considered the clinical effectiveness of nintedanib plus docetaxel compared with docetaxel alone for treating people with adenocarcinoma. The Committee was aware at the first meeting that, based on the final analysis after a median follow‑up of approximately 32 months, the gain in median progression‑free survival was 1.4 months and the gain in median overall survival was 2.3 months. The Committee considered that a difference in median overall survival of 2.3 months reflected a statistically significant effect but agreed that this was a clinically small benefit. The Committee noted that the data from the trial were mature, meaning that most people had died and all people had experienced disease progression but that, for the mean values to be calculated with certainty, all patients would have to have died. The Committee noted that, following consultation and in response to its question during the first meeting, the company provided the restricted mean difference in overall survival, which was 2.87 months (see section 3.50) and that the mean overall survival would likely be greater than this (see section 4.19). The Committee concluded that nintedanib plus docetaxel was more effective than docetaxel alone in people with adenocarcinoma whose disease has progressed after chemotherapy.
The Committee discussed concerns about safety and adverse effects associated with nintedanib plus docetaxel. It heard from the clinical and patient experts that most of the adverse events associated with nintedanib plus docetaxel were related to docetaxel rather than nintedanib. The clinical and patient experts highlighted that patients are willing to tolerate adverse events associated with nintedanib, such as diarrhoea, because of the added benefit from nintedanib. The Committee noted that there was an increase in the number of deaths associated with nintedanib plus docetaxel compared with docetaxel alone. The Committee accepted the company's explanation that the deaths in the nintedanib plus docetaxel treatment arm of the trial, although attributed to nintedanib, resulted instead from patients' underlying comorbidities. The Committee was aware that, overall, fewer patients treated with nintedanib plus docetaxel died than those treated with docetaxel alone. The Committee concluded that current evidence suggests that nintedanib plus docetaxel has an acceptable safety profile compared with docetaxel alone and that patients are willing to tolerate the adverse effects.
The Committee considered the structure of the model submitted by the company and whether it captured the natural history of adenocarcinoma of the lung. The Committee agreed that the company had structured the model well, and that it was similar to other economic models submitted to NICE for the same disease area and that the 15‑year time horizon was appropriate for this disease. The Committee noted that the company had used utility values in its model that had been obtained from EQ‑5D data collected during the LUME‑Lung 1 trial in line with the NICE reference case. The Committee concluded that the structure of the model was acceptable for assessing the cost effectiveness of nintedanib plus docetaxel.
The Committee discussed how the company extrapolated overall survival in the original model by fitting parametric curves to the data and the ERG's critique of this. The Committee observed that the Kaplan–Meier curves for progression‑free survival from the final analyses for nintedanib plus docetaxel and docetaxel alone converged after approximately 1 year into the trial (see sections 3.16 and 3.17). The ERG explained that the proportional hazards assumption (the relative risk of an event is fixed irrespective of time) is fundamental for applying a Weibull parametric curve, but is not needed for log‑normal or log‑logistic curves. The Committee understood that this means that the proportional hazards assumption cannot be applied to the nintedanib data.
The Committee then considered whether each treatment should be modelled separately or jointly using a hazard ratio for progression‑free survival and a hazard ratio for overall survival (see section 3.16). The Committee accepted that separate modelling was more appropriate than joint modelling because only separate modelling could accommodate the possibility that nintedanib might fundamentally alter the natural history of the disease.
The Committee then considered whether it was more appropriate to replace the trial data with a parametric model (as the company did in its original base case), or to use the trial data and a parametric model only for the period beyond the end of the trial. The Committee was aware of 2 divergent views: that modelled data might be more generalisable than data from a single trial; and, that it can also be considered preferable to 'maximise' use of trial data, particularly when the data are mature. The Committee concluded from the model's residual values that the company's base‑case log‑logistic curve did not provide a good fit to the actual trial data. The Committee preferred the use of the Kaplan–Meier curves from the LUME‑Lung 1 trial for the base‑case analysis, followed by extrapolation beyond the trial data, using a similar method to the ERG. However, the Committee was aware that such an approach depends on the point at which the extrapolation starts. The Committee queried at its first meeting how sensitive the results were to the point of extrapolation, but the ERG explained that it had not done such exploratory analyses. The Committee concluded that the ERG's approach to modelling therefore also resulted in uncertainty. When looking at the original models and the extrapolated data beyond the trial period, the Committee noted that the company's overall survival curves for nintedanib plus docetaxel and docetaxel alone continued to diverge for the 15‑year time horizon, suggesting ongoing and indefinite benefit beyond the end of treatment. The Committee considered the magnitude of this benefit to be implausible, and noted that the respective curves from the ERG remained parallel after 9 to 10 years. The Committee was not persuaded that any of the overall survival projections presented in the company's original model were plausible for a population with a poor prognosis. The Committee was aware that alternative methods of modelling the data, such as piecewise modelling, may have better reflected the data. The Committee concluded, after its first meeting, that both the company's and ERG's modelling approaches led to uncertainty in the survival results.
The Committee discussed the company's original scenario analyses which used registry data to validate the parametric curves, namely the National Lung Cancer Audit Data (LUCADA) from the UK and data from the Surveillance, Epidemiology and End Result (SEER) from the USA. The Committee understood that the company took the last point of the trial data and extrapolated from it with the registry data over the remaining time horizon. The Committee heard from the company that it was unable to provide any further details of the registries other than: the LUCADA data were matched by age, sex and histology and contained information from patients in the UK, and the SEER data were matched for age, sex and race, but not for line of treatment and contained information from patients in the USA. The Committee heard that the company had access only to summarised stratified LUCADA data which it used to generate a log‑normal curve. The Committee appreciated that this approach was associated with more uncertainty than had the company used individual level data. Although the LUCADA registry data were limited because the data did not provide information on line of therapy, the Committee agreed that, of the 2 sources of registry data, LUCADA was the more appropriate to use in this appraisal.
The Committee considered the company's revised economic analyses for this appraisal including the Committee's preferred approach to overall survival modelling – using the Kaplan–Meier data from the trial and extrapolating with the LUCADA registry data (see section 3.47).
Regarding cut‑off points: the Committee was concerned that the company and the ERG arbitrarily chose cut‑off points from which to start extrapolating. The Committee heard that the ERG prefers its own method as the basis of the cut‑off (that is, using the point at which both treatments have the same probability of survival, which occurred at different times during follow‑up) because the ERG's method takes censoring into account. In addition, the ERG further informed the Committee that this point balances 'the maximum use of direct Kaplan–Meier data whilst reducing as far as possible the inevitable uncertainty from the small numbers of survivors towards the end of the trial'.
Regarding modelling both treatments using the same data during extrapolation: the Committee heard from the ERG that this assumption was 'conservative' because it could not account for the possibility that nintedanib modifies disease, and that disease progression may differ between patients who have, or have not, received nintedanib. The Committee heard from the ERG that the cumulative hazards, for both overall survival and post‑progression survival, suggest that this is a possibility.
Regarding approaches to modelling: the Committee was aware that the company and ERG could have used other modelling approaches, such as piecewise modelling, including identifying the shape of the Kaplan–Meier curve, which is most likely to reflect subsequent mortality, or extrapolating from a point based on a biologically‑plausible hypothesis. The Committee was also aware that using individual patient level data from LUCADA, even with a different parametric model, would not address the modelling uncertainties or take into account the disease modification suggested by the trial data.
The company explained that it had carried out sensitivity analyses varying the risk of mortality from the LUCADA data and that the incremental cost effectiveness ratio (ICER) was not sensitive to such changes. The Committee accepted the ERG's rationale for its approach to defining a cut off point. It also accepted that assuming the same hazard in the extrapolation period for both the nintedanib and docetaxel arm may underestimate the treatment effect of nintedanib .The Committee concluded that both the company and the ERG used plausible methods, that other methods exist, and that it is not possible to establish 1 correct extrapolation method.
The Committee discussed how health‑related quality of life was incorporated into the economic model, noting that the ICER was sensitive to the utility values used. The Committee appreciated that the company had used EQ‑5D values derived directly from the LUME‑Lung 1 trial in its base‑case analysis for progression‑free survival and progressed disease. The Committee was concerned that the progressed‑disease utility value was not much lower than those for progression‑free disease, which may be because utility was measured early in the course of the progressed‑disease health state. The Committee noted that the company had also used alternative utility values published by Chouaid et al. (2013) in its sensitivity analyses, which had a higher utility value for progression‑free survival and a much lower utility value for progressed disease than those taken from the LUME‑Lung 1 trial. The Committee agreed that these alternative utility values were extreme and improbable values. The Committee appreciated that the utility values used in the base‑case analysis, being EQ‑5D values based on a trial, were in line with the recommendations of the NICE guide to the methods of technology appraisal 2013. The Committee acknowledged that the utility value from the LUME‑Lung 1 trial overestimated the average value throughout the course of progressed disease because it was measured early in the disease state. However, the Committee was aware that the company had carried out sensitivity analyses which were overly pessimistic because the analyses used third‑ or fourth‑line utility values, which were considerably lower than the second‑line utility values in the Chouaid et al. (2013) study. However, the Committee acknowledged that using a lower utility value than that in the company's base case would lead to a higher ICER for nintedanib plus docetaxel compared with docetaxel alone. The Committee concluded that a lower utility value than in the base case would be more appropriate for the progressed disease state in this appraisal, but higher than used in the company's sensitivity analysis.
The Committee discussed the costs of the adverse events in the company's economic model, and particularly the figure of £2,012.10 to treat febrile neutropenia. The ERG explained that this was substantially lower than the costs used in previous appraisals (review of TA162 and TA175) of more than £5,000 when adjusted for inflation to current costs. The Committee heard from the clinical expert that this figure seemed high and that a range of £2,000 to £3,000 was reasonable. The Committee noted that the company had not amended the cost of febrile neutropenia in its revised analyses (see section 3.47). The company explained that the values used in its models were within the range that the clinical experts consider reasonable and that the ICER was not particularly sensitive to the cost of febrile neutropenia. Therefore, the Committee concluded that it would not pursue any further the cost included in the model of a patient being treated for febrile neutropenia.
The Committee discussed the use and cost of docetaxel in clinical practice in England. It heard from the clinical expert that patients normally have up to 4 cycles of docetaxel and occasionally up to 6 cycles, but very rarely more because of the associated adverse events. In the LUME‑Lung 1 trial, and therefore in the company's model, patients were able to have up to 41 cycles of docetaxel. The Committee noted that the ERG did exploratory analyses in which it restricted the number of docetaxel cycles to 4. The Committee was aware this would reduce the costs of docetaxel in both treatment groups. However, the Committee noted that the ERG could not determine what effect reducing the number of docetaxel cycles would have on the adverse events profile, patient prognosis and the resulting effects on costs and quality of life. The Committee concluded that some uncertainty exists as to the effect of a reduction in docetaxel cycles.
The Committee considered the results from the company's revised base‑case analyses (see section 3.47) and the ERG's sensitivity analyses (see sections 3.52 and 3.53). The Committee noted that the company's revised analyses resulted in an ICER of £46,580 per quality‑adjusted life year (QALY) gained for nintedanib plus docetaxel compared with docetaxel alone, and that the ERG's updated base‑case ICER was £56,804 per QALY gained (see section 3.47and 3.53). The Committee concluded that, because of the issues related to utility values and uncertainties around the overall survival modelling, the most plausible ICER would lie between the company's and the ERG's estimates. However, it also concluded that the most plausible ICER was likely to be closer to the company's estimate, in part, because the ERG's extrapolation methods led to an estimated mean overall survival benefit lower than the restricted mean from the trial. The Committee therefore concluded that the ICER for nintedanib plus docetaxel compared with docetaxel alone was below £50,000 per QALY gained.
The Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:
The treatment is indicated for patients with a short life expectancy, normally less than 24 months.
There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months compared with current NHS treatments.
The treatment is licensed or otherwise indicated for small patient populations.
In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust.
The Committee heard from the clinical and patient experts that the life expectancy of patients needing second‑line treatment for non‑small‑cell lung cancer was shorter than 2 years and accepted that the criterion of short life expectancy was met. The Committee accepted the company's estimate that the total population was less than 800 patients. The Committee discussed whether the evidence was sufficient to show that nintedanib plus docetaxel offered an additional 3 months compared with current NHS treatment (that is, docetaxel). The Committee concluded that the ERG's updated base case for a mean extension to life of 2.69 months was implausible, because this was lower than the trial restricted mean of 2.87 months, provided by the company in response to consultation. Considering that the estimates modelled in the company's sensitivity analyses for the mean extension to life without using the most optimistic assumptions ranged between 3.00 months and 4.08 months, the Committee agreed that an extension of greater than 3 months was probable. The Committee concluded that nintedanib plus docetaxel fulfilled the NICE supplementary advice criteria to be considered as a life‑extending, end‑of‑life treatment. It further concluded that the weight placed on the QALYs gained was appropriate for nintedanib plus docetaxel and that nintedanib could be considered a cost‑effective use of NHS resources for previously treated, locally advanced, metastatic or locally recurrent non‑small‑cell lung cancer.
The Committee discussed whether nintedanib was innovative in its potential to make a significant and substantial impact on health‑related benefits. It heard from the patient expert that patients consider nintedanib to be innovative. It also heard from the clinical and patient experts that there were few options for treating patients with non‑small‑cell lung cancer who need second‑line treatment and that nintedanib would provide another option. The Committee agreed that nintedanib appeared to be pharmacologically innovative in its mechanism by appearing to provide benefits beyond progression, but that just having an extra treatment option for non‑small‑cell lung cancer did not mean that nintedanib was innovative. It concluded that there were no additional gains in health‑related quality of life over those already included in the QALY calculations.
The Committee noted a potential equality issue raised during the scoping workshop. A workshop attendee suggested that the LUME‑Lung 1 trial excluded patients whose disease progressed after maintenance therapy, but that some patients now have maintenance therapy after first‑line induction therapy. The marketing authorisation wording implies that this group is included: 'in combination with docetaxel for adult patients with locally advanced, metastatic or locally recurrent non‑small‑cell lung cancer (NSCLC) of adenocarcinoma tumour histology after first‑line chemotherapy'. The Committee was aware that people who have maintenance therapy are not a 'protected group' according to the equality legislation, and that there is no trial evidence for the effectiveness of nintedanib in this group. Therefore, it concluded that it is unclear whether this group would benefit from nintedanib plus docetaxel and agreed that this did not present an equality issue.
The Appraisal Committee considered whether it should take into account the consequences of PPRS 2014, and in particular the PPRS Payment Mechanism, when appraising nintedanib. The Appraisal Committee noted NICE's position statement in this regard, and 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 with regard to the relevance of the PPRS to this appraisal of nintedanib. It therefore concluded that the PPRS Payment Mechanism was irrelevant for the consideration of cost effectiveness of nintedanib.