Afatinib for treating epidermal growth factor receptor mutation-positive locally advanced or metastatic non-small-cell lung cancer

The ERG stated that the lack of a significant overall survival benefit with afatinib in the LUX-Lung 3 and 6 trials may have been masked by the high rates of crossover. The ERG considered Asian and non-Asian populations to be relevant subgroups. In response to the ERG request for clarification the manufacturer provided a subgroup analysis using updated data from LUX-Lung 3, which showed that Asian patients treated with chemotherapy may have a different progression-free survival and overall survival compared with non-Asian patients. The ERG undertook exploratory analyses using the manufacturer's data and noted that the mean expected post-progression survival was different for patients treated with afatinib in the Asian subgroup than in the non-Asian subgroup. The estimated mean progression-free survival in Asian patients was 19.5 months for afatinib and 8.7 months for pemetrexed plus cisplatin and in non-Asian patients was 14.8 months for afatinib and 4.7 months for pemetrexed plus cisplatin. The estimated mean overall survival in Asian patients was 37.3 months for both afatinib and pemetrexed plus cisplatin and in non-Asian patients was 31.4 months for afatinib and 25.3 months for pemetrexed plus cisplatin.

The ERG considered the population of the trials included in the mixed treatment comparison in light of evidence from the subgroup analysis of LUX-Lung 3. The subgroup analysis showed that the clinical effectiveness of afatinib differed according to family origin (Asian or non-Asian). This would also have an impact on the results of the mixed treatment comparison (which included the intention-to-treat population) which the ERG considered were not useful for decision-making. The ERG stated that the UK population is likely to be much closer in terms of characteristics and prognosis to the non-Asian subgroup than to the overall LUX-Lung 3 population who were predominantly of Asian origin.

The ERG questioned whether it was appropriate to include trials of EGFR mutation-positive populations with trials of unknown or mixed EGFR status populations in a single mixed treatment comparison. The ERG noted that there were differences in patient characteristics between studies of patients of EGFR mutation-positive NSCLC and those of unknown or mixed EGFR status in relation to the proportions of men, patients who had never smoked and patients with adenocarcinoma. The ERG also noted that the original mixed treatment comparison included patients with different histological types of NSCLC. The ERG concluded that the patient populations in the included trials were not sufficiently similar and therefore the results generated by the manufacturer's original mixed treatment comparison are not generalisable to a UK population.

During clarification the ERG requested additional sensitivity analyses on the mixed treatment comparison to assess the impact of local investigator assessments, updated overall survival data (if available), using only data from the population of patients with EGFR activating mutations for both progression-free survival and overall survival and excluding EURTAC trial data (because it included only European patients). The resulting hazard ratios (random-effects model) for the difference in median progression-free survival for afatinib compared with gefitinib were 0.50 (95% CI 0.02 to 10.72) when assessed by independent review and 0.48 (95% CI 0.03 to 9.57) when assessed by the trial investigator. The hazard ratio for the difference in median overall survival was 0.91 (95% CI 0.07 to 12.03) for afatinib compared with gefitinib. The ERG considered that the model should be populated with data from non-Asian patients to appraise the cost effectiveness of treatments for use in England; it is only appropriate to use data that have been generated from a non-Asian population of EGFR mutation-positive patients, whether in terms of primary clinical trials or supporting evidence for use in a simple indirect comparison or mixed treatment comparison. The ERG further highlighted an ongoing study (LUX-Lung 7) which directly compares afatinib and gefitinib in people with EGFR mutation-positive advanced NSCLC and is due to report in 2015.

The ERG disagreed with the approach taken by the manufacturer when fitting theoretical survival models to the LUX-Lung 3 data. The ERG did not consider that the Weibull models generated by the manufacturer for patients receiving afatinib or pemetrexed plus cisplatin accurately reflected the experience of LUX-Lung 3 patients, especially for progression-free survival which has an impact on the application of hazard ratios in the manufacturer's model. The ERG therefore considered that the progression-free survival results obtained from the Weibull model lacked credibility.

In view of the issues with the manufacturer's model, the ERG did not consider it appropriate to carry out an exploratory analysis using the manufacturer's model. The ERG specified that it was not possible to incorporate alternative survival projections into the model because it had been structured around the use of hazard ratios to generate survival estimates rather than using directly obtained estimates.

Because of the technical issues with the mixed treatment comparison, the ERG carried out an exploratory analysis to obtain an approximate estimate of the ICER for afatinib compared with combination chemotherapy. The results for the intention-to-treat population from LUX-Lung 3 showed that afatinib was associated with an ICER of £39,300 per QALY gained compared with pemetrexed plus cisplatin. The results for the non-Asian population showed that afatinib was associated with an ICER of £23,700 per QALY gained compared with pemetrexed plus cisplatin. The ERG concluded that the combination of patient access scheme pricing and use of data from the non-Asian subgroup of LUX-Lung 3 is likely to indicate that afatinib is cost effective compared with pemetrexed plus cisplatin in a predominantly white population of EGFR-positive patients.

The ERG also carried out a cost analysis of afatinib, erlotinib and gefitinib incorporating the patient access schemes which have been agreed by the Department of Health. Two separate analyses were undertaken, which differed with regards to the assumption of effectiveness. The first analysis assumed that patients experience the same overall survival hazard profile as experienced in the LUX-Lung 3 trial, but experience the individual progression-free survival hazard profile from the key clinical trial for each treatment (that is, IPASS for gefitinib, EURTAC for erlotinib and LUX-Lung 3 for afatinib). The second analysis assumed that patients experience both the same overall survival and progression-free survival hazard profiles as experienced in the LUX-Lung 3 trial, irrespective of treatment. Given the discounts of the patient access schemes for both afatinib and erlotinib are commercial in confidence, the results of the cost comparison cannot be presented here. The estimated cost per patient of gefitinib was £11,886 using the progression-free survival estimate from the IPASS trial and the same overall survival as afatinib, and £12,069 assuming the same overall survival and progression-free survival as afatinib.

Full details of all the evidence are in the manufacturer's submission and the ERG report.

The Committee discussed current clinical practice for treating EGFR mutation-positive locally advanced or metastatic NSCLC. The clinical specialists highlighted that the standard first choice of treatment for NSCLC with EGFR-positive tyrosine kinase mutations was a tyrosine kinase inhibitor, which is in line with NICE's technology appraisal guidance on erlotinib for the first-line treatment of locally advanced or metastatic EGFR-TK mutation-positive nsclc and gefitinib for the first-line treatment of locally advanced or metastatic nsclc. The Committee was also aware of evidence presented in the manufacturer's submission which stated that 99% of eligible patients receive either erlotinib or gefitinib as a first-line treatment. The Committee concluded that treatment with erlotinib and gefitinib is standard practice for most people presenting with EGFR mutation-positive locally advanced or metastatic NSCLC.

The Committee discussed the place of afatinib in the treatment pathway in relation to current clinical practice in the NHS. The Committee noted that the manufacturer's submission only presented evidence on the use of afatinib in people who have not been previously treated with a tyrosine kinase inhibitor and this was in line with afatinib's marketing authorisation. The Committee heard from the clinical specialists that if recommended, afatinib would be likely to be considered alongside erlotinib and gefitinib for locally advanced or metastatic NSCLC that had not been treated with a tyrosine kinase inhibitor. The Committee also heard from the clinical specialists that afatinib has a different adverse reaction profile from the other tyrosine kinase inhibitors, and that patients differ in their ability to tolerate different adverse reactions. They highlighted that if afatinib was recommended, it would enable clinicians to choose the tyrosine kinase inhibitor with the adverse reaction profile best suited to the individual patient. The Committee heard from clinical specialists that the irreversible binding of afatinib to the ErbB family of receptors (compared with the reversible binding of gefitinib and erlotinib) is believed to help reduce the possibility of resistance and delay its development. Therefore, the Committee concluded that erlotinib and gefitinib were appropriate comparators and that further first-line treatment options for EGFR mutation-positive locally advanced or metastatic NSCLC would be of value to clinicians and patients.

The Committee discussed the clinical effectiveness evidence, focussing on the results of the LUX-Lung 3 and 6 trials which compared afatinib with pemetrexed plus cisplatin (LUX-Lung 3) and gemcitabine plus cisplatin (LUX-Lung 6). The Committee heard from the clinical specialists that the chemotherapy doublets used in these trials were regarded as best clinical practice at the time. It noted that both trials reported a statistically significant increase in median progression-free survival with afatinib compared with chemotherapy. However, no statistically significant difference in overall survival was seen in LUX-Lung 3 or LUX-Lung 6 because the data were immature and could have been confounded by treatment crossover between the treatment and control arms in both trials. Therefore, the Committee agreed that there was sufficient evidence to conclude that afatinib was clinically effective in prolonging progression-free survival but because of the immaturity of the overall survival data available, there was uncertainty about whether treatment with afatinib resulted in an overall survival benefit compared with chemotherapy.

The Committee considered the pre-specified subgroup analyses of the LUX–Lung 3 progression-free survival data for baseline characteristics such as gender, age, family origin and common EGFR mutations, presented by the manufacturer in response to a request from the ERG for clarification. These analyses suggested there was no statistically significant difference in progression-free survival for any subgroup with the exception of common EGFR mutations compared with other EGFR mutations. The manufacturer's exploratory data (see section 3.21) suggested that people of Asian family origin may have a better progression-free survival than non-Asian patients. The Committee also noted that approximately one third of patients in LUX-Lung 3 were non-Asian, which represented a small number of patients and that the trial was underpowered to detect differences in progression-free survival based on ethnicity. The Committee noted that the results of a statistical test presented by the manufacturer for interaction between family origin and treatment effect were not statistically significant. However, the Committee also noted that the ERG analysis of cumulative mortality hazard in LUX-Lung 3 showed large differences in progression-free survival between the Asian and non-Asian populations both in the control and treatment arms of the trials, indicating that ethnicity may impact on the effectiveness of treatment.

The Committee considered whether there was any biologically plausible reason why the effectiveness of afatinib would differ according to a person's family origin. The clinical specialists stated that based on their limited use of afatinib in small numbers of patients in England, there were no physiological differences between Asian and non-Asian patients that would explain the apparent differences in the effectiveness of afatinib. They emphasised that differences in the effectiveness of afatinib in NSCLC are more likely to be determined by EGFR mutation status rather than ethnicity; patients who are EGFR mutation-positive have similar response rates regardless of ethnic background. The Committee heard from the clinical specialists that the differences in the outcomes between the Asian and non-Asian population may be explained by the different standard of care and drug regimens used at trial centres in Asian compared with non-Asian countries, some of which may be more clinically effective than other regimens. Therefore, the Committee concluded that although there was uncertainty about the underlying reason, on balance the ERG analysis showed that ethnicity had an impact on the effectiveness of afatinib, and that the effectiveness of afatinib in clinical practice in England would be best represented by clinical effectiveness data in a non-Asian group.

The Committee considered the evidence presented on the relative clinical effectiveness of afatinib compared with erlotinib and gefitinib. The Committee noted comments from the clinical specialists that the comparator chemotherapy regimen used in the LUX-Lung 3 trial, namely pemetrexed plus cisplatin, was considered to be more effective than the comparator chemotherapy regimens used in the erlotinib and gefitinib trials. The Committee noted that because there were no head-to-head trials comparing the clinical effectiveness of afatinib with erlotinib and gefitinib, the manufacturer presented a network meta-analysis (see sections 3.6 to 3.9). The Committee considered the methodology of the manufacturer's network mixed treatment comparison and the critique by the ERG. The Committee considered the ERG comments that in all 7 studies that included EGFR mutation-positive patients, the overall survival curves of the treatment arms cross. This indicated that the proportional hazards assumption had not been met, that is, the relative treatment effects captured by the hazard ratios were not constant across all time points. The Committee acknowledged that if the proportional hazards assumption was violated then using hazard ratios to form a network meta-analysis is not appropriate. It also heard from the ERG that although the manufacturer's original extrapolation of progression-free survival included in the economic model matched the trial data, ERG analysis of the Weibull models generated by the manufacturer to represent survival for patients receiving afatinib or pemetrexed plus cisplatin based on non-informative censoring (when each patient has a censoring time that is statistically independent of their treatment failure time) did not accurately reflect the experience of patients in LUX-Lung 3, especially for progression-free survival. The Committee acknowledged the ERG's view that based on a visual analysis, a 2-phase exponential model was a better fit to the trial data and therefore more accurately represented survival for patients treated with afatinib compared with pemetrexed plus cisplatin over the long term. The Committee therefore concluded that the underlying methodology of the mixed treatment comparison was not sufficiently robust.

The Committee also noted that the manufacturer's original mixed treatment model included trials of patients with mixed or unknown EGFR mutation status as well as patients with EGFR mutation-positive disease. It acknowledged that this had been necessary to enable the manufacturer to join the network in the mixed treatment comparison to ensure all the tyrosine kinase inhibitors could be compared. However, the Committee noted the ERG comment that differences in patient characteristics between studies of patients of EGFR mutation-positive NSCLC and those of unknown or mixed EGFR mutation status (for example, in relation to the proportion of men, those who have never smoked and patients with adenocarcinoma) meant that the populations of the included trials were not sufficiently similar to be included in a mixed treatment comparison. The Committee considered the manufacturer's mixed treatment comparison that was limited to EGFR mutation-positive patients to be the most appropriate because it is in line with the marketing authorisation for afatinib and because of the widely accepted improved prognosis of EGFR mutation-positive patients. It noted that this analysis gave a slightly improved hazard ratio for afatinib compared with erlotinib and gefitinib. The Committee noted the statements from the manufacturer that the similarity of the results of the original and EGFR mutation-positive subgroup analysis demonstrated the robustness of the mixed treatment comparison. However, it noted that there were fewer than 50 patients included from the gefitinib trial in the EGFR mutation-positive subgroup analysis.

The Committee also noted that the mixed treatment comparison of the EGFR mutation-positive subgroup included studies of predominantly Asian populations. It considered that a mixed treatment comparison for EGFR mutation-positive patients of non-Asian ethnicity would be more clinically relevant to people with NSCLC in England, but that this had not been done. The Committee noted that the European public assessment report considered the benefits of afatinib to be 'in line with the other tyrosine kinase inhibitors' and heard from the clinical specialists that based on their limited experience with small numbers of patients, afatinib has a similar efficacy to the tyrosine kinase inhibitors erlotinib and gefitinib. The Committee concluded that evidence from the mixed treatment comparison was not sufficiently robust because of the underlying methodology (violation of the proportional hazards assumption) and because it was based on a predominantly Asian population, who were not considered generalisable to the UK. The Committee concluded that on balance afatinib is likely to have similar clinical efficacy to erlotinib and gefitinib. The Committee was also aware of the LUX-Lung 7 study (due to report in 2015) which would provide more evidence on the relative clinical effectiveness of afatinib compared with gefitinib.

The Committee considered the adverse reactions experienced by patients receiving treatment for locally advanced or metastatic EGFR mutation-positive NSCLC in the pivotal clinical trials with afatinib (LUX-Lung 3) compared with erlotinib (EURTAC) and gefitinib (IPASS). It noted that the incidence of diarrhoea and rash was considerably higher with afatinib compared with erlotinib and gefitinib. The patient expert stated that patients found adverse reactions with afatinib to be more easily tolerated than the adverse effects associated with many of the chemotherapy regimens. The Committee also heard from clinical specialists that diarrhoea is easily managed by dose reduction and drugs, which is demonstrated by the low rate of discontinuation because of diarrhoea (1.3%). The Committee further noted the conclusions of the European public assessment report that afatinib had similar toxicity to erlotinib and gefitinib. The Committee agreed that although afatinib has a higher rate of diarrhoea and rash, these were well managed in clinical practice. The Committee concluded that although afatinib has a different adverse reaction profile from erlotinib and gefitinib, overall the toxicity of the tyrosine kinase inhibitors was similar.

The Committee considered the manufacturer's base-case cost-effectiveness analysis incorporating the patient access schemes for afatinib, erlotinib and gefitinib, and the ERG critique. The Committee considered the population included in the base-case model. It noted that the population in the model (that is, people with mixed EGFR status and a combination of Asian and non-Asian patients) was not relevant to clinical practice in England (that is, EGFR mutation-positive and predominantly non-Asian). It also noted that methodological issues with the mixed treatment comparison (related to the violation of the assumption of proportional hazards and the extrapolation of progression-free survival and overall survival with afatinib) have an impact on the credibility of the economic model. The Committee considered whether it was possible to model the cost effectiveness of afatinib compared with erlotinib and gefitinib based on assumptions of the same clinical efficacy (in a similar way to that in NICE's technology appraisal guidance on erlotinib for the first-line treatment of locally advanced or metastatic EGFR-TK mutation-positive nsclc). The Committee heard from the ERG that this was not possible because the structure of the model relies on using a single survival model formulation through a network of hazard ratios (assuming that the proportional hazard assumption applies throughout). Any attempt at modifying it would involve creating a new model. The Committee concluded that methodological issues related to the assumption of proportional hazards, the extrapolation of progression-free survival and the population of the base-case model prevented the Committee from assessing the cost effectiveness of afatinib compared with erlotinib and gefitinib based on the manufacturer's model. Therefore a most plausible ICER could not be estimated.

The Committee considered the exploratory cost analysis presented by the ERG in which the average daily acquisition costs of afatinib, erlotinib and gefitinib were compared and which included the patient access schemes agreed by the Department of Health for each treatment. The Committee considered the 2 scenarios presented, firstly in which progression-free survival and overall survival were the same for all tyrosine kinase inhibitors, and secondly in which overall survival was the same but progression-free survival depended on the results of the pivotal trials. The Committee noted that the total costs, which incorporate the patient access schemes for afatinib and erlotinib have been designated as commercial in confidence and cannot be reported here. It also noted that the complexities of the patient access scheme make it difficult to assess the daily cost of gefitinib, which varies depending on the proportion of patients who stop taking gefitinib before the third pack is received. The Committee heard from the ERG that for consistency with the assumptions in the erlotinib appraisal, their analysis assumed that 5% of patients stopped taking gefitinib before the third pack and therefore did not incur any cost for gefitinib treatment. Without robust evidence on differences in the effectiveness of afatinib compared with erlotinib and gefitinib, the Committee considered the scenario based on equal progression-free survival and overall survival to be the most appropriate. It also accepted that in clinical practice the tyrosine kinase inhibitors were likely to have similar efficacy (see section 3.37). The Committee concluded that assuming progression-free survival for afatinib is equivalent to the other tyrosine kinase inhibitors, afatinib is a cost-effective use of NHS resources because it has comparable costs to erlotinib. Although the gefitinib patient access scheme makes it difficult to assess the daily acquisition cost of gefitinib, the Committee concluded that on balance afatinib was likely to have similar cost effectiveness to gefitinib. The Committee therefore concluded that afatinib could be considered an appropriate treatment alternative to erlotinib and gefitinib.

The Committee considered the exploratory analyses conducted by the ERG, which estimated the cost effectiveness of afatinib compared with cisplatin in combination with pemetrexed, based on the trial data, noting that these analyses did not account for crossover in the trial, and could therefore be considered conservative. Although the comparator used in this analysis was not included in the scope, the Committee considered that it provided reassurance that afatinib was likely to be a cost-effective use of NHS resources compared with the chemotherapy that was the gold standard at the time the trials for afatinib were designed (before the tyrosine kinase inhibitors became established practice). The Committee concluded that on balance, based on all the evidence considered, afatinib is considered to be a reasonable alternative treatment option compared with erlotinib and gefitinib, in people with locally advanced or metastatic EGFR mutation-positive NSCLC that has not been previously treated with an EGFR tyrosine kinase inhibitor or chemotherapy.

The Committee noted that most patients with locally advanced or metastatic EGFR mutation-positive NSCLC receive a tyrosine kinase inhibitor as first-line treatment. However, the clinical specialists advised that there is regional variation in the speed of EGFR testing and that it generally takes between 1 and 3 weeks to get the results. The clinical specialists also stated that a minority of patients with aggressive disease will therefore need treatment before EGFR mutation status is confirmed and will start treatment with chemotherapy (a third generation agent plus platinum) and receive a tyrosine kinase inhibitor as second-line treatment. The Committee noted that there is only limited evidence in small numbers of patients for the effectiveness of afatinib after prior chemotherapy. However, it acknowledged that the phase II LUX-Lung 2 trial suggested that afatinib is also effective when used as second-line treatment after chemotherapy. The Committee concluded that afatinib is likely to be clinically and cost effective as a second-line treatment for the minority of patients who have received chemotherapy as first-line treatment. The Committee therefore recommended afatinib as a treatment option in line with its marketing authorisation; that is, if the person has not previously had an EGFR tyrosine kinase inhibitor.

The Committee considered whether afatinib should be considered as an innovative technology, given that it is another tyrosine kinase inhibitor for the treatment of EGFR mutation-positive NSCLC. The Committee noted that afatinib irreversibly binds to the ErbB family of receptors making it different, in vitro, from the tyrosine kinase inhibitors erlotinib and gefitinib (see section 2.1). The Committee heard from the clinical specialists that there is the possibility that, because of its mechanism of action, afatinib may be less likely to be associated with the development of resistance to tyrosine kinase inhibitors. However, the Committee concluded that the clinical evidence did not suggest that the mode of action for afatinib led to any significant benefit in clinical effectiveness compared with erlotinib and gefitinib. The Committee concluded that afatinib could not be considered to show significant innovation over the other tyrosine kinase inhibitors. The Committee again acknowledged the importance of the ongoing LUX-Lung 7 trial to provide further evidence on the clinical effectiveness of afatinib compared with gefitinib.