Erlotinib and gefitinib for treating non-small-cell lung cancer that has progressed after prior chemotherapy

Erlotinib

4.6 No trials of erlotinib were identified by the Assessment Group that were solely conducted in an EGFR‑TK mutation‑positive population. Two trials were identified that reported retrospective subgroup analyses of the EGFR‑TK mutation‑positive population (BR21; TITAN). Only 1 of the 2 trials reported results for progression‑free survival. No statistically significant differences in median progression‑free survival were found for erlotinib compared with docetaxel or pemetrexed (TITAN: median progression‑free survival in months not reported, hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.13 to 3.97). No statistically significant differences in median overall survival were found for erlotinib compared with:

Gefitinib

4.7 The Assessment Group did not identify any trials of gefitinib that were conducted solely in an EGFR‑TK mutation‑positive population. Four trials were identified that retrospectively reported a subgroup analysis of the EGFR‑TK mutation‑positive population (INTEREST; ISEL; Kim et al 2012; V‑15‑32). Limited data for progression‑free survival were available. The INTEREST trial showed statistically significantly longer median progression‑free survival for patients who had gefitinib than those who had docetaxel (7 months compared with 4.1 months, HR 0.16, 95% CI 0.05 to 0.49). A smaller proportion of patients who had gefitinib experienced disease progression compared with best supportive care in the ISEL trial (11 out of 21 patients compared with 4 out of 5 patients, median progression‑free survival not reported, HR not reported).

4.8 No statistically significant differences in median overall survival were found between gefitinib and docetaxel in the INTEREST trial (14.2 months compared with 16.6 months respectively, HR 0.83, 95% CI 0.41 to 1.67). A smaller proportion of patients who had gefitinib died compared with best supportive care in the ISEL trial (7 out of 21 patients compared with 3 out of 5 patients, median overall survival not reported, HR not reported). AstraZeneca also presented the results of a post hoc analysis in a first-line trial (IPASS) that compared patients whose disease had progressed on chemotherapy (paclitaxel and carboplatin) and who had subsequent EGFR‑TK inhibitor treatment (n=83), with those who did not have subsequent EGFR‑TK inhibitor treatment (n=46). Median overall survival was lower in patients who did not have subsequent EGFR‑TK inhibitor treatment compared with patients who did (the company labelled the data as academic in confidence, so it cannot be presented here). The Assessment Group stated that the median overall survival results for patients treated after chemotherapy with an EGFR‑TK inhibitor, reported in the company's post hoc analysis of the IPASS trial, were longer than estimates previously reported in trials of gefitinib, erlotinib or chemotherapy treatment. The Assessment Group concluded that this finding therefore needs to be validated by evidence from an independent randomised controlled trial, because it would represent an important therapeutic advance.

4.9 Three of the 4 trials that retrospectively reported a subgroup analysis of the EGFR‑TK mutation‑positive population presented response rates for each treatment group (INTEREST; Kim et al. 2012; V‑15‑32). Results suggested that patients randomised to have gefitinib had a higher response rate compared with those randomised to have docetaxel or erlotinib, but results of statistical significance were only presented in 1 trial (INTEREST; gefitinib compared with docetaxel, p=0.04).

Erlotinib

4.10 Four trials of erlotinib were identified by the Assessment Group that included patients known to be EGFR‑TK mutation-negative (TAILOR), patients with and without EGFR‑TK mutations whose EGFR‑TK status was known before randomisation (DELTA), or patients whose EGFR‑TK status was retrospectively reported in a subgroup analysis of the EGFR‑TK mutation-negative population (BR21; TITAN).

4.11 Three of the 4 trials reported results for median progression‑free survival. This was statistically significantly lower with erlotinib compared with docetaxel in 2 of the 3 trials (TAILOR: 2.4 months compared with 2.9 months, HR 1.39, 95% CI 1.06 to 1.82; DELTA: 1.3 months compared with 2.9 months, HR 1.44, 95% CI 1.08 to 1.92). In the remaining trial, no statistically significant differences in median progression‑free survival were estimated between patients randomised to erlotinib compared with patients randomised to either docetaxel or pemetrexed (TITAN: median progression‑free survival in months not reported, HR 1.25, 95% CI 0.88 to 1.78).

4.12 No statistically significant differences in overall survival were estimated between erlotinib compared with:

4.13 Because the TAILOR trial (conducted in 52 hospitals in Italy) is the only published study providing head‑to‑head evidence for erlotinib and docetaxel in the EGFR‑TK mutation-negative population, the Assessment Group further considered its relevance to clinical practice in England. It noted that:

Gefitinib

4.14 Gefitinib is not licensed for the treatment of adults with locally advanced or metastatic non‑small‑cell lung cancer whose tumours test negative for EGFR‑TK mutations (see section 3.4). NICE can only appraise treatments within their licensed indications, so the trial evidence available for gefitinib in this population is not applicable to this technology appraisal.

Erlotinib

4.15 The Assessment Group identified 3 trials of erlotinib that presented outcome data for the EGFR‑TK mutation‑unknown population. No statistically significant differences in median progression‑free survival were estimated between erlotinib and docetaxel (DELTA: 2.0 months compared with 3.2 months respectively, HR 1.22, 95% CI 0.97 to 1.55) and erlotinib compared with either docetaxel or pemetrexed (TITAN: 6.3 weeks compared with 8.6 weeks respectively, HR 1.19, 95% CI 0.97 to 1.46). The BR21 trial showed a statistically significantly longer median progression‑free survival with erlotinib compared with best supportive care (2.2 months compared with 1.8 months respectively, HR 0.61, 95% CI 0.51 to 0.74).

4.16 No statistically significant differences in median overall survival were estimated between erlotinib compared with docetaxel (DELTA: 14.8 months compared with 12.2 months respectively, HR 0.91, 95% CI 0.68 to 1.22) and erlotinib compared with either docetaxel or pemetrexed (TITAN: 5.3 months compared with 5.5 months respectively, HR 0.96, 95% CI 0.78 to 1.19). The BR21 trial showed a statistically significantly longer median overall survival with erlotinib compared with best supportive care (6.7 months compared with 4.7 months, HR 0.7, 95% CI 0.58 to 0.85).

4.17 Response rates were reported for 2 of the 3 trials (BR21; TITAN). The response rates were higher for erlotinib compared with best supportive care (BR21: 8.9% compared with less than 1%) and erlotinib compared with either docetaxel or pemetrexed (TITAN: 7.9% compared with 6.3%).

4.18 Patients who had erlotinib experienced a statistically significantly higher health‑related quality‑of‑life score compared with patients who had best supportive care when measured by the European Organisation for Research and Treatment of Cancer quality‑of‑life questionnaire (EORTC QLQ‑C30) in the BR21 trial. No statistically significant differences in health‑related quality of life were estimated between erlotinib and docetaxel when measured by the Functional Assessment of Cancer Therapy‑Lung (FACT‑L) questionnaire in the TITAN trial.

4.19 Roche Products stated that the most common grade 3 to 4 adverse reactions associated with erlotinib are skin rash (approximately 5–9% of patients) and diarrhoea (approximately 0.6–6% of patients) but these are easily manageable. It commented that life‑threatening adverse reactions are very rare and erlotinib is better tolerated than chemotherapy. The Assessment Group stated that it considered that the adverse reactions reported in the trials appear to be consistent with the information available for erlotinib in its summary of product characteristics (see section 3.2).

Gefitinib

4.20 Gefitinib is only licensed for treating adults with locally advanced or metastatic non‑small‑cell lung cancer who test positive for EGFR‑TK mutations (see section 3.4). NICE can only appraise treatments within their licensed indications, therefore the trial evidence available for gefitinib in the EGFR‑TK mutation-unknown population is not applicable to this technology appraisal.

EGFR‑TK mutation‑positive population

4.48 The Committee discussed the clinical effectiveness evidence for gefitinib in the EGFR‑TK mutation‑positive population. It understood that there were no trials of gefitinib solely conducted in this population whose disease has progressed after non‑targeted chemotherapy but some clinical effectiveness evidence is available from several retrospective analyses. The Committee discussed the retrospective analyses, including 2 from second‑line trials of gefitinib (ISEL and INTEREST) and 1 from the first‑line IPASS trial of gefitinib. The Committee was aware that the ISEL trial compared gefitinib and best supportive care but did not report the median survival for each treatment group and presented a pooled estimate, so the results were not meaningful for assessing the relative effectiveness. It noted that the INTEREST trial showed statistically significantly longer median progression‑free survival with gefitinib compared with docetaxel but there was no statistically significant difference in median overall survival. The Committee also noted that in the post hoc analysis of the IPASS trial, the median overall survival of patients who had subsequent EGFR‑TK inhibitor treatment was longer compared with those who did not have it. The Committee heard from the Assessment Group that in the post hoc analysis of the IPASS trial, 37 of the 46 patients who did not have subsequent EGFR‑TK inhibitor treatment did not have any treatment at all and therefore the results were heavily weighted against the comparator group (that is, the 'no subsequent EGFR‑TK inhibitor' group). The Assessment Group considered that the evidence available for the EGFR‑TK mutation‑positive population was weak and not sufficiently robust to inform decision‑making. The Committee agreed that these retrospective analyses were based on small patient numbers, were subject to imbalances in baseline patient characteristics (and so were highly selective) and lacked statistical power. AstraZeneca acknowledged the limitations of the retrospective analyses. The Committee was aware that established practice is to treat patients with EGFR‑TK mutation‑positive tumours with EGFR‑TK inhibitors in the first‑line setting (see section 4.45). However, the Committee was aware that a small proportion of the EGFR‑TK mutation‑positive population may have a delayed diagnosis of EGFR‑TK mutation status and, depending on their fitness, may need immediate treatment with non‑targeted chemotherapy (see section 4.45). It heard from the clinical experts that when a tumour tests positive for EGFR‑TK mutations, the disease responds to treatment with EGFR‑TK inhibitors to the same degree irrespective of whether the person has had non‑targeted chemotherapy or not. The Committee was persuaded that the EGFR‑TK mutation‑positive population would gain a clinical benefit from treatment with EGFR‑TK inhibitors if they have had chemotherapy because of a delayed diagnosis of EGFR‑TK mutation status. The Committee's preliminary conclusion was that for the small proportion of the EGFR‑TK mutation‑positive population who had a delayed diagnosis and needed immediate treatment with non‑targeted chemotherapy, treatment with gefitinib is clinically appropriate if a diagnosis of EGFR‑TK mutation‑positive status has been confirmed and the disease has progressed after chemotherapy. However, the Committee considered its preliminary conclusion further in the context of the cost‑effectiveness evidence (see section 4.60).

4.49 The Committee discussed the clinical effectiveness evidence for erlotinib in the EGFR‑TK mutation‑positive population. It understood that there were no trials of erlotinib solely conducted in this population but that clinical effectiveness evidence was available from 2 retrospective analyses of the BR21 and TITAN trials. The Committee noted that neither of these analyses reported statistically significant differences between erlotinib and the comparator group (that is, best supportive care in the BR21 trial and a pooled comparator of patients randomised to either docetaxel or pemetrexed in the TITAN trial). It recognised that these retrospective analyses of erlotinib were subject to the same weaknesses identified in the retrospective analyses of gefitinib but was persuaded by the clinical experts that the EGFR‑TK mutation‑positive population would gain a clinical benefit from treatment with EGFR‑TK inhibitors after chemotherapy (see section 4.48). The Committee concluded that for the small proportion of the EGFR‑TK mutation‑positive population who had a delayed diagnosis and needed immediate treatment with non‑targeted chemotherapy, second-line treatment with erlotinib is clinically appropriate if EGFR‑TK mutation‑positive status has been confirmed and the disease has progressed after chemotherapy.

EGFR‑TK mutation-negative population

4.50 The Committee discussed the clinical effectiveness evidence available for the EGFR‑TK mutation‑negative population, comparing the EGFR‑TK inhibitors with best supportive care. It noted that gefitinib does not have a UK marketing authorisation for treating the EGFR‑TK mutation‑negative population and therefore it could not be considered as a treatment option for this population. The Committee understood that only 1 retrospective analysis was available from the BR21 trial, comparing erlotinib and best supportive care in the EGFR‑TK mutation‑negative population. It was aware that the BR21 trial was completed in 2004 before EGFR‑TK mutation testing became established practice and part of clinical decision‑making. It also noted that the trial formed part of the evidence base for the NICE technology appraisal guidance on erlotinib for the treatment of non-small-cell lung cancer. The Committee heard from the company that many of the patients enrolled in the BR21 trial had already had first‑line or second‑line chemotherapy and that docetaxel was unsuitable for them because their performance status was poor. The Committee acknowledged that the BR21 trial did not report statistically significant differences in median overall survival between erlotinib and best supportive care but median overall survival was numerically longer for erlotinib (see section 4.12). It heard from the Assessment Group that the sample sizes were larger in the retrospective analysis of the BR21 trial in the EGFR‑TK mutation‑negative population than in the retrospective analyses of the trials in the EGFR‑TK mutation‑positive population, but the results were still less reliable than the main intention‑to‑treat analysis of the BR21 trial because of the risk of imbalances in baseline patient characteristics. The Committee heard from the clinical experts that erlotinib is now essentially regarded as a targeted therapy for mutation‑positive patients only. It concluded that the evidence only weakly suggests that erlotinib may be clinically effective compared with best supportive care in the EGFR‑TK mutation‑negative population for whom docetaxel is unsuitable.

4.51 The Committee considered the clinical effectiveness evidence available for the EGFR‑TK mutation‑negative population comparing erlotinib with docetaxel. It understood that clinical effectiveness evidence was available from 2 retrospective subgroup analyses of the DELTA and TITAN trials and the TAILOR trial conducted specifically in the EGFR‑TK mutation‑negative population. The Committee noted that:

EGFR‑TK mutation-unknown population

4.52 The Committee discussed the clinical effectiveness evidence available for the EGFR‑TK mutation‑unknown population. It noted that gefitinib does not have a UK marketing authorisation for treating this population and therefore it could not be considered as a treatment option for this population. For erlotinib, it understood that clinical effectiveness evidence was available from 3 trials (BR21, DELTA and TITAN), in which the intention-to-treat populations included patients whose tumours were not tested before randomisation. For the EGFR‑TK mutation‑unknown population, the Committee noted that the BR21 trial showed statistically significantly longer median progression‑free survival and median overall survival for erlotinib compared with best supportive care. It commented that the DELTA and TITAN trials showed no statistically significant differences between erlotinib and docetaxel for median progression‑free survival and median overall survival. The Committee understood that the diminishing population of unknown EGFR‑TK mutation-status generally follow the same clinical pathway as the EGFR‑TK mutation‑negative population (see section 4.47). The Committee noted the mean estimates of incremental survival it had been presented with, which compared erlotinib with best supportive care for the EGFR‑TK mutation‑unknown (see section 4.37) and the EGFR‑TK mutation‑negative populations (see section 4.38), and concluded that these were similar.

4.53 The Committee discussed the BR21 intention-to-treat population and its relevance to decision-making. It understood from the clinical experts that certain clinical characteristics are strong predictors of mutation status (see section 4.47). It noted that the overall results of the BR21 intention-to-treat population are likely to be poorer than the results of a population whose tumours have a high probability of testing positive for EGFR‑TK mutations. The Committee concluded that, in the EGFR‑TK mutation-unknown population, it is likely that erlotinib is more clinically effective compared with best supportive care in people who have clinical characteristics similar to those with confirmed EGFR‑TK mutation‑positive status than in those who do not.

EGFR‑TK mutation-negative population

4.55 The Committee discussed the Assessment Group's ICERs for the comparison of erlotinib with docetaxel in the EGFR‑TK mutation‑negative population. The Committee was aware of the conclusion in NICE technology appraisal guidance on erlotinib for the treatment of non-small-cell lung cancer stating although 'the difference in benefit between docetaxel and erlotinib was uncertain in the absence of direct comparisons, erlotinib could be acceptable if the total costs of treatment were lower or equal to those of docetaxel'. It noted that since the publication of the NICE technology appraisal guidance on erlotinib for the treatment of non-small-cell lung cancer, the results of the first published trial directly comparing erlotinib with docetaxel in patients whose tumours tested negative for EGFR‑TK mutations had become available (that is, the TAILOR trial). Additionally, the price of docetaxel had reduced by approximately 90%. The Committee acknowledged that the direct evidence from the TAILOR trial showed that erlotinib was less clinically effective than docetaxel (see section 4.51). It also considered, however, that the benefits of docetaxel were diminished by it resulting in febrile neutropenia in some patients. The Committee considered what rate of febrile neutropenia experienced by patients having docetaxel should inform the economic model. It considered comments received during consultation and the additional data on the incidence of febrile neutropenia presented by the Assessment Group in its second addendum. It understood that the 3‑weekly docetaxel regimen is established clinical practice in England and that the incidence of febrile neutropenia was approximately 6.35% in patients who had this regimen in the TAILOR trial. It also heard from some consultees that the incidence can be much higher in clinical practice than that reported in clinical trials. Finally, the Committee heard from the company that it considered the rate of febrile neutropenia in patients who had docetaxel to be approximately 15% in clinical practice but not as high as suggested by some consultees (that is, up to 40%). The Committee heard from the Assessment Group that erlotinib was still dominated (that is, docetaxel gave more QALYs and cost less than erlotinib) by docetaxel when increasing the incidence of febrile neutropenia from the rate observed in patients who had the 1‑weekly docetaxel regimen (3.85%) to the rate observed in patients who had the 3‑weekly docetaxel regimen (6.35%) in the TAILOR trial. The Committee understood from the Assessment Group that erlotinib only became cost neutral (at a health loss) compared with docetaxel when the rate of febrile neutropenia was equal to 16.2%. The Committee also highlighted that the ICER only exceeded £30,000 saved per QALY lost when the incidence rate of febrile neutropenia was assumed to be more than 63% and therefore erlotinib would only be considered cost effective at much higher incidence rates than those suggested by consultees during consultation on the first appraisal consultation document. The Committee acknowledged that there was considerable variability, and therefore uncertainty, around the most plausible incidence rate for febrile neutropenia but agreed that the most robust estimate was 6.35%. The Committee concluded that, for all incidence rates of febrile neutropenia suggested during the course of the appraisal, erlotinib did not represent a cost‑effective use of NHS resources for the EGFR‑TK mutation‑negative population.

4.56 The Committee discussed the estimated ICERs for the comparison of erlotinib and best supportive care in the EGFR‑TK mutation‑negative population for whom docetaxel is unsuitable. It noted that the Assessment Group's economic model estimated lower incremental costs and fewer incremental QALYs compared with the company's economic model but the estimated base‑case ICERs were similar for the comparison of erlotinib with best supportive care (£54,700 per QALY gained and £58,600 per QALY gained respectively). The Committee understood that the ICERs were robust to changes in all parameters included in the respective economic models. The Committee therefore concluded that erlotinib is not a cost‑effective use of NHS resources in the EGFR‑TK mutation-negative population for whom docetaxel is unsuitable.

EGFR‑TK mutation‑unknown population

4.57 The Committee discussed the estimated ICERs for the comparison of erlotinib and best supportive care in the EGFR‑TK mutation‑unknown population. It acknowledged that the Assessment Group's estimated base‑case ICER was higher than the company's base‑case ICER but both were over £50,000 per QALY gained (£61,100 per QALY gained and £51,000 per QALY gained respectively). The Committee understood that the ICERs were robust to changes in all parameters included in the respective economic models. The Committee therefore concluded that erlotinib is not cost effective compared with best supportive care in the EGFR‑TK mutation‑unknown population.

4.58 The Committee was aware that it had not been presented with any cost‑effectiveness analyses comparing erlotinib with docetaxel in the EGFR‑TK mutation‑unknown population. The Committee highlighted from its earlier deliberations that the mean estimates of incremental survival for erlotinib compared with best supportive care in EGFR‑TK mutation‑negative and EGFR‑TK mutation‑unknown populations were similar. It was therefore persuaded that the mean estimates of incremental survival comparing erlotinib with docetaxel in the EGFR‑TK mutation‑unknown population were likely to be similar to those it had been presented with for the EGFR‑TK mutation‑negative population (see section 4.51). It agreed that, in patients for whom docetaxel is suitable, the ICERs for erlotinib compared with docetaxel in the EGFR‑TK mutation‑unknown population are likely to be similar to those it had been presented with for the EGFR‑TK mutation‑negative population. The Committee therefore concluded that erlotinib compared with docetaxel is not a cost‑effective use of NHS resources in the EGFR‑TK mutation‑unknown population.

4.59 The Committee was persuaded, however, that some patients whose disease is of unknown EGFR‑TK mutation status can be recognised by clinical experts as having a high likelihood of testing positive for EGFR‑TK mutations. It agreed that for these patients, the economic modelling may well underestimate the benefits of erlotinib. The Committee concluded that for the EGFR‑TK mutation‑unknown population with clinical characteristics suggestive of EGFR‑TK mutation‑positive tumours, the ICER for erlotinib compared with best supportive care is likely to be lower than those estimated by the company and the Assessment Group.

EGFR‑TK mutation‑positive population

4.60 The Committee discussed the most plausible ICER for each of the populations. It noted that cost‑effectiveness estimates were not presented for each population considered in the appraisal so it had to use its judgement on whether erlotinib represented an equitable and cost‑effective use of NHS resources in these circumstances. The Committee was aware that a small population with EGFR‑TK mutation‑positive tumours are offered EGFR‑TK inhibitors after chemotherapy in clinical practice because of a delayed diagnosis. It noted that no trials were solely conducted in this population and that the clinical effectiveness evidence was limited to retrospective subgroup analyses that were not sufficiently robust for decision‑making. The Committee commented that it had not been presented with cost‑effectiveness estimates for either gefitinib or erlotinib in the EGFR‑TK mutation‑positive population and therefore it could not approximate the most plausible ICER. It highlighted that the population in the final scope for this appraisal included 'adults with locally advanced or metastatic non‑small‑cell lung cancer that has progressed following prior chemotherapy' and therefore concluded that it could only make recommendations for erlotinib and gefitinib for the EGFR‑TK mutation‑positive population at the time of (or after) disease progression after non‑targeted chemotherapy because of a delayed diagnosis. The Committee considered patients whose tumours test positive for EGFR‑TK mutations and who switch from chemotherapy to either erlotinib or gefitinib before disease progression because of a delayed diagnosis to be an extension of the first‑line population for whom NICE has recommended erlotinib and gefitinib (see NICE 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). The Committee noted that in the NICE technology appraisal guidance on gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer, there was both robust evidence and an agreed patient access scheme. It understood from the Department of Health that the fixed‑price patient access scheme for gefitinib would not apply to the EGFR‑TK mutation‑positive population whose disease had progressed after chemotherapy. In the absence of either robust evidence or a patient access scheme for the use of gefitinib for treating non‑small‑cell lung cancer that has progressed after chemotherapy, the Committee agreed that it could not recommend gefitinib in this population. The Committee agreed, however, that because erlotinib is provided with the discount agreed in the patient access scheme, the EGFR‑TK mutation‑positive population should have the option of treatment with erlotinib after chemotherapy once their disease has progressed because it would be unfair to disadvantage this small group of people because of a delayed diagnosis.

EGFR‑TK mutation-negative population

4.61 The Committee considered the population whose tumours test negative for EGFR‑TK mutations and for whom docetaxel is suitable (performance status of 0 or 1). The Committee acknowledged that there is evidence to suggest that some tumours that test negative for EGFR‑TK mutations may respond to erlotinib treatment (see section 4.51), and that spending less time at the hospital is important to people (see section 4.43). However, it was aware that direct evidence comparing erlotinib with docetaxel showed erlotinib to be less clinically effective. The Committee noted that although erlotinib was considered to be better tolerated than docetaxel, the health‑related quality of life and the cost associated with managing adverse reactions had been accounted for in the cost-effectiveness estimates. The Committee was aware that the price of both erlotinib and docetaxel had changed since the publication of NICE technology appraisal guidance on erlotinib for the treatment of non-small-cell lung cancer, and the Assessment Group's economic model estimated that erlotinib resulted in higher costs with fewer QALYs (that is, a health loss) compared with docetaxel. The Committee concluded that taking all these factors into account, erlotinib could not be recommended for the EGFR‑TK mutation‑negative population for whom treatment with docetaxel is suitable.

4.62 The Committee considered the population of people whose tumours test negative for EGFR‑TK mutations and for whom docetaxel is unsuitable (that is, those with a performance status of 2). The Committee stated that without new clinical effectiveness evidence and consistent with the recommendation in the NICE technology appraisal guidance on erlotinib for the treatment of non-small-cell lung cancer, erlotinib after chemotherapy did not represent a cost‑effective use of NHS resources in people with non‑small‑cell lung cancer whose tumours test negative for the EGFR‑TK mutation and for whom docetaxel is unsuitable, with the most plausible ICER likely to be over £50,000 per QALY gained compared with best supportive care. The Committee considered a comment received from the company on the appraisal consultation document, stating that based on the Assessment Group's base‑case ICER in this population "the QALY multiplier needed for approval was not substantially above that quoted in the Value Based Assessment consultation document (2.7 compared with 2.5 respectively) given the 'high burden of illness' and 'wider societal impact' associated with non‑small‑cell lung cancer". The Committee noted that in the Value Based Assessment consultation document, it was proposed that burden of illness and wider societal impact would be added to the existing set of modifiers that an Appraisal Committee is able to take into account, and that 2.5 represents the maximum weighting that the Appraisal Committee should consider when taking into account the cumulative impact of all the modifiers. However, the Committee was aware that following consultation on value based assessment of technologies, no changes to NICE's guide to the methods of technology appraisal are being made in the short term and that the current end‑of‑life treatments protocol is being retained in its current form, while NICE carries out further work. Based on NICE's current methods for appraising technologies and the ICERs presented, the Committee concluded that erlotinib could not be recommended for this population.

EGFR‑TK mutation-unknown population

4.63 The Committee noted that the EGFR‑TK mutation‑unknown population is diminishing because of the increasing role and advances in testing of EGFR‑TK mutation‑status. The Committee highlighted its conclusions that the clinical effectiveness and cost effectiveness of erlotinib in the EGFR‑TK mutation‑unknown and EGFR‑TK mutation‑negative populations were likely to be similar compared with docetaxel (see section 4.52), and therefore erlotinib could not be considered a cost-effective use of resources in this population (see section 4.58). The Committee noted that the ICERs for erlotinib compared with best supportive care were over £50,000 per QALY gained in the EGFR‑TK mutation‑unknown population for whom treatment with docetaxel is not suitable, and therefore erlotinib could not be considered a cost-effective use of resources in this population. However, the Committee highlighted its conclusion that the ICER for erlotinib compared with best supportive care was likely to be lower than those estimated by the company and the Assessment Group in the EGFR‑TK mutation‑unknown population with clinical characteristics suggestive of EGFR‑TK mutation‑positive tumours. The Committee acknowledged that a patient's EGFR‑TK mutation status may be unobtainable in clinical practice because of inadequate tissue samples. It heard from the clinical experts that if a person's disease is likely to respond to EGFR‑TK inhibitor treatment, that it will do so by 2 cycles of treatment. The Committee considered that it would be unfair to disadvantage this small group of people. It therefore concluded that erlotinib should be recommended as a treatment option in the EGFR‑TK mutation‑unknown population with clinical characteristics suggestive of EGFR‑TK mutation‑positive tumours if their disease has progressed after non‑targeted chemotherapy, and that people should be able to continue treatment until disease progression if their tumours have responded after 2 cycles.

4.64 The Committee considered whether there were any health‑related quality‑of‑life benefits that were not adequately captured in the QALY calculation. The Assessment Group's report recognised that a drug taken orally may provide people with non‑small‑cell lung cancer with a valuable alternative to intravenous docetaxel. The benefit of an oral mode of treatment was not captured in the Assessment Group's base‑case analysis comparing erlotinib with docetaxel but was explored in a scenario analysis (see section 4.39). The Committee was aware of the Assessment Group's comments that it was an extremely optimistic scenario analysis applying the maximum possible patient health utility increment and that any realistic estimation of utility benefit was very unlikely to have a substantial impact on the size of the ICER. The Committee noted that the Assessment Group's scenario analysis was not plausible but acknowledged that some people may have a preference for erlotinib because it is orally administered. However, it concluded that including a plausible estimation of the health‑related quality‑of‑life benefits of oral treatment would not change its conclusion about the cost effectiveness of erlotinib in the EGFR‑TK mutation‑negative population for whom docetaxel is suitable.

4.65 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 of the following criteria must be met:

4.66 The Committee discussed whether erlotinib fulfilled the criteria for a life‑extending, end‑of‑life treatment. It was aware that Roche Products did not make a case for erlotinib meeting the end‑of‑life criteria in its submission. The Committee noted that the median overall survival of patients with non‑small‑cell lung cancer after chemotherapy in the trials was 5–8 months. It considered that the life expectancy of patients with non‑small‑cell lung cancer after chemotherapy was less than 24 months. The Committee went on to consider whether erlotinib met the extension‑to‑life criterion. It understood that:

4.67 The Committee considered whether its recommendations were associated with any issues related to the equality legislation and the requirement for fairness. It noted a comment received in response to the appraisal consultation document that recommending erlotinib for use in a subgroup of patients whose tumours are likely to test positive for EGFR‑TK mutations based on sex, race or smoking status is discriminatory. Firstly, the Committee considered that the clinical benefit of EGFR‑TK inhibitors is greater in tumours that test positive for EGFR‑TK mutations than in those that test negative for EGFR‑TK mutations. It agreed that given its recommendation for use of erlotinib in the EGFR‑TK mutation‑positive population, it would be unfair to not recommend erlotinib for the small group of patients who are unable to obtain a diagnosis of EGFR‑TK mutation status but who are likely to have EGFR‑TK mutation‑positive tumours based on recognised factors. In addition, patients whose disease is not likely to test positive for EGFR‑TK mutations are likely to have alternative effective treatment options; for example, patients suitable for docetaxel are potentially having a more clinically effective therapy than erlotinib (that is, docetaxel as supported by the results of the TAILOR trial). Therefore, the Committee agreed that its recommendations do not constitute detrimental treatment of patients whose disease is likely to test negative for EGFR‑TK mutations and therefore its recommendations were fair and did not constitute an equality issue.