Osimertinib for untreated EGFR mutation-positive non-small-cell lung cancer

3.1 The patient experts explained that people with untreated locally advanced or metastatic epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) are often very unwell, with many distressing symptoms. There are no curative treatments. The prognosis is generally poor despite treatments such as targeted therapies and immunotherapy. People would therefore welcome new treatments that improve their symptoms and quality of life, and increase how long they live (even if this increase is only small). Locally advanced or metastatic EGFR mutation-positive NSCLC is first treated with an EGFR tyrosine kinase inhibitor, such as afatinib, gefitinib or erlotinib, in line with NICE guidance on afatinib, gefitinib and erlotinib. The clinical experts explained that people would usually be offered afatinib, based on the clinical evidence (see section 3.4). After afatinib, gefitinib or erlotinib, people may be offered either osimertinib if they have developed the T790M resistance mutation in the EGFR gene (in line with NICE's technology appraisal guidance on osimertinib for treating EGFR T790M mutation-positive advanced NSCLC), or chemotherapy if not. People who are not well enough to have further treatment would be offered best supportive care. After chemotherapy, people may be offered immunotherapy, docetaxel with or without nintedanib, or best supportive care. The clinical experts stated that osimertinib would be beneficial as an additional treatment option because it is better tolerated than existing treatments, with fewer side effects. Also, if osimertinib was a first-line treatment option, it would remove the need for T790M mutation testing before second-line treatment. This involves a biopsy, which is invasive and can be psychologically distressing. The committee agreed that additional options would be beneficial and concluded that osimertinib would be a useful addition to first-line treatment.

3.2 The clinical evidence for osimertinib came from the FLAURA randomised controlled trial. FLAURA compared the efficacy and safety of osimertinib with standard care (erlotinib or gefitinib) for people with locally advanced or metastatic EGFR mutation-positive NSCLC. Patients in the trial had either the exon 19 deletion (del19) or exon 21 (L858R) EGFR mutation. The clinical experts explained that these 2 mutations account for around 90% of all EGFR mutations. Also, most trials only include people with these mutations, including the trials that were carried out with other tyrosine kinase inhibitors. The committee acknowledged that, although other mutations may not respond as well to osimertinib, the marketing authorisation indication is not restricted to these 2 mutations (see section 2). It therefore agreed that the EGFR mutation status of patients in FLAURA generally reflected that seen in NHS clinical practice in England. The inclusion criteria allowed people with stable brain metastases to enter the trial but limited the trial population to people with an Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1. For this reason, the committee was aware that the clinical trial population may be in better health than people with stage 3b or stage 4 NSCLC in the NHS and that people with many comorbidities may not have been included in the trial. Also, it noted that afatinib was not a comparator in the standard care arm in FLAURA (see section 3.4) and that many subsequent treatments used in the trial are not routinely used in the NHS. Despite these concerns, the clinical experts explained that the evidence from FLAURA was broadly generalisable to NHS clinical practice. The committee agreed with the clinical experts.

3.3 An interim analysis of FLAURA showed that progression-free survival was statistically significantly longer with osimertinib than with erlotinib or gefitinib. At the interim data cut (12 June 2017; presented in the previous guidance), median progression-free survival was 18.9 months for osimertinib (95% confidence interval [CI] 15.2 to 21.4) and 10.2 months for standard care (95% CI 9.6 to 11.1). The hazard ratio was 0.46 (95% CI 0.37 to 0.57; p<0.001). Overall survival data were very immature (25% of events) but the interim results showed that osimertinib extended overall survival compared with standard care. This produced a hazard ratio of 0.63 (95% CI 0.45 to 0.88; p=0.007), which was not statistically significant (a p value of less than 0.0015 was needed for the result to be significant). The committee acknowledged that the FLAURA data were very immature and that there was uncertainty in overall survival because of the number of events still to be reported. The trial reported more data on overall survival after the previous guidance was published, but submitting this evidence was beyond the scope of the rapid review process, so it could not be fully considered by the committee. Therefore the committee concluded, based on the evidence for the previous guidance, that osimertinib lengthened progression-free survival, and possibly overall survival, compared with erlotinib or gefitinib. But it also concluded that the overall survival benefit was difficult to establish because the data were very immature.

3.4 The relevant comparators for this technology appraisal are erlotinib, gefitinib and afatinib. FLAURA compared osimertinib with either gefitinib or erlotinib, but not with afatinib. The Cancer Drugs Fund clinical lead noted that afatinib is currently the most prescribed EGFR tyrosine kinase inhibitor in England for this population. He also stated that previous trials, such as LUX-Lung 7, showed that afatinib statistically significantly improved progression-free survival compared with gefitinib. The clinical experts agreed that gefitinib and erlotinib are likely to have equal efficacy. They stated that people taking afatinib had a better response rate to treatment, a longer duration of response and longer progression-free survival than with erlotinib and gefitinib. Also, they usually stayed on afatinib for longer. The company stated that LUX-Lung 7 did not show a statistically significant increase in overall survival for afatinib compared with gefitinib. It therefore assumed that afatinib was equivalent in efficacy to erlotinib and gefitinib in its economic model. However, the clinical experts explained that LUX-Lung 7 was not powered (that is, it did not have enough people in the trial) to show a difference in overall survival compared with gefitinib. The ERG did its own exploratory indirect treatment comparison that suggested osimertinib statistically significantly improved progression-free survival compared with afatinib but showed no statistically significant difference in overall survival. The committee concluded that there was evidence of improved progression-free survival with afatinib compared with gefitinib, and erlotinib and gefitinib cannot be assumed to have equal efficacy with afatinib.

3.5 The company used a partitioned survival structure with 3 health states (progression-free, progressed disease and death) to model overall survival in FLAURA. It used a time horizon of 20 years to capture all relevant costs and benefits for people having treatment. The company initially assumed a treatment benefit for osimertinib for the full 20-year period. The committee agreed with the ERG and clinical experts that this assumption was optimistic considering the data available and would have to be adjusted to reflect a more realistic benefit from osimertinib treatment. The company therefore revised its base case, assuming a 6‑year duration of treatment effect after the start of treatment (that is, applying a hazard ratio of 1 to both the osimertinib and standard care arms 6 years after starting treatment). The committee recalled that, in previous appraisals for locally advanced or metastatic NSCLC, the preferred treatment effect duration for immunotherapies was 3 years to 5 years. However, it acknowledged that these appraisals involved drugs with a different mechanism of action to osimertinib and a maximum treatment duration. Therefore, it was not appropriate to compare them. The clinical experts agreed that, because osimertinib is associated with improved progression-free survival and duration of response, treatment effect would continue after symptomatic and radiological progression for some people. They stated that this could plausibly give about 3 months of additional benefit after stopping treatment with osimertinib compared with erlotinib and gefitinib. The clinical experts believed that because osimertinib penetrates the blood–brain barrier better than erlotinib and gefitinib, it may help improve control of brain metastases. The committee recalled that afatinib yields longer progression-free survival than erlotinib and gefitinib, but because there was no direct evidence comparing osimertinib with afatinib (see section 3.4), it could not establish how osimertinib compared with afatinib in terms of progression-free and overall survival. The ERG's preferred analyses used durations of 3 years and 5 years. The ERG explained that the company's 6‑year duration of treatment effect would mean that people who stopped taking osimertinib within 1 year or 2 years of starting it would still benefit for the full 6 years. The ERG emphasised the limitations of modelling the duration of treatment effect with a partitioned survival model. This is because a crude approach is needed to make adjustments around the assumptions (for example, assuming equivalence at a single time point). The ERG noted that this does not fully reflect what happens in a clinical setting. The committee concluded that a 6‑year duration of treatment effect for osimertinib was optimistic and that, without more evidence, the ERG's analysis using a 3‑year or 5‑year duration of treatment effect was more appropriate.

3.6 The committee was aware of NICE's position statement on handling comparators and treatment sequences in the Cancer Drugs Fund. This states that 'products recommended for use in the Cancer Drugs Fund after 1 April 2016 should not be considered as comparators, or appropriately included in a treatment sequence, in subsequent relevant appraisals'. But the committee accepted that it could consider the company's approach of including osimertinib as a subsequent treatment (in line with NICE's guidance on osimertinib for treating locally advanced or metastatic EGFR T790M mutation-positive NSCLC) in the model in this appraisal, because this reflected that some patients in FLAURA did receive osimertinib as a subsequent treatment. People in the standard care arm in the model could have osimertinib as a second-line treatment, assumed to be 33% of people (based on clinical opinion). The committee noted that, although the costs of osimertinib as a second-line treatment were applied in the standard care arm of the model, efficacy was not fully captured given that only around 20% of people had osimertinib as a second-line treatment in the trial at the time of the interim analysis. The committee was aware that the subsequent treatments used in the trial may not reflect NHS practice. It noted that different subsequent therapies would mean different survival prospects and health states that cannot be captured in the modelling. The ERG explained that, to overcome the limitations of the model in capturing the efficacy of subsequent treatments, and to create more flexibility to explore varying the duration of treatment benefits, additional health states would be needed. The ERG described how an individual patient simulation model would better account for these issues but it would need lots of additional data, and trial data are usually immature. The committee agreed that the company's model was broadly appropriate for decision making. It acknowledged the limitations of the model and, given the immaturity of the data, concluded that the model did not fully capture the benefits of subsequent treatments appropriately.

3.7 At the interim data cut considered in the previous guidance, median overall survival was not achieved in either the osimertinib or standard care arm. To estimate the overall survival of people in FLAURA, the company used a piecewise Weibull extrapolation of the Kaplan–Meier curve, which was based on observed data up to 7.90 months in the trial. This estimated that mean overall survival was 66.96 months with osimertinib and 44.39 months with standard care, assuming a 20‑year time horizon in the model. The committee was aware that this extrapolation resulted in the most conservative piecewise survival estimates of those presented and fitted the data well. It understood that the FLAURA data were immature (only 25% of events occurring), which introduced uncertainty into the survival estimates, and that further data collection is planned. It concluded that, although the company's and ERG's preferred choice of distribution for modelling overall survival was appropriate, the immaturity of the data introduces uncertainty in estimating the results.

3.8 The committee considered the additional analyses presented for the rapid review, which incorporated the updated confidential commercial arrangement for osimertinib, and its preferred modelling assumptions:

3.9 The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. It recalled that, at the interim data cut presented and considered in the previous guidance, median overall survival had not been reached in FLAURA, and that the increased survival in the osimertinib arm was not statistically significantly different from the standard care arm (see section 3.3). However, it also noted that the company's economic model predicted mean overall survival would be 22 months longer with osimertinib than with standard care. Based on evidence from FLAURA and predictions from the economic model (using the committee's preferred assumptions), the committee concluded that osimertinib was likely to extend life by over 3 months and therefore met the extension-to-life criterion.

3.10 For the previous guidance, the company presented registry evidence from a real-world data source (National Cancer Registration and Analysis Service [NCRAS] Public Health England data between 2014 and 2016), showing that median overall survival for the population in England was less than 24 months. The committee recognised that there was potential value in real-world evidence from the NHS in England to help inform its decision making. However, it considered there were several reasons why it was not appropriate to use these as the primary data source in isolation for its decision making on the short life expectancy criterion:

3.11 At consultation on the previous guidance, the company provided new analyses to support its case for meeting the end of life criteria when using the committee-preferred dataset (FLAURA). The company stated that the subgroup analyses most closely reflected the cohort of NHS patients in England. However, the Cancer Drugs Fund clinical lead's nominated deputy advised caution in interpreting these registry data because the systemic anticancer therapy (SACT) data set is currently incomplete and that gaps in the evidence exist between the secondary uses service data and the corresponding SACT data. The 3 subgroups were:

3.12 The Cancer Drugs Fund clinical lead highlighted that follow up in FLAURA is short, so the economic model was unlikely to fully capture osimertinib's beneficial effect in the brain. They also stated that osimertinib is better tolerated than other EGFR tyrosine kinase inhibitors with respect to chronic grade 1 and grade 2 skin-related toxicities, and this benefit was not captured in the economic model. The committee also understood that having osimertinib for untreated EGFR mutation-positive NSCLC will reduce the need for repeat bronchoscopic biopsies in people to identify those eligible for osimertinib after an EGFR tyrosine kinase inhibitor (this is currently available via the Cancer Drugs Fund). The committee concluded that osimertinib may be innovative and agreed that there may be benefits that are not captured by the cost-effectiveness analyses.

3.14 The committee concluded that the estimates of cost effectiveness for osimertinib were within the range that is considered to be a cost-effective use of NHS resources. This conclusion took into account the clinical evidence from FLAURA, all the relevant commercial arrangements, including an updated commercial arrangement for osimertinib and commercial information from NHS England, and the potential benefits of osimertinib not captured by the economic model. So, osimertinib is recommended for use in the NHS for untreated locally advanced or metastatic EGFR mutation-positive NSCLC in adults.