Mobocertinib for treating EGFR exon 20 insertion mutation-positive advanced non-small-cell lung cancer after platinum-based chemotherapy

Evidence-based recommendations on mobocertinib (EXKIVITY) for treating EGFR exon 20 insertion mutation-positive advanced non-small-cell lung cancer after platinum-based chemotherapy in adults.

# Recommendations
Mobocertinib is recommended, within its marketing authorisation, as an option for treating locally advanced or metastatic non-small-cell lung cancer (NSCLC) after platinum-based chemotherapy in adults whose tumours have epidermal growth factor receptor (EGFR) exon 20 insertion mutations. It is recommended only if the company provides it according to the commercial arrangement.
Why the committee made these recommendations
Current treatment for locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations after platinum-based chemotherapy can include platinum-based chemotherapy again, immunotherapies, and docetaxel with or without nintedanib.
Indirect comparisons using real-world evidence on immunotherapies and docetaxel with or without nintedanib, suggest that mobocertinib increases how long people live, and how long they have before their cancer gets worse. But this is uncertain because there is no direct comparison, and because of the way the real-world evidence was chosen and presented. So, the cost-effectiveness estimates are also uncertain.
Mobocertinib meets NICE's criteria to be considered a life-extending treatment at the end of life. Despite the uncertainty in the cost-effectiveness estimates, they are within what NICE considers an acceptable use of NHS resources for end of life treatments. So, mobocertinib is recommended.# Information about mobocertinib

# Marketing authorisation indication
Mobocertinib (EXKIVITY, Takeda) 'as monotherapy is indicated for the treatment of adult patients with epidermal growth factor receptor (EGFR) exon 20 insertion mutation-positive locally advanced or metastatic non-small cell lung cancer (NSCLC), who have received prior platinum-based chemotherapy'.

# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics for mobocertinib.

# Price
The list price for mobocertinib is 7,751 per pack of 112 capsules, each containing 40 mg of the active ingredient (excluding VAT; BNF online, accessed October 2022).
The company has a commercial arrangement. This makes mobocertinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Takeda, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.

# Clinical management

## People with EGFR exon 20 insertion mutation-positive advanced NSCLC will welcome a new treatment option that is targeted and well tolerated
The clinical experts explained that epidermal growth factor receptor (EGFR) exon 20 insertion mutations are rare, and only seen in a few people with non-small-cell lung cancer (NSCLC). Compared with other EGFR mutations, they are more common in women, people from an East Asian family background and people who do not smoke. Exon 20 insertion mutations are also associated with poorer outcomes than other EGFR mutations. The patient experts explained that, in people with exon 20 insertion mutation-positive NSCLC, the condition has a significant effect on their quality of life, and that of their families and carers. The patient experts highlighted the need for targeted treatments that have a lower toxicity and better survival outcomes than current treatments. The clinical experts explained that there is no standard treatment for exon 20 insertion mutation-positive NSCLC (see section 3.2), and no treatment options that specifically target the mutations. The committee concluded that there is an unmet need for more effective treatment options that specifically target the exon 20 insertion mutations.

# Comparators

## EGFR tyrosine kinase inhibitors are not appropriate comparators
The clinical experts explained that there is no standard treatment pathway for people with exon 20 insertion mutation-positive NSCLC. Treatment choice depends on stage of disease, PDL1 status, and patient and clinician preference. Treatment options can include docetaxel with or without nintedanib, immunotherapy (such as atezolizumab, nivolumab or pembrolizumab) or best supportive care. Because there is no established standard treatment pathway, the company included a blended comparator arm in its submission. In its base case, the comparators were atezolizumab, and docetaxel with or without nintedanib. The clinical experts explained that EGFR tyrosine kinase inhibitors (TKIs) have limited efficacy when there are exon 20 insertion mutations. Because of this, they are rarely used in this population and are unlikely to represent standard care in the NHS. The NHS England Cancer Drugs Fund clinical lead (from here, the Cancer Drugs Fund lead) stated that EGFR TKI use is not considered routine practice in the NHS. The committee concluded that EGFR TKIs were not an appropriate comparator.

## Using a blended comparator arm increases uncertainty
The company's approach compared mobocertinib with the average clinical effectiveness across all treatments in a blended comparator arm. The company explained that there was no robust way to define standard care (see section 3.2), making it unfeasible to identify a single treatment that would be displaced by mobocertinib. So, the most relevant comparator can only be accurately reflected by a blended comparator group, meaning that a full incremental analysis is not possible. The efficacy data for the blended comparator arm came from real-world evidence from 93 people across multiple treatment arms. The treatments included chemotherapy (with or without monoclonal antibodies), immunotherapy with chemotherapy, immunotherapy and EGFR TKIs. The company explained that their choice of blended comparators reflected the treatments used in 2 real-world evidence sources:
US cohort data from the Flatiron study
retrospective cohort data from the German Chart Review.The committee noted that EGFR TKIs have limited efficacy in people with exon 20 insertion mutations (see section 3.2). The ERG explained that including an ineffective treatment option (that is, EGFR TKIs) in the blended comparator may have led to overestimating the comparative effectiveness of mobocertinib. Also, the company included costs for a different blend of treatments (see section 3.13). In its response to the consultation, the company did scenario analyses that excluded EGFR TKIs from the real-world data for the blended comparator arm. This reduced the incremental cost-effectiveness ratio (ICER). The company did not exclude EGFR TKIs from the real-world data in its base-case analysis. This was because it reduced the sample size of the population and because the clinical experts stated that the outcomes of the real-world evidence reflected the outcomes in UK clinical practice. The ERG noted that the results of the scenarios excluding people having EGFR TKIs from the real-world data were counterintuitive. It said that it would expect excluding EGFR TKIs to result in a decrease in incremental quality-adjusted life years (QALYs), given the change in hazard ratios presented in the company's submission. The ERG was unable to verify and reproduce these analyses because of the lack of detail and justification provided. But it suspected that the method of modelling survival may have been flawed. It stated that its preference would have been to exclude people having EGFR TKIs from the real-world data in its base-case analysis. But this was not done because of the counterintuitive results provided by the company. The committee concluded that the effect of excluding EGFR TKIs from the real-world data for the blended comparator arm was uncertain. It also concluded that uncertainty remained about mobocertinib's relative effectiveness compared with current treatments.

# Clinical evidence

## Mobocertinib is clinically effective, but the size of this benefit compared with current treatments is difficult to establish
The main evidence for mobocertinib came from the platinum pretreated cohort (n=114) in Study AP3278815101. This was a single-arm, open-label, multicentre, phase 1 and 2 trial. Results from November 2021 showed a median investigator-assessed progression-free survival of 7.33 months (95% confidence interval  5.55 to 8.84) and a median overall survival of 20.17 months (95% CI 14.88 to 25.26). The clinical experts considered these results to be clinically meaningful. Overall, the committee concluded that Study AP3278815101 showed clinically meaningful results for mobocertinib. But it thought that the lack of direct comparative evidence meant the size of benefit compared with current treatments was difficult to establish.

## The approach used to identify real-world evidence for the blended comparator arm may not be robust and is associated with uncertainty
There was no comparator in Study AP3278815101 (see section 3.4). Also, no relevant trials were identified in the company's literature review of clinical trials and real-world studies comparing mobocertinib with the relevant comparators in people with EGFR exon 20 insertion mutations. So, the company did an adjusted indirect treatment comparison comparing mobocertinib with a blended comparator (see section 3.3) using real-world evidence. Because exon 20 insertion mutations affect the outcomes of people with NSCLC, the real-world evidence included was limited to people with NSCLC with these mutations. This evidence came from Flatiron and the German Chart Review (see section 3.3). The ERG highlighted that the clinical evidence may not have been generalisable because neither Study AP3278815101 nor the real-world evidence sources were from the UK. The company stated that, based on feedback from UK oncologists and health economists, it thought the evidence from the real-world evidence sources was generalisable to the UK. The ERG noted that the company did not provide a full, justified rationale for its choice of real-world evidence sources. Also, it was concerned that the literature had not been reviewed systematically. So, the company may have missed relevant sources. The committee noted that there may be additional relevant real-world evidence sources that were not identified by the company. To address this concern, the company provided a comparison of the baseline characteristics, index treatments and clinical efficacy outcomes between the pooled real-world evidence sources used in the blended comparator arm and Minchom et al. (2021). This study was used for NICE's technology appraisal guidance in development for amivantamab for treating EGFR exon 20 insertion mutation-positive advanced NSCLC after platinum-based chemotherapy. The company noted that, despite differences in baseline characteristics and index treatments between the sources of real-world evidence, there were no meaningful differences in outcomes. The committee noted that the company had chosen to only include the initial line of therapy after platinum-based chemotherapy in the Flatiron database. But, in Minchom et al., all lines of therapy after platinum-based chemotherapy were included. The company stated that this was to avoid double-counting and that their clinical experts had said the effect of previous lines of therapy was uncertain. Survival in people who went on to have subsequent lines of therapy may have been shorter because their condition was more advanced. But, also, their survival may have been longer because only the fittest individuals would go on to have subsequent treatments. The committee noted that it was surprised by the similarity in outcomes, given this difference in baseline characteristics. Also, the ERG noted that the company did not state how it identified Flatiron and the German chart review, or why they were chosen rather than other sources of real-world evidence. It emphasised that a systematic approach is the preferred way to identify real-world evidence. It explained that a direct comparison with Minchom et al. was not appropriate because this study was not identified systematically. The committee was concerned that the company had not provided enough information on how the sources were chosen from the pool of all potential data sources. It concluded that the approach to identifying real-world evidence to use in the blended comparator arm may not have been robust and was associated with uncertainty.

## The way the company has used real-world evidence is associated with some areas of uncertainty and may bias the results
The committee noted that, in general, there are several key differences between real-world evidence and clinical trials. Specific to this appraisal, efficacy and safety endpoints were followed up regularly in Study AP3278815101, but there were no scheduled visits in routine care in the real-world evidence. Also, treatment monitoring and follow up on treatment adherence may have differed between Study AP3278815101 and routine care. This would have affected the efficacy and safety results. Progressed disease is less accurately captured in retrospective studies such as Flatiron and the German Chart Review than in prospective studies such as Study AP3278815101, in which people generally have closer monitoring. The company also highlighted that the definition of the index-line of treatment differed between the German Chart Review and Flatiron. In the German Chart Review, baseline characteristics were collected at diagnosis or study entry and not at the start of each treatment line. So, the data from routine care may have been subject to bias. After the first committee meeting, the company provided more information about differences in baseline data collection and index-line treatment definition between Study AP3278815101 and the real-world evidence sources. It noted that the small differences between timepoints for collection of baseline data and definition of index treatment were expected to have a minimal effect on comparability between the sources. The committee acknowledged the known limitations with real-world evidence. But it considered that it can be valuable for resolving gaps in knowledge when best-practice methods are applied, such as those described in the NICE real-world evidence framework. It also acknowledged the rarity of exon 20 insertion mutation-positive NSCLC and the lack of direct comparative efficacy data. This meant that the real-world evidence may have been the best available source of evidence for the comparator arm. At the first committee meeting, the committee was concerned that the company had not provided enough information on data provenance, accuracy and suitability, and had not explored the effect of missing data. To address these concerns, the company provided additional information on the real-world evidence sources used in the model. It provided completed DataSAT and RECORDPE real-world evidence checklists for both real-world evidence sources. It also did several scenario analyses:
exploring the effect of excluding EGFR TKIs from the real-world data (see section 3.3)
using the sources of real-world evidence separately (rather than pooled).The company emphasised the strengths of the real-world evidence, including that it was mature, and that the baseline characteristics and efficacy outcomes between the 2 studies, and cost-effectiveness results when using each study separately, were similar. The committee acknowledged the additional information provided by the company. Overall, the committee concluded that some areas of uncertainty remained and some of this uncertainty was currently unresolvable. It noted that the level of uncertainty could have been reduced if the company had shown that a systematic approach had been taken to selecting real-world evidence sources. The committee concluded that it would take this uncertainty into account in its decision making.

# Indirect treatment comparison

## The company's indirect comparison is acceptable for decision making, but using this is associated with uncertainty
To account for differences in populations between Study AP3278815101 and the real-world evidence sources, the company adjusted for key prognostic variables and baseline characteristics. These were identified before the analysis by a targeted review and an oncologist survey. These results were further validated by clinical experts. Five common prognostic factors were identified. The data was adjusted using an inverse probability of treatment weighting method. Because of missing data from Flatiron, only brain metastases, age and time since advanced diagnosis were included in the base-case adjustments. Eastern Cooperative Oncology Group (ECOG) performance status and number of lines of previous treatment were excluded. At the first committee meeting, the ERG suggested using the multiple imputation method to adjust for ECOG performance status. In response, the company provided scenario analyses:
imputing missing data as ECOG performance status 0
imputing missing data as ECOG performance status 1
using a complete case approach that excluded all people with missing data.These scenarios had a small effect on the ICER. The company stated that all people included in the real-world evidence sources had previously had platinum-based chemotherapy, followed by immunotherapy, chemotherapy or EGFR TKIs. This meant that they were likely to have an ECOG performance status of 0 or 1, rather than of 2 or higher (which indicates a poorer level of functioning). The Cancer Drugs Fund lead explained that, in England, most treatments for lung cancer are only commissioned for people with an ECOG performance status of 0 or 1. But the committee noted that the Flatiron database is in the US. So, it was uncertain whether people with an ECOG performance status of 2 or higher would be included in the relevant population in this database. The committee was also concerned that the company had been unable to adjust for number of previous lines of therapy between Study AP3278815101 and the real-world evidence sources. This was because the company had chosen to only include the initial line of therapy had after platinum-based chemotherapy in the Flatiron database (see section 3.5). The committee noted that about 60% of people included in Study AP3278815101 had had 2 or more previous lines of treatment. So, it was concerned that lines of previous treatment had not been included as a prognostic factor in the indirect treatment comparison. It concluded that this increased uncertainty in the results. Also, at the first committee meeting, the ERG was concerned that the method of inclusion of prognostic factors was poorly justified, and that all possible confounding variables should have been included. In response, the company provided scenario analyses in which smoking status and gender were included in the inverse probability of treatment weighting. This reduced the ICER. The ERG noted that this suggested that the company's base-case approach of including prognostic factors in the indirect comparison was likely conservative. But the ERG noted that the company did not assess other factors that could have been included, such as race and type of previous therapy. The committee considered that the indirect treatment comparison was associated with uncertainty. It concluded that this was because of the risk of confounding noted by the ERG, and the potential evidence selection issues associated with the blended comparator data (see section 3.5 and section 3.6).

## Results from the indirect treatment comparison show statistically significant improvements with mobocertinib, but are uncertain
The indirect comparison showed statistically significant improvements in overall survival and progression-free survival with mobocertinib compared with the blended comparator arm. This was evidenced by the pooled real-world evidence analysis from the November 2021 data cut (overall survival hazard ratio 0.56, 95% CI 0.39 to 0.81; progression-free survival hazard ratio 0.54, 95% CI 0.36 to 0.82). The ERG explained that the results of the analyses were associated with uncertainties. These included that they were limited by the number of covariates included for adjustment and that there were issues with the company's approach to comparing clinical trial and real-world data (see section 3.7). Overall, the committee concluded that the indirect treatment comparison showed a statistically significant improvement with mobocertinib compared with standard care, but that the exact level of improvement was uncertain.

# Utility values in the economic model

## There is uncertainty surrounding the most appropriate utility values to use in the economic model
The company mapped EQ5D5L data from Study AP3278815101 to EQ5D3L. The mapped EQ5D3L utility scores were analysed using a type of regression model. This model included baseline utility, progression status and ongoing treatment emergent adverse event (TEAE) status of grade 3 or more. In the base case, the company used health-state specific utilities without TEAEs, which were included separately. The ERG noted that the company's approach to selecting utility values was reasonable. But the ERG also noted that the utility values for progression-free and progressed disease were higher than what was used in past appraisals in NSCLC (that is, NICE's technology appraisal guidance on nivolumab for advanced non-squamous NSCLC after chemotherapy and on nintedanib for previously treated locally advanced, metastatic or locally recurrent NSCLC). The exact utility values are considered confidential by the company and cannot be reported here. The company noted that using EQ5D data from a relevant clinical trial is in line with NICE's reference case. It also noted that its clinical experts had stated that utility values from non-mutationally driven NSCLC are not comparable with the population relevant for this appraisal. The committee noted that the utility values for both the progression-free survival and progressed-disease states were high compared with those for the general population and those used in past appraisals. It also noted that the difference between the utility values in the progression-free survival and progressed-disease states was smaller than has been seen in past appraisals. It noted that utility values in Study AP3278815101 were collected up until 30 days after the end of treatment. It also noted that compliance dropped from greater than 95% at all points during the trial period to 62% at the end of treatment visit and to 52% 30 days after last dose visit. So, the utility data collected in the trial only captured a short amount of time in the progressed-disease health state. The committee also considered that mobocertinib is an oral treatment and can be taken at home, which may present additional quality-of-life benefits compared with intravenous therapies (such as nivolumab). It concluded that there was uncertainty surrounding the most appropriate utility values to use in the economic model. It also concluded that the true utility values could fall somewhere between the utility values collected from Study AP3278815101 and the values from NICE's technology appraisal guidance on nivolumab for advanced non-squamous NSCLC after chemotherapy.

# Assumptions in the economic model

## The company's model structure is suitable for decision making
The company used a partitioned survival model with 3 mutually exclusive health states: progression-free survival, progressed disease and death. This approach allowed the company to use outcome data from the adjusted treatment comparison. It also enabled the clinical benefits of mobocertinib to be captured by reflecting the increased proportion of people expected to be alive or progression free over time. The committee agreed that the model structure was suitable for decision making.

## The ERG's choice of survival curves are more plausible than the company's
The company fitted parametric models to the KaplanMeier curves for weighted overall survival, progression-free survival and time to treatment discontinuation (TTD) for the mobocertinib and blended comparator treatment arms. Across all outcomes, hazards were assumed to be proportional between treatment arms, and joint models were fitted with treatment as a covariate. In its original submission, the company fitted a joint generalised gamma distribution for overall survival and a joint exponential distribution for both progression-free survival and TTD. At the first committee meeting, the ERG disagreed with the company's choice of progression-free survival and TTD models. This was because the observed progression-free survival and TTD hazard functions (rate at which events occurred) were not constant over time. This contradicted the underlying properties of an exponential distribution, making the distribution unsuitable. The ERG also highlighted that the exponential distribution had the worst statistical fits compared with other distributions. It preferred the generalised gamma distribution for progression-free survival and the Gompertz distribution for TTD. In response to consultation, the company used a generalised gamma distribution for overall survival, progression-free survival and TTD. It explained that it preferred using the generalised gamma distribution for TTD in its base case because it aligned with the distribution used to model progression-free survival. The company noted that:
Using a Gompertz distribution for TTD led to a mismatch between the TTD and progression-free survival curves, in which the cancer continued to progress without treatment stopping, which lacked face validity.
There was little difference between statistical fit for the Gompertz and generalised gamma distributions.
The generalised gamma better aligned with clinical expert feedback suggesting no one would be having treatment by year 5.The company presented a scenario analysis using the Gompertz distribution for TTD, which increased the ICER. The ERG considered that the company did not provide enough new compelling justification on why the mismatch between TTD and progression-free survival distributions was a problem in this case. The committee retained its preference for the Gompertz distribution for TTD. It agreed that the ERG's choice of survival curves was more plausible than the company's choice of survival curves.

## It is appropriate to exclude treatment effect waning from the modelling
The company's base case assumed that mobocertinib's treatment effect continued throughout the time horizon. The company explained that the survival data for mobocertinib was mature. Also, mobocertinib is usually given until progression and no stopping rules apply. The company assumed that any treatment effect waning would have been captured in the trial follow-up period. The ERG agreed with the company's approach. The committee noted that treatment effect waning has typically been applied in previous appraisals for immunotherapies when stopping rules have been applied. It also noted the limited impact of the treatment effect waning scenario done by the ERG. Based on this, the committee concluded that it was appropriate to exclude treatment effect waning from the modelling.

## The mismatch of efficacy, cost and disutility increases uncertainty, but the company's approach to costs is conservative
The company included costs and disutility of adverse events for docetaxel with or without nintedanib, and atezolizumab in the blended comparator arm. Efficacy outcomes were included from other treatments, for example, EGFR TKIs. But EGFR TKIs were not considered to be appropriate comparators (see section 3.2), so the company excluded their costs and disutilities. The company also highlighted that atezolizumab's list price is the cheapest, and that it is the most frequently used immunotherapy. So, the exclusion of pembrolizumab and nivolumab was a conservative assumption. The ERG highlighted that only 8 out of 93 people in the pooled real-world evidence had had 1 of the 3 treatments in the blended comparator arm. This resulted in a mismatch between the treatments used in the real-world evidence that informed efficacy and the treatments that informed the cost and adverse events disutility in the model. The committee saw scenarios including the costs of EGFR TKIs and immunotherapies. It agreed that the company had taken a conservative approach by excluding the costs of EGFR TKIs and immunotherapy treatments. As previously noted by the committee (see section 3.2), including EGFR TKIs in the efficacy outcomes could have underestimated the comparator efficacy. The committee concluded that the mismatch of efficacy, and cost and disutility of adverse events data increased the uncertainty in the cost-effectiveness results. But it acknowledged that the company's approach to costs was conservative.

# Costs in the economic model

## Exon 20 insertion mutation testing costs should be included in the economic model
In line with section 5.9.1 of NICE's guide to the methods of technology appraisal, the NICE scope for mobocertinib states that the 'costs associated with diagnostic testing for EGFR in people with NSCLC who would not otherwise have been tested' should be modelled. The company did not include exon 20 insertion mutation testing in the economic modelling for mobocertinib. It explained that these costs were expected to be included in routine NHS testing. The Cancer Drugs Fund lead explained that the gold standard for detecting exon 20 insertion mutations is next generation sequencing. But the availability of this varies across the NHS. Many treatment centres use polymerase chain reaction (PCR) instead, which is expected to identify about 50% of people with exon 20 insertion mutation-positive NSCLC. Because of this, using mobocertinib (or other exon 20 insertion mutation targeted treatments) in the NHS would mean switching from current local PCR testing to next generation sequencing at Genomic Laboratory Hubs. This could result in a 50% increase in detecting people with exon 20 insertion mutation-positive NSCLC. But the Cancer Drugs Fund lead suggested that this increase may only be 33% because there is already some next generation sequencing testing being done. They explained that it would be appropriate to add a testing cost of 550 per person with exon 20 insertion mutation-positive NSCLC. This cost would account for a 2% incidence of exon 20 insertion mutations, and the standard cost of adding a mutation test onto a next generation sequencing panel of 34. The company presented scenario analyses including the cost of genomic testing in the mobocertinib arm only and in both treatment arms in the model. The ERG stated that if exon 20 insertion mutation testing is not embedded in NHS practice for people with NSCLC, then additional diagnostic testing would be applicable with the introduction of mobocertinib. The committee concluded that exon 20 insertion costs should be included in the mobocertinib arm of the economic model.

# End of life

## Mobocertinib meets the criteria to be considered a life-extending treatment at the end of life
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. The company proposed that mobocertinib met the criteria for being a life-extending treatment for people with short life expectancy (normally less than 24 months). Both the company's base case and the model using the committee's preferred assumptions predicted a mean and median overall survival with current standard care of substantially less than 24 months. The mean overall survival for the blended comparator arm was 16.2 months from the company's base-case model. Having considered the survival data from the real-world evidence, the committee concluded that mobocertinib met the end of life criterion for short life expectancy. The company's and ERG's modelling suggested that mobocertinib was associated with a gain in overall survival of substantially more than 3 months. The company's base-case model showed a mean overall survival of 27.1 months for mobocertinib, an increase of 10.8 months. The committee noted the uncertainty in the real-world evidence and model estimates previously discussed (see section 3.8). It concluded that, despite the uncertainty in the size of the survival gain, mobocertinib met both of NICE's criteria to be considered a life-extending treatment at the end of life.

# Cost-effectiveness results

## Because of the uncertainty, the maximum acceptable ICER would be below 50,000 per QALY gained
NICE's guide to the methods of technology appraisal notes that, above a most plausible ICER of 20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. It recalled its conclusion from the first meeting that an acceptable ICER would be around 20,000 per QALY gained. But the committee also agreed that the end of life criteria applied to mobocertinib. When the end of life weighting was applied, the committee said that the maximum acceptable ICER would be substantially less than 50,000 per QALY gained. The committee acknowledged that, since the first committee meeting, the company had attempted to reduce the uncertainty around the use and selection of real-world evidence. But it noted the high level of outstanding uncertainty in the company's model, specifically:
the lack of direct comparative evidence
the lack of fully incremental analysis because of using a blended comparator
the effect of evidence selection issues because of the lack of a systematic approach to identifying real-world evidence sources
the potential for residual confounding in the indirect treatment comparison.The committee also took into account the lack of targeted treatment options available for this specific mutation, the emotional burden on people with EGFR exon 20 insertion mutation-positive NSCLC and their caregivers. It also heard that people with lung cancer may experience stigma, which could delay them seeking treatment. It noted the rarity of EGFR exon 20 insertion mutation-positive NSCLC and the difficulties this can create in generating evidence. The fact that mobocertinib met the end of life criteria in this indication was also considered. Taking these factors into account and the uncertainty that remained, the committee concluded that an acceptable ICER would need to be below the maximum acceptable ICER for end of life treatments (50,000 per QALY gained) to be considered a cost-effective use of NHS resources.

## The cost-effectiveness estimates are uncertain but are likely within what NICE considers to be an acceptable use of NHS resources
The company's updated base-case ICER for mobocertinib compared with the blended comparator arm was markedly below 50,000 per QALY gained. This was when confidential commercial arrangements for mobocertinib and all the comparators were included, so the exact ICERs cannot be reported here. The company's base case included the following assumptions, which were preferred by the committee:
excluding the costs of EGFR TKIs from the blended comparator arm (see section 3.13)
a joint generalised gamma model for overall survival and progression-free survival (see section 3.11)
using the individual patient weighting method for the indirect treatment comparison (see section 3.7)
excluding treatment waning (see section 3.12).The company's updated base case used a joint generalised gamma distribution for TTD. This differed from the committee's preferred approach, which was to use a joint Gompertz distribution for TTD (see section 3.11). The committee considered the scenario including its preferred assumptions using a joint Gompertz model for TTD and the additional testing costs for EGFR exon 20 insertion mutation testing. It noted that the ICER for this scenario was also below 50,000 per QALY gained. The exact ICERs are commercial in confidence and cannot be reported here. But the committee noted that there was uncertainty about the most appropriate utility values to use in the economic model and that the utility values from the company's trial lacked face validity (see section 3.9). It also noted that a scenario analysis using utility values from NICE's technology appraisal guidance on nivolumab for advanced non-squamous NSCLC after chemotherapy produced an ICER slightly above 50,000 per QALY gained. But the committee also noted that some of the assumptions included in the company's base-case analysis were conservative, for example, excluding the costs of pembrolizumab and nivolumab in the blended comparator arm. The committee considered the uncertainty and the range in the cost-effectiveness estimates. But it agreed that the most plausible ICER was sufficiently below 50,000 per QALY gained to be considered an acceptable use of NHS resources.

# Other factors

## Mobocertinib is innovative but all benefits are captured in the analysis
The committee considered mobocertinib to be innovative because it represents a step-change in the treatment of exon 20 insertion mutation-positive NSCLC. The company did not present any evidence to suggest that there were additional benefits that were not captured in the QALY calculations. The committee considered the unmet need and the burden of stigma in its deliberations, and recognised that mobocertinib provides important benefits for people with exon 20 insertion mutation-positive NSCLC. But it did not consider that there were any additional benefits that had not been captured in the QALY calculations.

## There are no equality issues relevant to the recommendations
The company explained that exon 20 insertion mutation-positive NSCLC is associated with a higher prevalence in people from an East Asian family background. Differences in prevalence cannot usually be resolved in a technology appraisal, although the committee can consider whether a specific equality issue has a significant impact on access to treatment. Also, the recommendation for mobocertinib is for the full population in the marketing authorisation. So, the committee agreed that its recommendations would not have a different effect on people protected by the equality legislation than on the wider population. The committee concluded that there were no equality issues relevant to the recommendations.

# Conclusion

## Mobocertinib is recommended for routine use
The committee concluded that there was substantial uncertainty in the cost-effectiveness estimates. But it agreed that the most likely estimates are within what NICE considers a cost-effective use of NHS resources when the end of life modifier is applied. So, mobocertinib is recommended as an option for treating EGFR exon 20 insertion mutation-positive advanced NSCLC after platinum-based chemotherapy.