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

People with EGFR exon 20 insertion mutation-positive advanced NSCLC will welcome a new treatment option that is targeted and well tolerated

3.1 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 improved 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 exon 20 insertion mutations.

EGFR tyrosine kinase inhibitors are not appropriate comparators

3.2 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, PD‑L1 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. However, the efficacy outcomes 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 tyrosine kinase inhibitors (TKIs). The company explained that their choice of blended comparators reflected the treatments used in 2 real-world evidence sources:

Using a blended comparator arm increases uncertainty

3.3 The company's approach compared mobocertinib with a group of blended comparators (see section 3.2). The company explained that there was no robust way to define standard care, so it was not feasible to identify a single treatment that would be displaced by mobocertinib. The committee noted that company's base-case approach only allowed mobocertinib to be compared with the average clinical effectiveness across all treatments in the blended comparator arm. Also, the company included costs for a different blend of treatments (see section 3.14). The committee concluded that using a blended comparator substantially increased the uncertainty of mobocertinib's relative effectiveness compared with current treatments.

Mobocertinib is clinically effective, but the size of this benefit compared with current treatments is difficult to establish

3.4 The main evidence for mobocertinib came from the platinum pretreated cohort (n=114) in Study AP32788‑15‑101. This was a single-arm, open-label, multicentre, phase 1 and 2 trial. Results from November 2020 showed a median investigator-assessed progression-free survival of 7.33 months (95% confidence interval [CI] 5.55 to 8.84) and a median overall survival of 23.95 months (95% CI 14.55 to 28.81). Results from November 2021 for progression-free and overall survival were also available but are considered confidential by the company so cannot be reported here. The clinical experts considered these results to be clinically meaningful. Overall, the committee concluded that Study AP32788‑15‑101 showed clinically meaningful results. But it thought that that the lack of direct comparative evidence meant the size of benefit compared with current treatments was difficult to establish.

Approach to using real-world evidence for the blended comparator arm may not be robust and is associated with uncertainty

3.5 Study AP32788‑15‑101 did not have a comparator arm (see section 3.4), and the company did not identify any other trials for comparing mobocertinib with the relevant comparators. So, it did an indirect treatment comparison of mobocertinib compared with the blended comparator arm 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 these mutations. This evidence came from Flatiron and the German Chart Review. The ERG highlighted that the clinical evidence may not have been generalisable because neither Study AP32788‑15‑101 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 suggested using data from UK's NHS National Cancer Registration and Analysis Service (NCRAS). The company stated that the NCRAS evidence did not include data on exon 20 insertion mutation-specific clinical outcomes, making it unusable. The committee noted this, and that the US and German real-world evidence included data on progression-free survival, time to next treatment and overall survival. The ERG noted that the company did not provide a full, justified rationale for its choice of real-world evidence sources. 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. It concluded that the choice of real-world evidence may not have been robust and was associated with uncertainty.

The way the company has used real-world evidence is associated with several areas of uncertainty and likely biases the results

3.6 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 AP32788‑15‑101, 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 AP32788‑15‑101 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 Study AP32788‑15‑101, in which people generally have closer monitoring. The company also highlighted that the definition of the index-line of therapy 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. The ERG stated that it was unable to explore the extent of bias based on the information provided by the company. The committee noted that real-world evidence can be associated with limitations. But it noted that, despite these known limitations, it can be valuable in resolving gaps in knowledge when best-practice methods are applied (such as those described in the NICE real-world evidence framework). It also acknowledged that, because of the rarity of exon 20 insertion mutation-positive NSCLC, real-world evidence may be the best available source of evidence for the comparator arm. However, the committee considered that the company had not provided enough information on data provenance, data accuracy and data suitability, and had not explored the effect of missing data. The committee concluded that the way the company had chosen and used real-world evidence was associated with several areas of uncertainty. It thought that this had likely biased the results in the modelling.

The level of uncertainty from the real-world evidence can be reduced

3.7 The committee noted that the company could have used well-validated real-world evidence checklists and reporting tools (such as the RECORD-PE checklist or the STaRT-RWE template). The company could have done a sensitivity analysis using a multiple imputation approach to assess the effect of missing data. It could also have reduced uncertainty by providing further detail on how it chose data sources and assessed their suitability. In particular, for the 2 sources in the company's submission, further information to reduce uncertainty, based on the NICE real-world evidence framework, could have included:

The committee noted that a study protocol was provided for the German chart review and not for Flatiron. It thought that full study protocols for the German chart review and Flatiron according to the NICE real-world evidence framework requirements should have been provided. The committee concluded that the level of uncertainty could be reduced if further information was provided, although some bias would likely remain.

The company's indirect treatment comparison is suitable for decision making but is associated with uncertainty

3.8 To account for differences in populations between Study AP32788‑15‑101 and the real-world evidence sources, the company adjusted for key prognostic variables and baseline characteristics. The factors 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 therapy were excluded. The ERG suggested using the multiple imputation method to adjust for ECOG performance status. It was concerned that the method of inclusion of prognostic factors was poorly justified, and that all possible confounding variables should have been included. The committee agreed that it was not clear how people were excluded from the real-world evidence analysis, which increased the risk of selection bias. The committee noted that the indirect treatment comparison was associated with uncertainty. It concluded that this was because of the residual confounding noted by the ERG, and the potential evidence selection issues associated with the blended comparator data (see section 3.5 and section 3.7).

Results from the indirect treatment comparison show statistically significant improvements with mobocertinib, but are uncertain

3.9 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, such as being limited by the number of covariates included for adjustment (see section 3.8). 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.

It is more appropriate to use utility values from past appraisals

3.10 The company mapped EQ‑5D‑5L data from Study AP32788‑15‑101 to EQ‑5D‑3L. The mapped EQ‑5D‑3L 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 utility values for progression-free and progressed disease were higher than what was used in past appraisals (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 committee considered the similarity between the general population utility and the progression-free health-state utility value. It concluded that the company's utility values lacked face validity. Because of the number of people who had cerebral involvement in Study AP32788‑15‑101, the committee expected the utility differences to be larger when compared with the general population. It discussed that the company's progressed-state utility was higher than that used in past appraisals. It also discussed that it did not reflect reality because the data was collected at early-progression compared with later on in the progressed health state. The committee concluded that the utility values for the progression-free survival state (0.713) and post-progression state (0.569) from NICE's technology appraisal guidance on nivolumab were more appropriate.

The company's model structure is suitable for decision making

3.11 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

3.12 The company fitted parametric models to the Kaplan–Meier 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. For overall survival, the company fitted a joint generalised gamma model. The company explained that predicted overall survival was in line with clinical expert advice. The ERG explored the Weibull distribution for overall survival in a scenario because it had a better statistical fit than the generalised gamma distribution. The ERG stated that the Weibull outcomes were also aligned with the company's clinical expert opinion values. For progression-free survival and TTD, the company fitted a joint exponential distribution. The company explained that, for progression-free survival, the exponential distribution was chosen based on clinical plausibility and long-term outcomes. For TTD, the company chose the exponential distribution. This was because everyone was expected to stop treatment after 5 years, and because it aligned with progression-free survival. The ERG disagreed with the company's choice of progression-free survival and TTD models 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. The ERG preferred the generalised gamma distribution for progression-free survival and Gompertz for TTD. The committee agreed with the ERG's choice. It was aware that using the ERG's choice only had a small effect on the cost-effectiveness results. But it considered the ERG's choice was more plausible than the company's.

It is appropriate to exclude treatment effect waning from the modelling

3.13 The company's base case assumed that mobocertinib's treatment effect is 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

3.14 The company only 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. It 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 EGFR TKIs and immunotherapies. It agreed that the company had taken a conservative approach by excluding 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.

Exon 20 insertion mutation testing costs should be included in a scenario analysis

3.15 In line with section 5.9.1 of NICE's guide to the methods of technology appraisal, the 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 committee concluded that it would be appropriate to consider scenarios with additional testing costs in the economic modelling.

Mobocertinib meets the criteria to be considered a life-extending treatment at the end of life

3.16 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 with the real-world evidence and model estimates previously discussed (see section 3.6 and section 3.9). 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.

Because of the uncertainty, an acceptable ICER would be substantially below £50,000 per QALY gained

3.17 NICE's guide to the methods of technology appraisal notes that, above a most plausible ICER of £20,000 per quality adjusted life year (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. The committee noted the high level of uncertainty in the company's model, specifically:

Because of this, the committee would expect an acceptable ICER to be around £20,000 per QALY gained. However, the committee also agreed that the end of life criteria applied to mobocertinib, which allows it to consider ICERs of up to £50,000 per QALY gained. The committee agreed that, when taking into account the substantial levels of uncertainty associated with the company's approach an acceptable ICER would be at the lower end of the range normally considered cost effective This means that when end of life weighting is applied, the maximum acceptable ICER would be substantially less than £50,000 per QALY gained. It highlighted that this acceptable ICER was based on the substantial levels of uncertainty associated with the company's approach to using real-world evidence.

The range of cost-effectiveness estimates are above £50,000 per QALY gained

3.18 The company's base-case ICER for mobocertinib compared with the blended comparator arm was over £50,000 per QALY gained, when commercial arrangements for mobocertinib and all the comparators were included. The committee considered the scenario including its preferred assumptions, which were:

It noted that the ICERs for this scenario, and for all other scenarios presented, were all above £50,000 per QALY gained, when commercial arrangements for mobocertinib and all the comparators were included. The exact ICERs are commercial in confidence and cannot be reported here. The committee also recognised that none of the scenarios presented considered the additional costs for exon 20 insertion mutation testing (see section 3.15). These costs, if included, would likely increase the ICER. It also noted the substantial uncertainty in all the cost-effectiveness estimates, and concluded that it could not recommend mobocertinib for routine use.

Mobocertinib does not meet the criteria to be included in the Cancer Drugs Fund

3.19 Having concluded that mobocertinib could not be recommended for routine use, the committee then considered whether it could be recommended for treating exon 20 insertion mutation-positive NSCLC in the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). The committee recalled that the main uncertainties in this appraisal related to the limitations of the company's approach to existing real-world evidence (including the real-world evidence selection issues; see section 3.5). The Cancer Drugs Fund lead explained that making mobocertinib available in the Cancer Drugs Fund would not generate data to resolve the main uncertainties. This was because Study AP32788‑15‑101 was mature. The committee recalled that all plausible ICERs were above £50,000 per QALY gained, and were substantially higher than the maximum considered acceptable because of the uncertainty in this appraisal. The committee concluded that it is unlikely that Cancer Drugs Fund data collection would reduce the uncertainties and improve the cost-effectiveness estimate for mobocertinib. So, mobocertinib could not be recommended for use in the Cancer Drugs Fund.

Mobocertinib is innovative but all benefits are captured in the analysis

3.20 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 recognised that mobocertinib provides important benefits for people with exon 20 insertion mutation-positive NSCLC. But it did consider that there were no additional benefits that had not been captured in the QALY calculations.

There are no equality issues relevant to the recommendations

3.21 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.

Mobocertinib is not recommended

3.22 The committee concluded that mobocertinib is not recommended for treating EGFR exon 20 insertion mutation-positive NSCLC after platinum-based chemotherapy. This was because of the uncertainties in the evidence and because all the ICERs were above the range considered to be a cost-effective use of NHS resources when the end of life modifier was applied.

Dr Lindsay Smith
Chair, appraisal committee
August 2022