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3 Committee discussion

The evaluation committee considered evidence submitted by Merck Sharp and Dohme (MSD), a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence.

The condition

Details of condition

3.1

The patient experts explained that the symptoms of gastric or gastro-oesophageal junction (GOJ) cancer have a substantial impact on quality of life. The symptoms of advanced stage cancer may include a lack of appetite, weight loss, fluid in the abdomen and blood in the stool. The patient experts noted that symptoms can affect physical, social, and work life, and impact nutritional status and the ability to eat. They also highlighted the psychological distress because of poor prognosis and the demanding treatment pathway of gastric or GOJ cancer. The committee noted the wide impact of symptom burden, particularly in advanced stages, on the quality of life for people with gastric or GOJ cancer. The patient experts highlighted that the cancer is mostly diagnosed at an advanced stage because of a lack of screening and vague early symptoms. So, there are limited effective treatment options (see section 3.2) and survival prognosis is poor. The clinical experts explained that treatment aims to slow progression of the disease, extend life, and maintain or improve quality of life for as long as possible but new and effective treatment options are still needed. The committee noted the poor survival prognosis of people with gastric and GOJ cancer and understood that there is an unmet need for additional treatment options.

Clinical management

Treatment pathway and comparators

3.2

Trastuzumab plus platinum-containing chemotherapy (from now, trastuzumab plus chemotherapy) is recommended by NICE for people with HER2-positive metastatic gastric or GOJ cancer (see NICE's technology appraisal guidance on trastuzumab for the treatment of HER2-positive metastatic gastric cancer). People with a performance status of 0 to 2 and no significant comorbidities may also be offered 5-fluorouracil or capecitabine with cisplatin or oxaliplatin (doublet chemotherapy) or 5-fluorouracil or capecitabine with cisplatin or oxaliplatin plus epirubicin (triplet chemotherapy) (see NICE guideline 83 on oesophago-gastric cancer: assessment and management in adults). The company used trastuzumab plus chemotherapy as the only comparator in its submission. It noted that trastuzumab plus chemotherapy is recommended by NICE for metastatic gastric or GOJ cancer, but not for locally advanced cancer. The company stated that the European Society of Medical Oncology guidelines and clinical experts suggested that locally advanced unresectable gastric or GOJ cancers are treated similarly to metastatic cancer. So, it considered doublet or triplet chemotherapy, without trastuzumab, not to be relevant comparators. The EAG agreed that trastuzumab plus chemotherapy is the most relevant comparator. The committee concluded that trastuzumab plus chemotherapy is the most appropriate comparator for this appraisal.

Clinical effectiveness

Data sources

3.3

Clinical evidence for pembrolizumab plus trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy (from now, pembrolizumab plus trastuzumab and chemotherapy) compared with trastuzumab plus chemotherapy is from KEYNOTE-811. This is a phase 3, randomised, double-blind, placebo-controlled trial, that included people aged 18 and over with untreated locally advanced or unresectable HER2-positive gastric or GOJ cancer. KEYNOTE-811 is a global study, carried out across 192 centres in 19 countries, including 29 people from the UK across 10 centres. Randomisation in KEYNOTE-811 was arranged by:

  • Geographic region:

    • Western Europe, Israel, North America and Australia

    • Asia

    • 'rest of the world', including South America

  • PD-L1 status:

    • combined positive score (CPS) of 0

    • CPS of 1 or more

The company's evidence submission (including its economic modelling, see section 3.7) focused on a subgroup of people from KEYNOTE-811 whose tumours express PD-L1 with a CPS of 1 or more, which is in line with the marketing authorisation for pembrolizumab with trastuzumab and chemotherapy. The company also only used evidence from people outside the Asia region (the non-Asia cohort). This was generated in a post-hoc analysis by combining data from the Western Europe, Israel, North America and Australia cohort and the 'rest of the world' cohort (see section 3.5). The committee concluded that KEYNOTE-811 was appropriate for decision-making.

Clinical study results

3.4

The company presented the results of interim analysis 2 (data cut off May 2022) which had a median follow-up of 17 months in the pembrolizumab plus trastuzumab and chemotherapy arm and 13.9 months in the trastuzumab plus chemotherapy arm. For the non-Asia cohort with PD-L1 with a CPS of 1 or more, pembrolizumab plus trastuzumab and chemotherapy significantly improved both progression‑free survival (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.49 to 0.78; p-value equal to 0.0001) and overall survival (HR 0.67, 95% CI 0.52 to 0.85; p-value equal to 0.0006), compared with trastuzumab plus chemotherapy. The committee was aware of the recently published interim analysis 3 of KEYNOTE-811 with a median follow up of 38.4 months in the pembrolizumab plus trastuzumab and chemotherapy arm and 38.6 months in the trastuzumab plus chemotherapy arm.

Generalisability of trial population

3.5

The EAG questioned the validity of using clinical effectiveness data from the non-Asia cohort. This is because the non-Asia cohort was not a pre-specified subgroup in KEYNOTE-811. The EAG also highlighted that the progression-free and overall survival data from the 'rest of the world' cohort was more favourable for pembrolizumab plus trastuzumab and chemotherapy, compared with survival data from the Western Europe, Israel, North America and Australia cohort. It considered that the company did not provide justification for this so requested that the company do a scenario analysis using clinical effectiveness data from the Western Europe, Israel, North America and Australia cohort. The company stated that clinical experts considered that all trial centres within the non-Asia cohort, including trial centres in the 'rest of the world' cohort, to be generalisable to NHS clinical practice. It also highlighted that using data from the non-Asia cohort, including the 'rest of the world' cohort, meant that a larger sample size could be used. The clinical experts at the appraisal committee meeting considered that the non-Asia cohort, including the 'rest of the world' cohort, is generalisable to NHS clinical practice. The committee asked whether excluding data from people treated in Asia would affect the generalisability of the evidence to people of an Asian family background who are receiving treatment in the NHS. The clinical experts explained that outcomes are better for people in East Asia compared with the 'rest of the world'. This is because of differences in clinical practice in these regions, which means that people are diagnosed earlier so treatments are more effective, rather than biological differences based on family background. So, the committee considered that it is appropriate to not include the Asia cohort in the analysis for decision-making. It also noted that there was no clear reason for any difference between the Western Europe, Israel, North America and Australia cohort and the 'rest of the world' cohort, and that using data from the non-Asia cohort maintains a larger sample size. The committee concluded that the non-Asia cohort is generalisable to NHS clinical practice and is appropriate for decision-making.

Economic model

Company's modelling approach

3.6

The company submitted a partitioned survival model to estimate the cost-effectiveness of pembrolizumab plus trastuzumab and chemotherapy compared with trastuzumab plus chemotherapy. It had 3 health states: progression‑free, progressed disease and death. The committee acknowledged that the partitioned survival model is a standard approach to estimate the cost-effectiveness of cancer drugs and considered it to be appropriate for decision-making.

Long-term overall survival extrapolations

3.7

In the company's model after technical engagement, the company used independently fitted survival curves to predict the long-term survival for the pembrolizumab plus trastuzumab and chemotherapy and trastuzumab plus chemotherapy arms. The curves were fitted to data from interim analysis 2 of the non-Asia cohort with PD-L1 with a CPS of 1 or more from KEYNOTE-811. For overall survival, the company's preferred long-term extrapolations were:

  • 2-knot odds spline model for the pembrolizumab plus trastuzumab and chemotherapy arm;

  • Weibull for the trastuzumab plus chemotherapy arm.

The company justified its choice of overall survival extrapolations based on the Kaplan-Meier data from KEYNOTE-811 and clinical expert opinion provided to the company and the EAG. It highlighted that there is a lack of immunotherapies for this condition, so suggested that clinical experts may underestimate the long-term survival benefit of pembrolizumab. The EAG considered that the company had not provided enough evidence to support the choice of overall survival extrapolation models for each treatment arm. It highlighted that the company's preferred extrapolations have the highest overall survival predictions for the pembrolizumab plus trastuzumab and chemotherapy arm and the lowest overall survival predictions for the trastuzumab plus chemotherapy arm. This means that the company's preferred extrapolations predict the highest overall survival benefit for pembrolizumab plus trastuzumab and chemotherapy of all fitted parametric and spline models. The EAG also noted that the statistical goodness-of-fit and visual assessment suggests that the company's preferred extrapolation for the trastuzumab plus chemotherapy arm does not fit the data from KEYNOTE-811 well. The EAG preferred the one-knot hazard spline model for overall survival extrapolation in the pembrolizumab plus trastuzumab and chemotherapy arm and the one-knot normal spline model in the trastuzumab plus chemotherapy arm. The committee noted that the choice of overall survival extrapolations has a large impact on the cost-effectiveness results. It considered that the survival estimates based on interim analysis 2 of KEYNOTE-811 are very uncertain. The committee recalled that overall survival data with longer follow-up from interim analysis 3 of KEYNOTE-811 is now available (see section 3.4). It considered that this may reduce the uncertainty in the long-term overall survival extrapolations. So, the committee concluded that it was unable to determine the most appropriate overall survival extrapolations and requested additional analyses using interim analysis 3 of KEYNOTE-811. It also requested that the company provides clear justification for its choice of overall survival extrapolations, including validation with clinical experts.

Source of utility values

3.8

The company used EQ-5D-5L data collected directly from the non-Asia cohort with PD-L1 with a CPS of 1 or more from KEYNOTE-811 to estimate utility values. The utility values were mapped to the EQ-5D-3L value set using the mapping function developed by the Decision Support Unit. In its base case, the company included utility values based on a time-to-death approach with 4 categorical groups:

  • less than 30 days from death

  • 30 to 179 days from death

  • 180 to 359 days from death

  • 360 days or more from death.

The company also did a scenario using a progression-based approach. The EAG also used the time-to-death approach in its base case, but considered that there is considerable uncertainty related to using a time-to-death approach for applying utility values. The EAG highlighted that both the time-to-death and progression-based approach have limitations because the data collected has been heavily censored, either at the point of progression or at treatment discontinuation. It noted that a progression-based approach is more widely used and that clinical advice to the EAG suggested that progression and adverse events are the key drivers of utility in this disease area. The EAG also considered that the company's estimated utility values lack face validity for populations with advanced gastric or GOJ cancer. The utility values are considered confidential by the company so cannot be reported here. The committee noted that there is a lack of utility data in gastric or GOJ cancer. It also acknowledged that although the progression-based approach is more widely used, the time-to-death approach has also been previously used in NICE appraisals. The committee considered that there was uncertainty about the most appropriate approach but noted that the choice of approach had a relatively small impact on the cost-effectiveness results. It concluded that it was appropriate to use the time-to-death approach in the analyses for decision-making. The company used descriptive statistics without adjustment for repeated measures to estimate utility values in its base case. The company explained that this means that people with multiple measurements contribute more to the estimate of the utility than those with a single measurement. It considered that this was appropriate because people who spend the longest in a health state should contribute more to the estimate of utility for that health state. The EAG preferred to use a linear mixed effect regression model with adjustment for repeated measures in its base case model. This is because this approach adjusts for repeated measures and for covariates which may be important confounders. The committee concluded that the linear mixed effects regression model, which accounts for repeated measures, is more appropriate than using a descriptive analysis. So, its preferred approach to utility values was a time-to-death approach using linear mixed effect regression modelling.

Time to treatment discontinuation of trastuzumab

3.9

The company used time-to-treatment discontinuation data from KEYNOTE-811 to inform treatment acquisition and administration costs for each treatment in the model. The company also applied a cap on the maximum treatment duration for each treatment. In its base case, the company applied a cap of 35 cycles to trastuzumab treatment. The EAG disagreed with this approach as there is no restriction on the duration of trastuzumab treatment in NICE's technology appraisal guidance on trastuzumab for the treatment of HER2-positive metastatic gastric cancer, other than for disease progression or unacceptable toxicity. Clinical advice to the EAG stated that, in clinical practice, trastuzumab treatment should continue until disease progression or unacceptable toxicity. So, the EAG removed this cap. The clinical experts at the appraisal committee meeting agreed that trastuzumab should be continued until disease progression. The committee concluded that it is appropriate to model trastuzumab treatment based on the time-to-treatment discontinuation curve from KEYNOTE-811 with no cap applied.

Trastuzumab administration cost

3.10

In its base case, the company applied a reference cost based on health resource group (HRG) code SB13Z (complex delivery) to trastuzumab whether given alone or with pembrolizumab after the completion of chemotherapy. The EAG considered that there should be some difference in administration costs for trastuzumab given alone (simple delivery, HRG code SB12Z) compared with trastuzumab given in combination with pembrolizumab (complex delivery, HRG code SB13Z). The NHS England Cancer Drugs Fund (CDF) clinical lead advised the NICE technical team that there is variation in the HRG codes used in clinical practice. They recommended that most NHS trusts would use different HRG codes for the administration of trastuzumab monotherapy after chemotherapy (HRG code SB12Z) and the administration of pembrolizumab with trastuzumab after chemotherapy (HRG code SB17Z). The EAG did an additional scenario analysis exploring the impact of using updated costs for trastuzumab administration provided by the NHS England CDF clinical lead. The committee noted the additional EAG scenario had little impact on the cost-effectiveness results. It considered that there was uncertainty in the HRG codes that would be used in clinical practice. The committee concluded that the scenario analysis with updated costs for trastuzumab administration provided by the NHS England CDF clinical lead is appropriate for decision-making.

PD-L1 testing

3.11

The company's base case model assumes that no additional testing will be needed to determine eligibility of pembrolizumab for locally advanced unresectable or metastatic HER2-positive gastric or GOJ cancer in adults whose tumours express PD-L1 with a CPS of 1 or more. The company considered that these people are already routinely tested for PD-L1 at the same time they are tested for HER2 to determine eligibility for nivolumab with platinum- and fluoropyrimidine-based chemotherapy, which is recommended by NICE for untreated HER2-negative advanced gastric, GOJ or oesophageal adenocarcinoma. The company noted that if testing was not already being carried out, the cost of PD-L1 testing would be £424 per person eligible to receive pembrolizumab. This was based on a cost of £53 per test and an estimate that 8 people would need testing to identify a single eligible person. The clinical experts explained that there are regional variations in testing and in some centres PD-L1 testing is not routinely carried out alongside HER2 testing. If pembrolizumab plus trastuzumab and chemotherapy was recommended, then PD-L1 testing strategies would change in clinical practice and HER2 and PD-L1 testing would be done at the same time. The committee concluded that PD-L1 testing costs should be included in the economic model.

Severity

3.12

The committee considered the severity of the condition (the future health lost by people living with the condition and having standard care in the NHS). The committee may apply a greater weight to QALYs (a severity modifier) if technologies are indicated for conditions with a high degree of severity. When using data from the non-Asia cohort with PD-L1 with a CPS of 1 or more, the company and the EAG agreed that it was appropriate to apply a severity weight of 1.2 to the QALYs. The committee concluded that a severity weight of 1.2 applied to the QALYs was appropriate.

Cost-effectiveness estimates

Company and EAG cost-effectiveness estimates

3.13

The cost-effectiveness estimates used by the committee for decision making took into account all of the available confidential discounts, including those for comparators and follow up treatments. These estimates are confidential and cannot be reported here. The company and the EAG's base case results for pembrolizumab plus trastuzumab and chemotherapy compared with trastuzumab plus chemotherapy were above the range normally considered a cost-effective use of NHS resources.

The committee's preferences

3.14

The committee preferred the model to include:

  • data from the non-Asia cohort (see section 3.5)

  • data from interim analysis 3 of KEYNOTE-811 to inform the long-term survival extrapolation, with clear rationale and external validation of the most appropriate long-term overall survival estimates (see section 3.7)

  • utility values from time-to-death approach using linear mixed effect regression modelling (see section 3.8)

  • PD-L1 testing costs (see section 3.11)

  • treatment with trastuzumab modelled based on the time-to-treatment discontinuation curve from KEYNOTE-811, with no cap applied (see section 3.9)

  • costs for trastuzumab administration in line with EAG's scenario analysis (see section 3.10)

  • severity weight of 1.2 applied to the QALYs (see section 3.12).

The committee could not identify the most plausible incremental cost-effectiveness ratio because overall survival extrapolations based on interim analysis 3 were not available. It requested an updated model using data from interim analysis 3 of KEYNOTE-811 (see section 3.7).

Other factors

Equality

3.15

The patient experts stated that people from the most deprived areas and younger people are more likely to be diagnosed with gastric or GOJ cancer at more advanced stages. They noted that people from an East Asian family background have a higher risk of developing gastric or GOJ cancer. They also noted potential language barriers in sharing information with hard-to-reach community groups. The committee noted that the analyses for decision-making were based on the non-Asia cohort of KEYNOTE-811 (see section 3.5). The committee heard that outcomes are better for people in East Asia compared with the rest of the world because of differences in clinical practice in these regions, rather than biological differences based on family background. So, the committee considered that excluding data from people treated in Asia would not affect the generalisability of the evidence to people of an Asian family background who are receiving treatment in the NHS. The committee discussed equality issues, and agreed that its recommendations do not have a different impact on people protected by the equality legislation than on the wider population. The committee considered that there were no equalities issues that could be addressed by its recommendations.

Innovation

3.16

The committee did not identify any additional benefits of pembrolizumab plus trastuzumab and chemotherapy not captured in the economic modelling.

Conclusion

Recommendation

3.17

The committee agreed that further data from interim analysis 3 of KEYNOTE-811 was needed to inform the most appropriate overall survival extrapolations for pembrolizumab plus trastuzumab and chemotherapy, and for trastuzumab plus chemotherapy. Because of the uncertainties and the overall survival extrapolations based on data from interim analysis 3 were not available, the committee was unable to identify the most plausible cost-effectiveness estimate. But it was aware that the company and EAG base cases were above the level normally considered cost effective. So, pembrolizumab plus trastuzumab and chemotherapy is not recommended for untreated locally advanced unresectable or metastatic HER2-positive gastric or GOJ cancer.