3 Committee discussion
The evaluation committee considered evidence submitted by Merck Sharp and Dohme, 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
Gastric and gastro-oesophageal junction (GOJ) adenocarcinomas are types of cancer. The patient experts explained that the symptoms of gastric or GOJ cancer have a substantial effect on quality of life. Symptoms may include indigestion, poor appetite or early satiety, weight loss and abdominal pain. A patient expert noted that symptoms can cause eating and swallowing difficulties, which can lead to people needing a jejunostomy feeding tube as the condition advances. Side effects of current treatments, such as chemotherapies, can reduce the quality of life of those having treatment with them. The clinical and patient experts highlighted a particular unmet need in younger adults with gastric or GOJ cancer. Younger adults can have non-specific symptoms that are not easily identified as cancer, which can lead to the condition being diagnosed at a later stage. A patient expert noted that younger adults may particularly benefit from new technologies because they are likely to be well enough to tolerate the treatment. If symptoms are present at the time of diagnosis, the cancer is often advanced and incurable, leading to poor survival prognosis. The committee concluded that the symptoms of gastric or GOJ cancer can have a considerable effect on quality of life and that life expectancy with the condition is poor. It noted that this may particularly be the case for younger adults who tend to be diagnosed when their cancer is more advanced.
Clinical management
Treatment pathway and comparators
3.2
People with an Eastern Cooperative Oncology Group performance status score of 0 to 2 and no significant comorbidities may be offered doublet chemotherapy comprising fluoropyrimidine-based chemotherapy (fluorouracil or capecitabine) with platinum-based chemotherapy (cisplatin or oxaliplatin). They can also be offered triplet chemotherapy comprising fluorouracil or capecitabine with cisplatin or oxaliplatin plus epirubicin (see NICE's guideline on oesophago-gastric cancer: assessment and management in adults). In previous technology appraisals for this condition, it has been noted by clinical experts that, in practice, triplet chemotherapy is not a standard treatment in the NHS. This is because it increases toxicity without increasing the clinical effectiveness of the chemotherapy. The committee heard from the clinical expert that each of the doublet chemotherapy combinations are considered clinically equivalent. The choice of chemotherapy may depend on several factors. These include whether the treatment is oral or intravenous (because some people with gastric or GOJ cancer may have difficulty swallowing), the potential adverse effects and how often the doses are administered. Nivolumab plus platinum- and fluoropyrimidine-based chemotherapy (nivolumab plus doublet chemotherapy) is recommended for untreated HER2‑negative, advanced or metastatic gastric, GOJ or oesophageal adenocarcinoma in adults whose tumours express PD‑L1 with a combined positive score (CPS) of 5 or more (see NICE's technology appraisal guidance on nivolumab with platinum- and fluoropyrimidine-based chemotherapy for untreated HER2-negative advanced gastric, GOJ or oesophageal adenocarcinoma). In its submission, the company presented a comparison with doublet chemotherapy as the only comparator for people whose tumours express PD‑L1 with a CPS of 1 or more. The committee agreed that this would be the relevant comparator for the subgroup of people whose tumours express PD‑L1 with a CPS of 1 to 4. The committee also agreed that there was a particular unmet need for this group because there were no immunotherapy treatments recommended by NICE for people whose tumours express PD‑L1 with a CPS of 1 to 4. Nivolumab plus doublet chemotherapy was the comparator for people whose tumours express PD‑L1 with a CPS of 5 or more. The committee concluded that doublet chemotherapy and nivolumab plus doublet chemotherapy were appropriate comparators for this evaluation.
Clinical effectiveness
Clinical trial evidence
3.3
Clinical evidence for pembrolizumab plus doublet chemotherapy compared with placebo plus doublet chemotherapy is from the KEYNOTE‑859 trial. This was an international, phase 3, randomised, double-blind, placebo-controlled trial that included people with untreated, unresectable or metastatic HER2‑negative gastric or GOJ adenocarcinoma. The relevant data came from the subgroup of people whose tumours express PD‑L1 with a CPS of 1 or more (from now, the CPS of 1 or more subgroup) because this group reflects the population for whom pembrolizumab plus doublet chemotherapy is licensed. The company presented the results of the first interim analysis (data cut October 2022) which had a median follow up of 11.9 months. For the CPS of 1 or more subgroup, pembrolizumab plus doublet chemotherapy statistically significantly improved both progression-free survival (hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.63 to 0.82; p<0.0001) and overall survival (HR 0.74, 95% CI 0.65 to 0.84; p<0.0001), compared with placebo plus doublet chemotherapy. The clinical expert stated that response to treatment is a key outcome. They added that this affects not only symptomatic relief and increased survival but may enable people whose cancer responds to treatment to be able to have cytotoxic chemotherapy for a shorter time. Pembrolizumab plus doublet chemotherapy increased the proportion of people whose cancer had a complete or partial response to treatment. In the pembrolizumab plus doublet chemotherapy arm 52.1% (95% CI 48.1 to 56.1) of people had cancer that reached this secondary outcome compared with 42.6% (95% CI 38.7 to 46.6) in the placebo plus doublet chemotherapy arm. As part of its response to draft guidance consultation, the company submitted results of the longer-term follow-up analysis (data cut August 2023). This analysis provided 10 months of data on progression-free survival and overall survival in addition to the interim analysis. The longer-term follow-up data also showed that for the CPS of 1 or more subgroup, pembrolizumab plus doublet chemotherapy statistically significantly improved both progression-free survival and overall survival, compared with placebo plus doublet chemotherapy. The committee concluded that pembrolizumab plus doublet chemotherapy was clinically effective compared with doublet chemotherapy alone. It concluded that it delayed the time to cancer progression, increased the proportion of people whose cancer responded to treatment and improved overall survival.
PD-L1 with a CPS of 1 to 4 subgroup
3.4
The committee noted that the data for pembrolizumab plus doublet chemotherapy compared with doublet chemotherapy alone came from a broader group of people than would currently have doublet chemotherapy alone in clinical practice. That is, the CPS of 1 or more subgroup included people whose tumours express PD‑L1 with a CPS of 5 or more, who would have nivolumab plus doublet chemotherapy. A consultee commented that people whose tumours have a higher PD‑L1 CPS potentially benefit more from immunotherapies such as pembrolizumab. So, the CPS of 1 or more subgroup may overestimate the clinical effectiveness of pembrolizumab plus doublet chemotherapy compared with doublet chemotherapy alone, if applied specifically to people whose tumours express PD‑L1 with a CPS of 1 to 4. The company commented that KEYNOTE‑859 was not powered to detect statistically significant differences in the PD‑L1 CPS 1 to 4 subgroup. It also noted that the clinical trial's randomisation would need to be broken to be able to do analyses on this subgroup. The committee acknowledged that there was a risk that analyses using the CPS of 1 or more subgroup may overestimate the effectiveness of pembrolizumab plus doublet chemotherapy compared with doublet chemotherapy alone. But it also agreed that doing further subgroup analyses for people whose tumours express PD‑L1 with a CPS of 1 to 4 would be less methodologically robust and be subject to bias. The committee concluded that it was appropriate to have applied the results from the CPS of 1 or more subgroup for people with a CPS of 1 to 4, for the comparison with doublet chemotherapy alone. The committee agreed it would take into account the uncertainty around potential overestimation of treatment effect in its decision making.
Adverse events
3.6
The company suggested that any observed differences in the adverse event profiles for pembrolizumab and nivolumab from the trials are explained by the difference in their concomitant doublet chemotherapy. The clinical expert confirmed this assumption, noting that adverse events related to immunotherapy are very similar for pembrolizumab and nivolumab and are manageable in clinical practice. The company also included a scenario that assumed that pembrolizumab's and nivolumab's adverse event profiles were equivalent, which had little effect on the incremental cost-effectiveness ratio (ICER). The committee concluded that pembrolizumab and nivolumab were similarly tolerated.
Economic model
Company's modelling approach
3.7
The company submitted a partitioned survival model to estimate the cost effectiveness of pembrolizumab plus doublet chemotherapy compared with doublet chemotherapy alone (for the CPS of 1 or more subgroup) and nivolumab plus doublet chemotherapy (for the CPS of 5 or more subgroup). It had 3 health states: progression-free, progressed disease, and death. The model included survival curves for progression-free survival and overall survival which were extrapolated beyond the trial period. The company and EAG used the same methods for extrapolating beyond the trial period in their base case and exploratory base case, respectively. That is, in the CPS of 1 or more population, a 3‑knot odds spline model for overall survival and a 2‑knot hazards spline for progression-free survival were used in both treatment arms. In the CPS of 5 or more subgroup, fractional polynomial models were used (see section 3.5). For the CPS of 5 or more subgroup the company presented both cost-utility results and a cost-minimisation analysis. The committee acknowledged that the partitioned survival model is a standard approach used to estimate the cost effectiveness of cancer medicines and considered it to be appropriate for decision making.
Treatment-effect waning
3.8
The company's economic model included a 35‑cycle maximum treatment duration for pembrolizumab based on KEYNOTE‑859. The company noted that there was no clear evidence of treatment-effect waning based on the independent estimation of survival curves for the intervention and comparator arms of the clinical trials. The EAG commented that it was not reasonable to assume a lifetime treatment effect after pembrolizumab plus doublet chemotherapy has stopped. The committee heard from the clinical expert that the available follow-up data is for less than 5 years. So, there is no data to demonstrate whether the treatment effect of pembrolizumab plus doublet chemotherapy is maintained in the longer term or not. They added that, for the 10% to 15% of people whose cancer has a complete response, treatment-effect waning would not be expected. But for people whose cancer has not had a response within 3 to 6 months, treatment-effect waning would be expected because they would have moved on to less clinically effective follow-on treatments. For the CPS of 1 or more subgroup, the company assumed a gradual treatment-effect waning beginning 7 years after starting treatment that reduced to the same as the comparator arm over the next 2 years. This assumption was only applied to the proportion of people whose cancer did not have a complete response to pembrolizumab plus doublet chemotherapy in KEYNOTE‑859. The company considers the exact percentage of people whose cancer did not have a complete response to be confidential, so it could not be reported here. The EAG was satisfied with this approach. It also noted that the impact of applying a treatment-effect waning assumption to all people (irrespective of response to treatment) had a minimal effect on the cost-effectiveness results. The company also provided scenario analyses in which treatment-effect waning began 6 years and 5 years after starting treatment. The company's chosen timepoints for when treatment-effect waning began were influenced by treatment-effect waning assumptions from previous technology appraisals. This included NICE's technology appraisal guidance on nivolumab with platinum- and fluoropyrimidine-based chemotherapy for untreated HER2-negative advanced gastric, GOJ or oesophageal adenocarcinoma. In that appraisal, the company preferred treatment-effect waning to start 6.5 years after starting treatment with nivolumab plus doublet chemotherapy. But the EAG preferred treatment-effect waning to start 5 years after starting treatment. For both assumptions, the hazard of dying became the same as the comparator arm at the point of treatment waning. The committee concluded that it was appropriate to apply treatment-effect waning for pembrolizumab for the CPS of 1 or more subgroup. It agreed that scenarios in which waning starts at either 5 years, 6 years or 7 years after starting treatment and reduces to the same as the comparator after 2 years, were all plausible. For the CPS of 5 or more subgroup, the company assumed there was no treatment-effect waning for pembrolizumab plus doublet chemotherapy in its base-case analysis. The committee noted that if waning assumptions were applied to the pembrolizumab plus doublet chemotherapy arm and nivolumab plus doublet chemotherapy arm, they would likely cancel each other out. So, the committee concluded that treatment-effect waning did not need to be applied to the CPS of 5 or more subgroup.
Chemotherapy time on treatment
3.9
In the company model, the costs for people having doublet chemotherapy were capped at 6 cycles in line with what the company reported as NHS clinical practice. In KEYNOTE‑859, some people had doublet chemotherapy for more than 6 cycles. The EAG noted that capping doublet chemotherapy costs at 6 cycles does not account for the fact that overall survival and progression-free survival in both treatment arms were based on some people having doublet chemotherapy for more than 6 cycles. The EAG noted that overall survival and progression-free survival in KEYNOTE‑859 may have been higher than what would be observed in clinical practice. The clinical expert explained that there isn't a cap on doublet chemotherapy in clinical practice, although treatment beyond 6 cycles would be rare. This is because the treatment effect of doublet chemotherapy after 6 cycles is modest. So, healthcare professionals will aim to prescribe doublet chemotherapy for the shortest course possible to give a response without toxicity. The clinical expert also noted that the number of cycles could be influenced by the adverse event profiles of different doublet chemotherapy combinations and the use of concomitant immunotherapies. The company stated that a scenario in which the cap on chemotherapy cycles was not applied had a minimal effect on the cost-effectiveness results. The committee concluded that applying a cap of 6 cycles on the costs of doublet chemotherapy in the model was appropriate. So the company's method for modelling survival estimates reflected what would be expected in NHS practice.
Utility values
3.10
Utility values were estimated using EQ‑5D data from the KEYNOTE‑859 trial using 2 different approaches. In its base case the company used a time-to-death approach and presented a health-state approach in scenario analyses. The time-to-death approach estimates utilities using time intervals that describe life expectancy rather than utility values associated with the non-progressed and progressed condition. The company explained that there were a limited number of utility assessments for people with progressed cancer in KEYNOTE‑859. So, health state utilities from the trial data may only reflect quality of life close to the time of cancer progression, rather than the entirety of living with progressed cancer. The company considers the exact estimated utility values to be confidential, so they could not be reported here. The EAG agreed that the time-to-death approach may have been more appropriate to capture the quality of life for people with progressed cancer in this evaluation. The EAG also noted that using either a time-to-death or health-state approach had a minimal effect on both the cost-effectiveness results and the company's preferred base case. The committee concluded that using a time-to-death approach to estimate utilities based on KEYNOTE‑859 was appropriate for decision making.
Cost-minimisation analysis
3.11
At the first committee meeting the committee concluded that pembrolizumab plus doublet chemotherapy is likely to have similar clinical effectiveness and tolerability to nivolumab plus doublet chemotherapy. So, it agreed that it may be relevant to include a cost-minimisation analysis for the CPS of 5 or more subgroup. As part of its response to draft guidance consultation, the company submitted a cost-minimisation analysis for the CPS of 5 or more subgroup. The analysis used the longer-term follow-up data from KEYNOTE‑859. Quality-adjusted life years (QALYs) were made equal in the pembrolizumab plus doublet chemotherapy arm and the nivolumab plus doublet chemotherapy arm. This reflected that the overall survival, progression-free survival and adverse events were all assumed to be equal in each of the treatment arms. Time on treatment was based on Kaplan–Meier data from KEYNOTE‑859 and was also assumed to be the same in both treatment arms. Treatment costs in the pembrolizumab plus doublet chemotherapy arm were the same or lower than the treatment costs in the nivolumab plus doublet chemotherapy arm. Costs for managing the condition, adverse events, progression, subsequent treatments and end of life care were equivalent in both treatment arms. Before the second committee meeting, the company submitted a correction of a programming error in its cost-minimisation model that had underestimated the administration costs for nivolumab. The EAG confirmed that the correction was appropriate. The company also noted that the treatment administration costs for the pembrolizumab and doublet chemotherapy arm could be reduced by using a 6‑weekly administration regimen. The committee concluded that the cost-minimisation analysis submitted by the company was appropriate.
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. The company provided absolute and proportional QALY shortfall estimates in line with NICE's health technology evaluations manual. For the CPS of 1 or more subgroup, both the company's and EAG's shortfall analyses suggested that a severity weight of 1.2 should be applied to the QALYs. For the CPS of 5 or more subgroup, both the company's and EAG's shortfall analyses suggested a severity weight was not applicable. The committee concluded that, for the CPS of 1 or more subgroup, a severity weight of 1.2 should be applied to the QALYs. The committee also concluded that, for the CPS of 5 or more subgroup, no severity weight should be applied to the QALYs.
Cost-effectiveness estimates
The committee's preferences and 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 the comparators and follow-up treatments. The company considers the exact estimates to be confidential so they could not be reported here. For the population with a CPS of 1 or more, the committee noted that the company's and EAG's base cases used the same assumptions. Also, both ICERs were within the range NICE usually considers a cost-effective use of NHS resources (between £20,000 and £30,000 per QALY gained). The committee noted that the company had updated its base case after the first meeting, to use longer follow-up data to inform its modelling and to adhere to the committee's preferred assumptions. The committee also noted that it was helpful to see all the treatment-effect waning scenarios presented by the company and EAG. The company's and EAG's cost-effectiveness estimates for different treatment-effect waning scenarios (see section 3.8) were all between £20,000 and £30,000 per QALY gained. The exact ICERs could not be reported here because they are considered confidential by the company. For the population with a CPS of 5 or more, the committee was satisfied that pembrolizumab plus doublet chemotherapy and nivolumab plus doublet chemotherapy were similarly effective (see section 3.5) and tolerated (see section 3.6). At the first committee meeting, the committee agreed that this meant it was reasonable to consider that the QALYs were the same for the 2 treatments and to compare only the costs for the modelling. As part of its response to draft guidance consultation, the company submitted a cost-minimisation analysis for the CPS of 5 or more subgroup (see section 3.11). The total costs of pembrolizumab plus doublet chemotherapy were the same or lower than nivolumab plus doublet chemotherapy over 2‑year and 30‑year time horizons. The exact costs could not be reported here because they are considered confidential by the company and included confidential comparator discounts.
Acceptable ICER
3.14
NICE's manual on health technology evaluations 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. But it will also take into account other aspects including uncaptured health benefits. The committee noted that there are no immunotherapy treatments recommend by NICE for people whose tumours express PD‑L1 with a CPS of 1 to 4 (see section 3.2). So, it concluded that there is a particular unmet need for this group. The committee noted that a severity weight of 1.2 was applied to the QALYs for the CPS of 1 or more subgroup and took this into account. It also acknowledged that no severity weighting was applied to the QALYs for the CPS of 5 or more subgroup (see section 3.12). The committee noted there was uncertainty around potential overestimation of treatment effect for people whose tumours express PD‑L1 with a CPS of 1 to 4 (see section 3.4). So, an acceptable ICER would be sufficiently below £30,000 to take into account the uncertainty around the exact treatment effect in the subgroup of people whose tumours express PD‑L1 with a CPS of 1 to 4. For the CPS of 1 or more subgroup, the committee concluded that an acceptable ICER would be towards the upper end of the range NICE considers a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained). For the subgroup of people whose tumours express PD‑L1 with a CPS of 5 or more, in a cost-minimisation analysis pembrolizumab would have to have the same or lower costs than nivolumab to be considered a cost-effective use of NHS resources.
Other factors
Equality
3.15
No equality issues were raised by the company, EAG or stakeholders. The committee did not identify any equality issues.
Conclusion
Recommendation
3.16
The committee was aware that for the CPS of 1 or more subgroup, the company's and EAG's cost-effectiveness estimates for pembrolizumab with doublet chemotherapy compared with doublet chemotherapy alone were within the range that NICE considers an acceptable use of NHS resources. The committee noted that the company's and EAG's cost-effectiveness estimates for pembrolizumab plus doublet chemotherapy compared with nivolumab plus doublet chemotherapy in the CPS of 5 or more subgroup were cost effective. This was because pembrolizumab plus doublet chemotherapy had the same or lower costs than nivolumab plus doublet chemotherapy in the cost-minimisation analysis. So, the committee concluded that pembrolizumab plus doublet chemotherapy is recommended for untreated locally advanced unresectable or metastatic HER2‑negative gastric or GOJ adenocarcinoma in adults whose tumours express PD‑L1 with a CPS of 1 or more.