Nivolumab with ipilimumab and chemotherapy for untreated metastatic non-small-cell lung cancer [ID1566]

Nivolumab combination is another option for untreated, metastatic non-small-cell lung cancer

3.1 The clinical experts explained that immunotherapy with platinum-doublet chemotherapy (chemo-immunotherapy) is standard care in the NHS for untreated metastatic non-small-cell lung cancer (NSCLC) with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations. Most people having chemo-immunotherapy stop treatment before 2 years because their disease progresses or there are tolerability issues, and few survive in the long term. The side effects of long-term immunotherapy are usually mild but can sometimes be considerable, needing specialist management. The clinical experts considered that nivolumab combination is likely to have similar efficacy to other first-line chemo-immunotherapy combinations. Limiting the duration of chemotherapy to 2 cycles may reduce renal toxicity and allow platinum-doublet chemotherapy to be offered again as a later-line therapy. However, the clinical experts also noted that combining 2 immunotherapies is likely to cause more immune-related toxicities than current regimens, which include only 1 immunotherapy. The committee concluded that nivolumab combination offers another treatment option for untreated metastatic NSCLC with no EGFR or ALK mutations, which may have advantages for some people.

Treatment and prognosis differ based on histology and PD-L1 status, and subgroups based on these should be considered separately

3.2 The clinical experts explained that current treatment is based on histology and PD-L1 TPS, in line with NICE guidance. The ERG considered that the population with untreated metastatic NSCLC who have no EGFR or ALK tumour mutations should be split into 3 subgroups, according to the treatments currently available:

The clinical experts also explained that prognosis may differ by histology and PD-L1 TPS, with outcomes tending to be worse for people with squamous NSCLC. The committee concluded that it was appropriate to consider the 3 subgroups identified by the ERG separately.

The comparators are appropriate, but pembrolizumab plus pemetrexed and platinum chemotherapy is also relevant for non-squamous NSCLC

3.3 The committee heard that, in line with NICE's technology appraisal guidance on pembrolizumab plus pemetrexed and platinum chemotherapy for non-squamous NSCLC, and pembrolizumab plus carboplatin and paclitaxel for squamous NSCLC, these combinations are widely used in NHS clinical practice. When the scope for this appraisal was developed, pembrolizumab plus pemetrexed and platinum chemotherapy was recommended for use within the Cancer Drugs Fund. So, it was not included as a comparator in line with NICE's position statement on handling comparators and treatment sequences in the Cancer Drugs Fund. However, it is now recommended for routine commissioning, and is therefore an appropriate comparator for non-squamous NSCLC. NICE's technology appraisal guidance on pembrolizumab plus carboplatin and paclitaxel is being reviewed, but this technology is still recommended for use within the Cancer Drugs Fund while the review is ongoing. It is therefore not an appropriate comparator. The committee understood that, in line with the scope, the following comparators were included in the cost-effectiveness analysis:

The committee agreed that these comparators were appropriate. However, it concluded that pembrolizumab plus pemetrexed and platinum chemotherapy was also a relevant comparator for non-squamous NSCLC, and should be included in the analysis to reflect established NHS practice.

CheckMate-9LA does not include all the relevant treatments used in NHS clinical practice

3.4 The main clinical effectiveness evidence for nivolumab combination came from CheckMate-9LA. This is an ongoing open-label phase 3 randomised controlled trial, comparing nivolumab combination with standard platinum-doublet chemotherapy. For people with non-squamous NSCLC, platinum-doublet chemotherapy was pemetrexed plus either cisplatin or carboplatin, with optional pemetrexed maintenance therapy. For people with squamous NSCLC, platinum-doublet chemotherapy was paclitaxel plus carboplatin. The committee was aware that CheckMate‑9LA included adults with untreated recurrent or metastatic NSCLC (with no EGFR or ALK mutations) with an Eastern Cooperative Oncology Group performance status of 0 or 1. The trial included people regardless of PD‑L1 status. CheckMate-9LA did not include some comparators used in NHS clinical practice:

The committee acknowledged that, because there was no head-to-head evidence with these comparators, indirect treatment comparisons were needed to assess the relative effectiveness of nivolumab combination.

Nivolumab combination improves overall and progression-free survival compared with standard chemotherapy

3.5 An interim analysis of CheckMate-9LA showed a statistically significant difference in overall and progression-free survival in favour of nivolumab combination compared with standard platinum-doublet chemotherapy. At the most recent data cut (March 2020), median overall survival was 15.6 months for nivolumab combination and 10.9 months for standard chemotherapy (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.55 to 0.80). Median progression-free survival was 6.7 months for nivolumab combination and 5.0 months for standard chemotherapy (HR 0.68, 95% CI 0.57 to 0.82). Some people having nivolumab combination in CheckMate-9LA had either immunotherapy or a therapy targeted against EGFR, ALK or vascular endothelial growth factor as a subsequent therapy. This did not represent NHS clinical practice, because people would not have immunotherapy again or a targeted therapy on disease progression. The clinical experts stated that this was unlikely to have had a major impact on treatment outcomes. But it meant that the survival of people having nivolumab combination may have been overestimated in CheckMate-9LA. The committee concluded that nivolumab combination was clinically effective compared with standard chemotherapy.

The company's indirect treatment comparisons are acceptable for decision making, despite uncertainty

3.6 The company did indirect treatment comparisons because there were no head-to-head trials comparing nivolumab combination with pembrolizumab monotherapy and atezolizumab combination. The company considered that the proportional hazards assumption (that is, the relative risk of an event is fixed irrespective of time) was not met. It therefore used fractional polynomial models to estimate time-varying hazard ratios. For the indirect comparison with pembrolizumab monotherapy in the subgroup with a PD-L1 TPS of at least 50%, the company used the data from the full intention-to-treat (ITT) population from CheckMate-9LA. For the comparison with atezolizumab combination for the subgroup with non-squamous NSCLC and a PD-L1 TPS between below 50%, the company used the data from the relevant subgroup of CheckMate-9LA. The results of the indirect comparisons are confidential and cannot be reported here. At technical engagement, it was agreed that the CheckMate-227 data should also be included in the indirect treatment comparisons. CheckMate-227 is an ongoing open-label phase 3 randomised controlled trial in a similar population to that in CheckMate‑9LA. It includes a nivolumab plus ipilimumab treatment arm and a platinum-doublet chemotherapy treatment arm, both stratified by PD-L1 TPS. The most recent data cut from CheckMate-227 (February 2020) had a minimum follow up of 37.7 months compared with 12.7 months for CheckMate-9LA. So, it provided more data to inform the long-term extrapolations of the fractional polynomial model. The committee noted that some of the company's indirect treatment comparison results had wide confidence intervals and were uncertain, but concluded that they were acceptable for decision making.

Nivolumab combination is likely to be less well tolerated than other chemo-immunotherapy combinations

3.7 The clinical experts explained that immunotherapy is generally well tolerated, but is associated with some rare but unpleasant, and potentially serious, adverse events. These were likely to be more common for nivolumab combination (2 different immunotherapies) than current chemo-immunotherapy combinations (only 1 immunotherapy). The committee understood that clinicians are experienced in recognising and managing these serious adverse events, and there are established toxicity management algorithms in place. It concluded that nivolumab combination was likely to be less well tolerated than other chemo-immunotherapy combinations, so more specialist management would be needed to address severe toxicities.

The company's model structure is acceptable for decision making

3.8 The company presented a 3-state partitioned survival model to estimate the cost effectiveness of nivolumab combination compared with platinum-doublet chemotherapy, atezolizumab combination and pembrolizumab monotherapy. People were able to move to different health states; from pre-progression to post-progression and death and from post-progression to death. The ERG agreed with the company's model structure, noting that it was consistent with previous appraisals. For people having nivolumab combination and people having standard platinum-doublet chemotherapy, the company used the results from CheckMate-9LA to model overall and progression-free survival for the first 13 months. The results from CheckMate-227 were used after this point because longer-term data was available (see section 3.6). Survival curves were modelled for the ITT population and applied for everyone, regardless of histology and PD-L1 TPS. Hazard ratios from the indirect comparisons were then applied to the nivolumab combination data to estimate overall and progression-free survival for atezolizumab combination and for pembrolizumab monotherapy. The committee concluded that the company's model structure was acceptable for decision making. But it noted that there was uncertainty about whether it was appropriate to use the same survival curves for everyone (see section 3.10).

Including a 2-year stopping rule is acceptable

3.9 The company included a 2-year treatment stopping rule in its model. The maximum possible duration for nivolumab combination in CheckMate‑9LA was 24 months, and this was also stated in the summary of product characteristics. The committee understood that implementing a 2-year stopping rule was consistent with other NICE technology appraisal guidance on untreated NSCLC. It also reflected how nivolumab combination would be used in clinical practice. The committee concluded that a 2-year treatment stopping rule, in line with the clinical- and cost-effectiveness evidence, was acceptable.

Survival curves should be modelled separately for each subgroup

3.10 The committee considered whether it was appropriate to use the same overall and progression-free survival curves across all 3 subgroups, based on the ITT data from CheckMate-9LA and CheckMate-227 (see section 3.8). The company took this approach because it believed there was a consistent efficacy benefit across subgroups in CheckMate‑9LA, including those based on PD-L1 and histology. However, the ERG noted that the CheckMate-9LA and CheckMate-227 results suggested there were differences in the absolute and relative efficacy of nivolumab combination across some of the subgroups. Clinical advice to the ERG was that people whose NSCLC has a higher PD-L1 TPS generally have greater benefit with anti-PD-L1 immunotherapies. The company considered that using the ITT data was more appropriate than the subgroup data, because the subgroups were not pre-specified and included smaller numbers of people. The company also noted the lack of external clinical data available to validate the subgroup curves, placing greater reliance on clinical opinion. Also, it considered that by combining 3 different mechanisms of action, nivolumab combination was not expected to have the same efficacy differences by histology or PD-L1 TPS as other immunotherapies. The committee considered that because it had agreed to separate the population into 3 subgroups (see section 3.2), it was appropriate to reflect this heterogeneity in the data used to generate the survival curves. It also noted that applying separate survival curves based on the subgroup data had a considerable impact on the cost-effectiveness results. The committee agreed that there was uncertainty about the validity of applying survival curves derived from the ITT data across all the subgroups. It concluded that survival curves should be modelled separately for each subgroup.

Survival for people having platinum-doublet chemotherapy should be modelled using the CheckMate-227 data alone

3.11 The ERG noted that median overall survival for people having platinum-doublet chemotherapy was longer in CheckMate-227 than in CheckMate‑9LA. This could have been because fewer people had subsequent therapy in CheckMate-9LA than in CheckMate-227. The ERG considered that the proportion of people having subsequent therapy after platinum-doublet chemotherapy in CheckMate-9LA was lower than in NHS clinical practice. It was therefore concerned that using the CheckMate-9LA data to estimate survival for the first 13 months (see section 3.8) may have underestimated survival for people having platinum-doublet chemotherapy. The ERG did a scenario analysis in which survival for people having platinum-doublet chemotherapy was modelled using the CheckMate-227 data alone. In this, the relative efficacy of nivolumab combination was taken from the indirect treatment comparison. However, the ERG preferred to retain the company's original approach of using the CheckMate-9LA data followed by the CheckMate‑227 data for its base case. This was because it used the same data sources for people having nivolumab combination and people having platinum-doublet chemotherapy. The committee noted that in NICE's technology appraisal guidance on pembrolizumab with carboplatin and paclitaxel for untreated metastatic squamous non-small-cell lung cancer, it was estimated that around 50% of people having first-line chemotherapy have immunotherapy after disease progression. The clinical experts noted that this may be an underestimate based on the proportion of people switching from chemotherapy to pembrolizumab in the KEYNOTE‑024 trial. KEYNOTE-024 was an open-label phase 3 randomised controlled trial, comparing pembrolizumab with chemotherapy for untreated metastatic NSCLC. The committee understood that around 28% of people had subsequent immunotherapy after first-line chemotherapy in CheckMate-9LA, compared with around 41% in CheckMate-227. It considered that the rate of subsequent immunotherapy in CheckMate-227 was likely closer to that in NHS clinical practice. The committee concluded that the survival curves for people having platinum-doublet chemotherapy should be based on the CheckMate-227 data alone.

A treatment effect lasting 3 to 5 years after starting treatment is appropriate and consistent with previous appraisals

3.12 The company's base case included a lifetime treatment effect with nivolumab combination. The company justified this using pooled data from 4 clinical trials of nivolumab for previously treated NSCLC, which showed that nivolumab had a long-term survival advantage over docetaxel. The ERG noted that a lifetime treatment effect was inconsistent with previous technology appraisals for NSCLC. For those, a treatment effect lasting from 3 to 5 years after starting treatment had been accepted. The ERG also considered the pooled data referenced by the company to be of limited relevance. This was because the data was from trials of nivolumab as a monotherapy in a population who had previous treatment, and survival outcomes were only reported to 4 years. The ERG preferred a scenario with a treatment effect lasting 5 years after stopping treatment. This was modelled by setting the mortality rate as equal to that of platinum-doublet chemotherapy from this timepoint onwards. The committee understood that the assumption around the duration of treatment effect had a considerable impact on the cost-effectiveness results. It agreed that, although it was biologically plausible for the treatment effect to continue after stopping treatment with nivolumab combination, its duration was uncertain. The clinical experts explained that there was insufficient evidence to suggest the treatment effect of nivolumab combination lasted longer than for other immunotherapies. The committee concluded that a treatment effect lasting 3 to 5 years after starting treatment was appropriate for decision making, for consistency with previous immunotherapy appraisals in NSCLC.

The ERG's approach of using progression-based utility values is preferred

3.13 The ERG explained that the company's time-to-death approach was not appropriate. This was because in previous technology appraisals in which this approach had been accepted, health-related quality-of-life data had only been collected for up to 30 days after stopping treatment. This meant that the utility value for the post-progression state may have been overestimated, because the full effects of progression may not yet have been evident. However in CheckMate-9LA, health-related quality-of-life data was collected until death, and there were many observations (1,004) contributing to the post-progression health state. In contrast, there were only 114 observations contributing to the utility value for 4 weeks or less to death in the company's approach. The ERG also had concerns with using time to death to determine health-related quality of life. A time-to-death approach meant that people entering the model had a different health-related quality of life depending on the treatment arm they were assigned to. The ERG preferred a progression-based approach, using utility values derived from the EQ-5D data collected in CheckMate‑9LA. The clinical experts explained that quality of life may not immediately decline after disease progression. The committee was also aware that progression-based utility values may be overestimated because there were fewer observations in people with more severe disease. However, it agreed with the ERG that utility values based on disease progression were more appropriate for decision making, given the large amount of data captured after progression.

Separate chemotherapy regimen distributions should be used for each subgroup to reflect differences in clinical practice

3.14 To calculate the costs associated with platinum-doublet chemotherapy, the company based the distribution of chemotherapy regimens on the CheckMate-9LA data. It applied the same assumption for everyone having platinum-doublet chemotherapy, regardless of histology or PD-L1 TPS. The ERG considered that the distribution of chemotherapy regimens in CheckMate-9LA may not reflect NHS clinical practice. For example, some people with squamous NSCLC were modelled as having pemetrexed, when they would not have this in practice. It noted that there were differences in acquisition and administration costs between chemotherapy regimens, which meant that the costs calculated from the company's distribution may not have been representative. The ERG preferred to apply a specific distribution of chemotherapy agents for each subgroup (see section 3.2), including different proportions of people having pemetrexed maintenance therapy. The ERG took these distributions from reported UK market share information in:

At technical engagement, with clinical input the company revised the proportion of people having each chemotherapy regimen but continued to apply a single weighted distribution for everyone. The clinical experts explained that the most widely used chemotherapy regimens in clinical practice differed by histology. Carboplatin plus either gemcitabine or vinorelbine were the most common combinations for people with squamous NSCLC, but pemetrexed was preferred for people with non-squamous NSCLC. The committee considered that these differences should be reflected in the composition of platinum-doublet chemotherapy in the economic model. It concluded that the ERG's approach of applying separate distributions of chemotherapy regimens for each subgroup was more appropriate for decision making.

The proportion of people having subsequent therapy should be based on the CheckMate-227 data

3.15 In the company's model, 31% of people having nivolumab combination as their first-line treatment had subsequent therapy, based on the CheckMate-9LA data. The same assumption was used for people having pembrolizumab monotherapy and atezolizumab combination. In the model, 40% of people having platinum-doublet chemotherapy as their first-line treatment had subsequent therapy. The ERG noted that the data on the rates of subsequent therapy from CheckMate-9LA was immature, and likely an underestimate. The rates from CheckMate-227 were higher (45% for people having nivolumab combination as first-line treatment, and 61% for people having platinum-doublet chemotherapy). The ERG considered that the CheckMate-227 rates were more in line with those seen in NHS clinical practice. They were also based on more mature data. Also, using the CheckMate-227 data was consistent with the approach used for modelling long-term survival. At technical engagement, the company accepted that the rates of subsequent therapy in CheckMate‑9LA may be lower than expected in a clinical trial, but considered that they reflected NHS clinical practice. The committee recalled its earlier conclusion that the proportion of people having subsequent therapy in the clinical trials was likely lower than NHS clinical practice (see section 3.11). Therefore, it concluded that the higher rates from CheckMate-227 better reflected clinical practice and should be used in the model.

The difference between the company and ERG's relative dose intensity adjustments has minimal impact on the cost-effectiveness results

3.16 Relative dose intensity is the percentage of the prescribed dose of a treatment that people take. The company applied the relative dose intensities to the drug acquisition costs, after these had been estimated from the number of vials needed based on the treatment dose in the marketing authorisation. The ERG considered it more appropriate to apply the relative dose intensities to the expected treatment dose, and then calculate the number of vials and associated drug acquisition costs from these adjusted numbers. Because this may not necessarily reduce the number of vials, the ERG was concerned that the company may have underestimated drug acquisition costs. The committee concluded that the relative dose intensity likely lay between the company and ERG's assumptions. However, it noted that this had minimal impact on the cost-effectiveness results.

Nivolumab combination is likely to meet the end of life criteria for squamous NSCLC with a PD-L1 TPS less than 50%

3.17 The committee considered the advice about life-extending treatment for people with a short life expectancy in NICE's guide to the methods of technology appraisal. It understood that the company and ERG agreed that nivolumab combination did not meet the criteria for end of life treatments for:

For the subgroup with squamous NSCLC and a PD-L1 TPS of below 50%, both the company's and ERG's base cases predicted a mean overall survival of around 24 months for people having platinum-doublet chemotherapy. The clinical experts stated that the life expectancy for this subgroup was likely to be less than 2 years, even with immunotherapy. The company and ERG estimated that the mean life extension for nivolumab combination in this subgroup was more than 3 months compared with platinum-doublet chemotherapy. The committee was satisfied that nivolumab combination was likely to meet the criteria for end of life treatments in the subgroup with squamous NSCLC and a PD-L1 TPS below 50%.

Nivolumab combination is not cost effective in any subgroup and further analyses are needed

3.18 The committee recalled that its preferred assumptions were:

The cost-effectiveness results are commercial in confidence because they included the discounts from commercial access agreements and patient access schemes for atezolizumab, pembrolizumab, bevacizumab and pemetrexed maintenance.

The committee concluded that the cost-effectiveness estimates for nivolumab combination were higher than what NICE normally considers a cost-effective use of NHS resources. It also recalled that pembrolizumab plus pemetrexed and platinum chemotherapy was a relevant comparator for non-squamous NSCLC (see section 3.3). It concluded that the decision problem was incomplete without these analyses.

Nivolumab combination is not recommended for routine use in the NHS

3.21 Nivolumab combination is more clinically effective than standard chemotherapy, and likely to have similar efficacy to other chemo-immunotherapy treatments. The committee agreed that the most plausible ICERs for nivolumab combination compared with platinum-doublet chemotherapy, atezolizumab combination and pembrolizumab monotherapy were above the range normally considered to be a cost-effective use of NHS resources. Therefore, it concluded that nivolumab combination could not be recommended for routine use as an option for untreated metastatic NSCLC with no EGFR or ALK mutations.

Nivolumab combination is not recommended for use in the Cancer Drugs Fund

3.22 Having concluded that nivolumab combination could not be recommended for routine use, the committee then considered if it could be recommended within 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 was aware that the company had expressed an interest in the treatment being considered for funding through the Cancer Drugs Fund. It also understood that CheckMate-9LA and CheckMate-227 were ongoing, and further data would become available. However, the committee agreed that this would likely be insufficient to reduce the key uncertainties affecting the cost-effectiveness results, that is:

The committee concluded that nivolumab combination did not meet the criteria to be considered for inclusion in the Cancer Drugs Fund.