The appraisal committee considered evidence submitted by Pfizer and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
The appraisal committee reviewed the data on the clinical and cost effectiveness of crizotinib, having considered evidence on the nature of untreated anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC) and the value placed on the benefits of crizotinib by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.
The committee considered the nature of the condition noting that the prognosis for advanced NSCLC is poor, and that there is no cure. The committee heard from the clinical and patient experts that crizotinib could potentially extend life and improve quality of life. The committee concluded that additional treatment options would be valuable to people with ALK-positive NSCLC.
The committee considered the population relevant to this appraisal and noted that the marketing authorisation includes adults with ALK-positive advanced NSCLC, whereas the company's base case focused on non-squamous ALK-positive advanced NSCLC. The committee heard from a clinical expert that the ALK-positive mutation is more common in people with non-squamous advanced NSCLC than in people with squamous advanced NSCLC. It heard that testing for the ALK mutation is routinely done in the non-squamous population. Because the ALK-positive mutation is relatively rare in people with squamous advanced NSCLC, the committee concluded that the population in the company's submission, that is, people with non-squamous advanced NSCLC, accurately reflects people with ALK-positive advanced NSCLC seen in UK clinical practice.
The committee considered the treatment pathway for people with untreated ALK-positive NSCLC and the comparators relevant to this appraisal:
The committee heard from the clinical experts that most people with ALK-positive NSCLC in England would first have a platinum-based chemotherapy (as described in NICE's guideline on diagnosing and managing lung cancer and NICE's technology appraisal guidance on pemetrexed for first-line treatment of NSCLC). The committee was aware that pemetrexed can be given in combination with either cisplatin or carboplatin, which the experts considered to be equally effective. The committee concluded that platinum-based chemotherapy was the most relevant comparator for crizotinib.
The committee noted that the company's submission only compared crizotinib with platinum-based chemotherapy, and therefore did not consider people who could not take platinum-based chemotherapy. It heard from clinical experts that there is no biological reason to expect a different response with crizotinib in this group.
The committee discussed whether testing for the ALK mutation is established practice in the NHS. It heard from the clinical experts that ALK-mutation testing is needed before starting crizotinib, and that all people whose condition is considered for treatment, almost all with non-squamous disease, are tested. The committee concluded that the cost of ALK-mutation testing of non-squamous tumours should be taken into account, to reflect current clinical practice.
The committee considered the clinical-effectiveness evidence for crizotinib. It acknowledged that the main trial presented by the company was PROFILE 1014, which investigated whether crizotinib prolongs progression-free survival compared with pemetrexed plus either cisplatin or carboplatin in people with locally advanced, recurrent or metastatic non-squamous NSCLC. The committee was aware that crizotinib treatment continued until (and in some cases beyond) disease progression, whereas pemetrexed with either cisplatin or carboplatin was given for a maximum of 6 cycles. At disease progression, the trial allowed patients to switch treatment groups. The committee noted the evidence review group's (ERG) comments that the trial population was younger and had a higher proportion of patients who do not smoke compared with other studies of NSCLC. The committee heard from the company and the clinical experts that the patients' characteristics in PROFILE 1014 reflected people with ALK-positive NSCLC in England, and so the committee concluded that PROFILE 1014 was suitable for its decision-making.
The committee discussed the results of PROFILE 1014 and the primary outcome measure of progression-free survival:
It noted that progression was determined using radiographic criteria, specifically the Response Evaluation Criteria in Solid Tumours (RECIST). The committee heard from the clinical experts that radiographic criteria are the gold standard for monitoring NSCLC.
The committee noted that crizotinib increased progression-free survival compared with pemetrexed with either cisplatin or carboplatin (hazard ratio [HR] 0.45; 95% confidence interval [CI] 0.35 to 0.60).
The committee was aware that the company used a Cox proportional hazards model to estimate the hazard ratio for progression-free survival. It noted the ERG's critique that in this case, the proportional hazards assumptions needed to analyse data using a Cox proportional hazards model may not hold because the 2 treatment regimens are given differently (in PROFILE 1014, crizotinib was given until progression whereas platinum-based chemotherapy [the control group] was given for a finite number of cycles). The ERG stated that this did not have a large effect on cost effectiveness, but because patient-level data were available, the company could have modelled the data using separate independent parametric curves with fewer assumptions.
On balance, the committee concluded that crizotinib increases progression-free survival compared with pemetrexed plus either cisplatin or carboplatin in people with ALK-positive NSCLC.
The committee discussed the results of PROFILE 1014 and the secondary outcome measure of overall survival. It noted the ERG's comments that the results for overall survival were based on relatively immature data, that is, that few patients had died at the time of data analysis. It also noted that a high proportion of patients crossed over from chemotherapy to crizotinib. The committee was aware that because crossover occurred at or after disease progression, it would not affect progression-free survival, but would affect overall survival. The committee concluded that it was appropriate for the company to adjust for crossover when estimating the size of the benefit on overall survival associated with crizotinib.
The committee discussed the methods for adjusting for crossover in PROFILE 1014. The company presented evidence using different methods to adjust overall survival for crossover (rank-preserving structural failure time, iterative parameter estimation, and 2‑stage methods) and presented a range of analyses, which accounted for different confounders. The committee recognised that the company had used the 2‑stage method for its cost-effectiveness analyses. It was aware that there was some uncertainty about whether all confounders were measured at the time of crossover, but noted that the ERG agreed this was the most appropriate approach because it did not assume a common treatment effect (that is, that the treatment effect is the same regardless of when a person starts treatment). The committee concluded that the 2‑stage method was appropriate.
The committee discussed the size of the benefits associated with crizotinib on overall survival. The committee noted that crizotinib increased overall survival compared with pemetrexed plus either cisplatin or carboplatin (HR 0.62; 95% CI 0.41 to 0.96), when using the 2‑stage method to account for crossover. It noted that applying different methods to account for crossover did not vary the hazard ratio substantially. It noted the ERG's comments that the results for overall survival were based on relatively immature data (that is, few patients had died at the time of data analysis). The committee recognised that the size of the benefit was uncertain because of relatively immature data and the high proportion of patients crossing over from chemotherapy to crizotinib. On balance, the committee concluded that crizotinib is very likely to increase overall survival compared with pemetrexed plus either cisplatin or carboplatin in people with ALK-positive NSCLC, but the size of the increase is uncertain.
The committee considered the approach and structure of the company's economic model. The company used a semi-Markov model structure with 3 health states: the progression-free health state, progressed-disease health state and death. The model included either crizotinib or chemotherapy as the first treatment, followed by docetaxel and then best supportive care. The committee concluded that the model was consistent with the approaches used for other appraisals in NSCLC.
The committee discussed the company's approach to modelling overall and progression-free survival. It noted that, to generate more realistic survival estimates relevant to the UK population, the company had adjusted PROFILE 1014 data to reflect the characteristics of patients in a retrospective cohort study from the US and Canada (Davis et al. 2015). The committee discussed whether the characteristics of patients in the study reflected those of patients in England and noted from the company's sensitivity analyses that the assumptions were conservative. The committee concluded that it was satisfied with the company's approach.
The committee considered whether assuming proportional hazards between treatments was appropriate for extrapolating progression-free and overall survival to estimate how long, on average, crizotinib extended the progression-free period and delayed death. The committee noted consultation comments from the company that the recommended statistical checks in NICE's Decision Support Unit technical support document 14, including log-cumulative hazard plots for overall survival, had shown that the proportional hazards assumptions held. The committee recalled the different methods of administration between treatments (see section 3.7) and noted that the log-cumulative hazard plots for each treatment were not parallel. The committee therefore disagreed with the company, noting that the hazard ratios were likely to change over time and that the assumption of proportional hazards was unlikely to hold. The committee was aware that NICE's Decision Support Unit technical support document 14 suggests using separate parametric curves for each treatment group. The committee concluded that using separate parametric curves for each group was appropriate.
The committee considered whether the parameters used to adjust the parametric curves to the UK population should be the same or different for both treatments (that is, use independent covariate stratification). The committee noted comments received during consultation that there is no evidence suggesting a difference in prognosis between treatments or that covariates (such as age or sex) influence outcomes depending on treatment. The committee heard from the ERG that stratifying covariates independently uses fewer assumptions, and noted that it had a minor effect on the incremental cost-effectiveness ratios (ICERs). On balance, the committee agreed that it was appropriate to adjust each treatment for the population separately and concluded that using independent prognostic covariates was appropriate.
The committee discussed which parametric curves for extrapolating progression-free and overall survival it considered most plausible:
The committee was aware that the company's base case used a generalised gamma distribution for progression-free survival and a Weibull distribution for overall survival. It noted that the ERG presented exploratory analyses using separate parametric curves for each treatment (that is: progression-free survival – a log-normal distribution for crizotinib and a generalised gamma distribution for chemotherapy; overall survival – a generalised gamma distribution for crizotinib; and an exponential distribution for chemotherapy). The committee recognised that different parametric distributions predicted a range of differences in progression-free and overall survival. The committee noted comments received from the company during consultation that the overall survival increase using the ERG's selected distributions was implausible (0.8 months increased survival with crizotinib compared with chemotherapy). It heard from the clinical experts that they expected no less than a 6‑month increase in overall survival with crizotinib. The committee agreed that curves used in the ERG's exploratory analysis (that is: progression-free survival – a log-normal distribution for crizotinib and a generalised gamma distribution for chemotherapy; overall survival – a generalised gamma distribution for crizotinib; and an exponential distribution for chemotherapy) were not plausible.