Aflibercept in combination with irinotecan and fluorouracil-based therapy for treating metastatic colorectal cancer that has progressed following prior oxaliplatin-based chemotherapy

Clinical-effectiveness evidence

3.1 The manufacturer did a systematic literature review of studies evaluating the efficacy and safety of second-line treatments for metastatic colorectal cancer. It identified 1 relevant randomised controlled trial (RCT), the VELOUR trial, from which it obtained the key clinical evidence. The VELOUR trial was a double-blind placebo-controlled phase III study that was conducted in 176 centres in 28 countries, including the UK. Eligible patients were adults who had inoperable metastatic colorectal cancer, and whose disease progressed on or after treatment with only 1 prior oxaliplatin-based chemotherapy regimen. Investigators randomised patients in a 1:1 ratio to either aflibercept plus folinic acid/5-fluorouracil/irinotecan (FOLFIRI) (n=612) or placebo plus FOLFIRI (n=614). They stratified randomisation by patients' wellbeing and ability to perform daily activities using the Eastern Cooperative Oncology Group Performance Status (ECOG PS), and whether or not the patient had received prior therapy with bevacizumab. Patients received either aflibercept at a dose of 4 mg/kg or placebo over 1 hour on day 1, every 2 weeks, both intravenously, immediately followed by FOLFIRI. During the trial, patients could stop 1 study treatment (aflibercept or placebo, or FOLFIRI) but still receive the other components of the regimen. Treatment continued until disease progressed, unacceptable toxicity occurred, or the patient declined further treatment.

3.2 The primary end point in the VELOUR trial was overall survival, defined as time from randomisation to death from any cause. One of the secondary end points was progression-free survival as assessed by an independent review committee based on radiologic progression; it was determined as time from randomisation to first observation of disease progression (at least a 20% increase in the sum of the longest diameter of target tumours, the unequivocal increase in the size of non-target tumours or the appearance of 1 or more new tumours), or death from any cause. In addition, disease progression determined by local investigators was recorded during the trial. Other secondary end points were objective response (complete and partial responses) according to Response Evaluation Criteria In Solid Tumors criteria version 1, and adverse events and abnormal laboratory findings.

3.3 The manufacturer stated that patient characteristics and disease history at baseline were well balanced between the aflibercept and placebo groups. Of the patients randomised in the study, the median age was 61 years, 58.6% were men, 97.8% had a baseline ECOG PS of 0 or 1, and 2.2% had a baseline ECOG PS of 2. The marketing authorisation for aflibercept stipulates prior treatment with an oxaliplatin-containing regimen. In the VELOUR trial, 90.2% of patients randomised to aflibercept plus FOLFIRI and 89.4% of those randomised to placebo plus FOLFIRI had received prior oxaliplatin-based chemotherapy for locally advanced or metastatic disease. Approximately 10% of patients had received prior oxaliplatin-based chemotherapy in the adjuvant setting (that is, as an additional treatment given after the primary treatment). Oxaliplatin-based regimens were given in combination with bevacizumab in 30.4% of patients.

3.4 The manufacturer determined that it needed 863 death events to detect a statistically significant 20% risk reduction in the aflibercept group compared with the placebo group; this determined the study cut-off date. To estimate time-to-event parameters (overall survival and progression-free survival), the manufacturer used survival analysis. It calculated hazard ratios and confidence intervals for the primary and subgroup analyses using a Cox proportional hazards model. It also established heterogeneity of treatment effect among subgroups using a Cox proportional hazards model, and provided an interaction test for each subgroup analysis. If a patient neither died nor had disease progression during the trial, the manufacturer censored the patient at the date when the tumour was last assessed or at the study cut-off date.

3.5 The median follow-up for the overall population at the time of the primary analysis was 22.28 months, with the longest follow-up being 36 months. At the study cut-off date, 403 patients (65.8%) randomised to aflibercept and 460 patients (74.9%) randomised to placebo had died. Median overall survival was estimated to be 1.44 months longer for aflibercept than placebo (aflibercept 13.50 months, placebo 12.06 months), and the corresponding hazard ratio was 0.817 (95.34% confidence interval [CI] 0.713 to 0.937, p=0.0032), suggesting a reduction in the risk of death of 18.3% with aflibercept compared with placebo. The probabilities of overall survival at 6, 12, 18, 24 and 30 months were consistently higher in the aflibercept group than in the placebo group; the probability of overall survival was 4% higher at 6 months, and 85% higher at 30 months.

3.6 The manufacturer noted that the Kaplan–Meier curves for overall survival separated early and continued to separate over time, and suggested that there were patients who experienced a sustained benefit after treatment with aflibercept. Because of this, the manufacturer indicated that the difference in median overall survival of 1.44 months may underestimate the overall clinical benefit of adding aflibercept to FOLFIRI. In addition, the manufacturer calculated hazard ratios for overall survival by 6-month periods up to 18 months after randomisation, and it combined all time points thereafter into a single hazard ratio. This analysis showed that hazard ratios improved over time, implying that the difference in overall survival increased in favour of aflibercept the longer patients received treatment. In response to a clarification request by the ERG, the manufacturer provided hazard ratios and the number of patients at risk of dying 18 months after randomisation by 6-month periods. These hazard ratios continued to decrease over time (suggesting that the difference in overall survival continued to increase in favour of aflibercept), but had confidence intervals that crossed 1.00 (that is, the differences were not statistically significant).

3.7 The manufacturer estimated the mean overall survival by fitting separate parametric functions to the trial data for each treatment group, and extrapolating to provide complete curves (given that calculating the mean required all patients to have died). It modelled each treatment group separately, rather than modelling treatment as a covariate, because the log-cumulative hazard plots (used to evaluate the assumption that a hazard ratio between 2 treatments remains constant over time) were not parallel and crossed. The manufacturer considered that the log-logistic function provided the best fit for overall survival for both treatment groups. The log-logistic function, however, gave a long tail (implying that some patients would live implausibly long), so the manufacturer truncated the curves at 15 years after randomisation (this assumed that all patients die by 15 years). Using this approach, the manufacturer estimated that aflibercept would extend mean overall survival by 4.7 months compared with placebo (aflibercept 22.8 months, placebo 18.1 months); without truncating the survival curves, the difference in mean overall survival was 6.6 months. In response to a clarification request by the ERG, the manufacturer provided estimates with the analysis truncated at 5 and 10 years. The manufacturer designated the results of this analysis as academic in confidence. The manufacturer also provided 'restricted' mean overall survivals for each treatment group based on actual data rather than an extrapolated model (that is, excluding patients who were alive at the end of the trial). This analysis estimated a difference in mean overall survival of 1.92 months in favour of aflibercept.

3.8 The manufacturer found that aflibercept also prolonged progression-free survival compared with placebo; the difference in median progression-free survival was estimated to be 2.23 months when disease progression was assessed by an independent review committee (aflibercept 6.90 months, placebo 4.67 months, hazard ratio 0.758 [95% CI 0.661 to 0.869]). The manufacturer also provided an estimate of 1.74 months for median progression-free survival when local investigators determined disease progression. For response rate (complete and partial responses), the results favoured aflibercept, with an estimated response rate of 19.8% (95% CI 16.4 to 23.2) in the aflibercept group and 11.1% (95% CI 8.5 to 13.8) in the placebo group.

3.9 The manufacturer performed pre-specified subgroup analyses according to the following:

3.10 For all the pre-specified subgroups, the manufacturer carried out an analysis of overall survival. It found no evidence of heterogeneity in treatment effect (non-significant interaction test), except in the subgroup of patients with liver metastases only (p value for interaction was 0.0899, statistically significant at the 10% level). The hazard ratio for this subgroup was 0.649 (95.34% CI 0.492 to 0.855) compared with a hazard ratio of 0.868 (95.34% CI 0.742 to 1.015) in patients who had no liver metastases or in whom the cancer spread to the liver and other organs (estimates of survival times are academic in confidence). In response to a clarification request by the ERG, the manufacturer provided the difference in mean overall survival for the subgroup using actual, rather than extrapolated, data; this estimate is academic in confidence. In the post hoc subgroup analysis, which excluded patients whose disease had relapsed 6 months or less after starting oxaliplatin-based adjuvant therapy, the difference in median overall survival was estimated to be 1.9 months in favour of aflibercept. In this subgroup, the unadjusted hazard ratio was 0.78 (95% CI 0.68 to 0.90) compared with 1.09 (95% CI 0.70 to 1.69) in patients whose disease had relapsed 6 months or less after starting adjuvant therapy (p value for interaction 0.1265).

3.11 For progression-free survival, the manufacturer did not find a statistically significant subgroup effect except in patients with liver metastases only (interaction test was statistically significant at the 10% level). These results, and those of the subgroup that excluded patients whose disease had relapsed 6 months or less after starting oxaliplatin-based adjuvant therapy, are academic in confidence.

3.12 The incidence of adverse events of any grade (according to the Common Terminology Criteria for Adverse Events v3.0) was similar in the aflibercept and placebo groups of the VELOUR trial (99.2% and 97.9% respectively), but the incidence of some adverse events was considerably higher in the aflibercept group (for example, 41.4% of patients receiving aflibercept had hypertension [any grade] compared with 10.7% of those receiving placebo). Grade 3–4 adverse events were reported in 83.5% of patients in the aflibercept group and 62.5% of those in the placebo group. The grade 3–4 adverse events that occurred at least twice as frequently in the aflibercept group than in the placebo group, in order of decreasing relative incidence, were: hypertension (19.3% versus 1.5%), proteinuria (7.8% versus 1.2%), hand-foot syndrome (2.8% versus 0.5%), headache (1.6% versus 0.3%), arterial thromboembolic events (1.8% versus 0.5%), weight loss (2.6% versus 0.8%), stomatitis and ulceration (13.8% versus 5.0%), diarrhoea (19.3% versus 7.8%) and decreased platelet count (3.4% versus 1.6%). Typical anti-VEGF adverse reactions and adverse reactions associated with FOLFIRI were more common in the aflibercept group. The manufacturer indicated that most of the adverse events associated with aflibercept plus FOLFIRI were reversible and manageable using current clinical practice, although some (physical weakness, infections, diarrhoea and hypertension) led to permanent discontinuation of study treatment in 26.8% of patients receiving aflibercept compared with 12.1% of those receiving placebo. Furthermore, the European Public Assessment Report notes that more patients in the aflibercept than the placebo groups had their dose of FOLFIRI reduced or their treatment cycle delayed.

3.13 To further characterise the adverse events of aflibercept, the manufacturer performed a meta-analysis by pooling safety data from 3 RCTs (VELOUR, VITAL and VANILLA). The VITAL trial evaluated aflibercept plus docetaxel compared with placebo plus docetaxel in patients with non-small cell lung cancer and, in the VANILLA trial, patients with metastatic pancreatic cancer were randomised to aflibercept plus gemcitabine or placebo plus gemcitabine. Overall, the meta-analysis included data from 2662 patients (1333 receiving aflibercept and 1329 receiving placebo). The analysis was framed so that risk ratios greater than 1 favoured placebo. The manufacturer found that, among patients treated with aflibercept, 0.4% and 0.5% had grade 4 hypertension and nephrotic syndrome respectively. It also found that adding aflibercept to concurrent chemotherapies did not increase the risk of venous thromboembolism, but it did increase the risk of grade 3–4 adverse reactions related to anti-VEGF therapy; the difference in this risk was statistically significant for hypertension (risk ratio [RR] 9.21, 95% CI 5.91 to 14.36), proteinuria (RR 8.37, 95% CI 4.37 to 16.06) and haemorrhage (RR 2.04, 95% CI 1.20 to 3.47). The incidence of adverse reactions typically associated with the background chemotherapy used in the 3 RCTs also increased with the addition of aflibercept, most notably for neutropenia (including neutropenic complications), various gastrointestinal toxicities and physical weakness.

3.14 Data on health-related quality of life were not collected in the VELOUR trial. The manufacturer conducted the 'mCRC utilities study', an observational, cross-sectional study to estimate utility values in patients with metastatic colorectal cancer who would be eligible for treatment with aflibercept plus FOLFIRI as per the licensed indication, or who had progressed to subsequent phases of the disease. The study took place in the Netherlands and the UK, and collected EQ-5D data. The manufacturer used these data as its main source to estimate health-related quality of life for the cost-effectiveness analysis.

Cost-effectiveness evidence

3.23 The manufacturer did not identify any published economic evaluations relevant to the decision problem. It submitted a de novo economic model to establish the cost effectiveness of aflibercept in patients with metastatic colorectal cancer who are eligible for second-line combination chemotherapy, and who were previously treated with an oxaliplatin-based regimen. The manufacturer performed subgroup analyses for patients with liver metastases only, and for a subgroup that excluded patients who had received oxaliplatin-based therapy in the adjuvant setting and whose disease relapsed within the following 6 months. The manufacturer conducted the analysis from the perspective of the NHS and personal social services and chose a time horizon of 15 years. It used a 2-week treatment cycle to reflect the treatment schedules of aflibercept and FOLFIRI, and applied a half-cycle correction. Costs and health effects were discounted at an annual rate of 3.5%.

3.24 The manufacturer developed a state-transition Markov cohort model simulating 3 states: stable disease, progressed disease and death. The manufacturer further split the stable-disease health state into sub-states of 'on second-line treatment' and 'discontinued second-line treatment' to distinguish between patients who receive second-line treatment until their disease progresses, and those who stop second‑line treatment before their disease progresses. All simulated patients enter the model in the stable-disease health state and in the 'on second‑line treatment' sub-state. Patients can then continue treatment and remain in the 'on second-line treatment' sub-state, or move to the 'discontinued second‑line treatment' sub-state; they can instead move to the progressed-disease health state (and stop second-line treatment), or death. Patients cannot receive second-line treatment again once treatment is stopped, but they can receive further active therapy (systemic anticancer treatment, radiotherapy or surgery) or best supportive care. The manufacturer stated that the duration of second-line treatment in the model is based on the mean durations in the VELOUR trial to take into account dose delays or the discontinuation of aflibercept or FOLFIRI (for patients who were in the aflibercept group), or FOLFIRI (for patients who were in the placebo group), as observed in the trial. The manufacturer modelled adverse events as events (rather than health states) and it applied a utility decrement (disutility) for each adverse event.

3.25 The manufacturer's model included parameters for overall survival, progression-free survival and time to discontinuing second-line treatment (before or after disease progression). To estimate the survival parameters, the manufacturer fitted alternative parametric functions (Weibull, log-normal, log-logistic and exponential) to observed Kaplan–Meier data from the VELOUR trial, and extrapolated the curves beyond the trial period for overall survival and time to discontinuing treatment, but not for progression-free survival, because the disease had progressed in all patients during the trial. In extrapolating those curves, the manufacturer assumed non-proportional hazards (that is, the hazard ratios between aflibercept plus FOLFIRI and FOLFIRI alone varied over time) so it modelled each treatment group separately. The manufacturer chose the base-case survival functions based on the results of statistical tests, visual inspection of the fit to the data and the clinical plausibility of the extrapolated portion of the curve. For overall survival, the manufacturer used the log-logistic function, and assumed that the survival benefit from treatment with aflibercept plus FOLFIRI increases relative to treatment with FOLFIRI alone until around 12 months after starting treatment, and then decreases over the 15-year time horizon, but does not cease at any point during the extrapolation period (that is, the overall survival curves start converging 12 months after starting treatment but never fully converge later in the extrapolation period). The manufacturer used the Weibull function for progression-free survival and time to treatment discontinuation. The difference in mean progression-free survival estimated by the manufacturer was 1.2 months in favour of aflibercept. Other parametric functions were explored in scenario analyses.

3.26 The manufacturer stated that the model predicted a median overall survival and a median progression-free survival similar to those from the VELOUR trial. The largest difference was for progression-free survival in the FOLFIRI group, which the model overestimated compared with the survival time observed in the trial.

3.27 Adverse events in the model included grade 3–4 adverse events that affected more than 5% of patients in the VELOUR trial, together with 6 rarer adverse events that the manufacturer's clinical advisory board considered important (gastrointestinal perforation, haemorrhage, febrile neutropenia, peripheral neuropathy, urinary tract infections and hand-foot syndrome). The subgroup analyses incorporated data specific to each subgroup.

3.28 The manufacturer applied utility values in the model from its 'mCRC utilities study', in which investigators assigned patients to 1 of the following 3 groups: patients with stable disease who are receiving second-line treatment, and patients who had previously received second-line treatment but stopped it because of an adverse event, or because their disease progressed. Because the sample size of the group of patients who had an adverse event and stopped treatment was very small, the manufacturer did not use the utility estimates from this group, and instead assumed that all patients with stable disease have the same utility, equal to the utility of patients with stable disease who are receiving second-line treatment. The manufacturer got descriptions of health states from patients using the EQ-5D system, and derived the utility weights by applying UK valuation of health states estimated using the time trade-off method. The utility estimate used in the model for patients with progressed disease was 0.708. The manufacturer assumed that the utility in the progressed-disease health state is independent of time spent in the state. The manufacturer explained that, despite the age and health of patients, the utility values used in the model are relatively high because candidates for second-line chemotherapy must be fit enough to receive treatment.

3.29 The manufacturer also identified relevant utility studies from a systematic review of the literature. It did not use the values in those studies to source the model, but used them to compare the estimates from its utility study, and noted that they were reasonably consistent. The utility estimates in the literature that the manufacturer considered relevant ranged from 0.73 to 0.81 for stable disease, and from 0.68 to 0.69 for the progressed disease. One other study, Best et al. (2010), reported utility values of 0.51 for stable metastatic disease and 0.21 for progressed metastatic disease, but the manufacturer did not consider this study relevant because the population included patients receiving adjuvant chemotherapy and patients in remission.

3.30 The manufacturer got the disutilities associated with adverse events from the published literature, and supplemented these with clinical expert opinion. To calculate the average disutility per adverse event, the manufacturer assumed that an adverse event causes the same disutility regardless of the type of cancer. This gave an average disutility per adverse event of −0.0127 for patients receiving aflibercept plus FOLFIRI, and −0.0108 for those receiving FOLFIRI alone.

3.31 The costs of aflibercept plus FOLFIRI and FOLFIRI alone did not depend on the duration of second-line treatment in the model; the manufacturer calculated them separately based on data from the VELOUR trial to reflect the dose delays (for example, because of an adverse event) and dose reductions observed in the trial. It assumed that any unused drug in a vial was discarded (wasted) for aflibercept and irinotecan (a component of FOLFIRI), but explored in scenario analyses other possibilities to model drug wastage. The cost of aflibercept in the model took into account the patient access scheme discount.

3.32 To estimate costs of caring for people with metastatic colorectal cancer ('management costs' including supportive medications, clinician and nurse visits [hospital and community], imaging, laboratory tests, hospitalisations, palliative care, and personal and social care), the manufacturer conducted a retrospective observational study, and undertook a questionnaire-based survey of 6 UK clinical oncologists (both unpublished studies). In the observational study, the manufacturer collected resource-use data from patients who received oxaliplatin-based chemotherapy followed by FOLFIRI as second-line treatment, and used those data to estimate total management costs per 2-week cycle for different groups of patients (the manufacturer advised that every patient would eventually receive end-of-life care regardless of prior treatment, so it did not include resource use associated with end-of-life care in the model). The clinician survey aimed to gather data on community-based care, and on personal and social care. In this, the manufacturer elicited the average treatment practices of each oncologist to get data on managing patients with metastatic colorectal cancer. It also used the results of the survey, together with NHS reference costs, to estimate the costs associated with adverse events. The manufacturer used mean resource use for adverse events, but median resource use for community-based care, and personal and social care. The cost of subsequent therapies that patients could receive after stopping second-line treatment or experiencing disease progression was calculated based on the manufacturer's study of resource use, and was assumed to be independent of the type of second-line treatment.

3.33 The manufacturer's deterministic base-case results estimated that the addition of aflibercept to FOLFIRI provides an additional 0.243 quality-adjusted life years (QALYs). This benefit is achieved with an additional cost of £8816, resulting in an incremental cost-effectiveness ratio (ICER) of £36,294 per QALY gained for aflibercept plus FOLFIRI compared with FOLFIRI alone.

3.34 The manufacturer presented deterministic sensitivity analyses in which it varied the 20 parameters with the largest impact on the ICER, one at a time. The results showed that the ICER is most sensitive to the parametric function chosen for overall survival, the utility value chosen for the progressed-disease health state, and the number of administrations assumed for second-line treatment drugs. The manufacturer explained that improving overall survival and progression-free survival increased incremental QALYs in favour of aflibercept, but also increased drug costs and the costs incurred from prolonged overall survival after disease progression.

3.35 The manufacturer carried out a probabilistic sensitivity analysis to summarise the uncertainty in the ICER. This showed that the probability of aflibercept plus FOLFIRI being cost effective when compared with FOLFIRI alone is less than 5% if the maximum acceptable ICER is £20,000 per QALY gained, and 22% at £30,000 per QALY gained.

3.36 The manufacturer investigated the structural uncertainty in the model by fitting alternative parametric functions for overall survival and progression-free survival, and by directly applying patient-level data from the VELOUR trial to model progression-free survival (given that disease had progressed in all patients during the trial). It also performed scenario analyses to test the sensitivity of the ICER to alternative assumptions around drug wastage. In these, it explored the possibility of no drug wastage, and of reducing the dose to the nearest number of whole vials for patients who would otherwise use less than 5% of the vial contents. The highest ICER from these analyses was £49,805 per QALY gained (using the Weibull function to model overall survival).

3.37 The manufacturer provided subgroup analyses to establish the cost effectiveness of aflibercept plus FOLFIRI compared with FOLFIRI alone in patients with liver metastases only, and in a subgroup that excluded those who had received oxaliplatin-based therapy in the adjuvant setting and whose disease had relapsed within the following 6 months. In comparison with the deterministic base-case ICER of £36,294 per QALY gained, the ICERs were £30,474 per QALY gained (incremental costs £10,974, incremental QALYs 0.360) and £32,480 per QALY gained (incremental costs £8573, incremental QALYs 0.264) respectively. At a maximum acceptable ICER of £30,000 per QALY gained, the probability of aflibercept plus FOLFIRI being cost effective compared with FOLFIRI alone in both subgroups is around 50% (numerical values not provided in the manufacturer's submission).

Manufacturer's response to consultation on the appraisal consultation document

3.53 To address the Committee's considerations of the evidence described in the appraisal consultation document, the manufacturer submitted a response to the consultation, which included:

3.54 The ASQoP study was an international single-arm open-label phase III study. The primary objective of the study was to evaluate the safety of aflibercept in patients with metastatic colorectal cancer whose disease progressed following treatment with an oxaliplatin-based regimen. Its secondary objective was to establish health-related quality of life in this population. Because the study was not completed at the time of the second Committee meeting, the manufacturer provided interim results for mean EQ-5D utility values at baseline and after patients received 3 and 5 cycles of treatment. Data from this study were available for the stable-disease state only. The manufacturer derived a utility value of 0.78 for the stable-disease state by using a weighted average of the utility values for patients who received 3 and 5 cycles of treatment.

3.55 In its response, the manufacturer made the following comments on some of the parameters in the model originally considered by the Committee:

3.56 The manufacturer revised its original base case by:

3.57 The manufacturer performed the following scenario analyses, in which it varied one parameter at a time: