Bortezomib for previously untreated mantle cell lymphoma

The company's systematic literature review identified 1 randomised controlled trial (RCT) investigating the clinical efficacy and safety of bortezomib in combination with rituximab, cyclophosphamide, doxorubicin and prednisone (VR‑CAP) in adult patients with previously untreated mantle cell lymphoma. LYM‑3002 trial was a randomised, open-label, multicentre study that compared VR‑CAP against rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone (R‑CHOP). The study involved 128 sites worldwide, and people were randomised in a 1:1 ratio based on the International Prognostic Index and the stage of disease at diagnosis.

In total, 487 people were randomised; 243 to bortezomib and 244 to R‑CHOP. The median age was 69 years. People were given 6 to 8 cycles (18 to 24 weeks) of treatment depending upon the response documented at the cycle‑6 assessment. Approximately 80% of people in both groups completed treatment. The total study duration from randomisation of the first patient until the last progression‑free survival event needed for the final analysis was expected to be approximately 42 months (24 months for enrolment and 18 months for follow-up). Average treatment duration was 17.6 weeks in the bortezomib treatment group and 16.1 weeks in the R‑CHOP group. Treatment discontinuation was comparable between the 2 groups (18% and 19% respectively). The majority of people had at least 6 cycles of treatment: 84% of people randomised to VR‑CAP, and 83% of people randomised to R‑CHOP.

The trial included 80 patients (16.4%; 38 out of 243 in VR‑CAP arm, 42 out of 244 in R‑CHOP arm) who were suitable for haematopoietic stem cell transplantation from a medical perspective but access was prevented due to availability or socio-economic reasons. The inclusion of these patients arose due to a protocol amendment part way through the LYM-3002 trial where patients who were ineligible or not considered for haematopoietic stem cell transplantation were enrolled. However concerns over the heterogeneity and interpretability of the study results resulted in a further amendment, realigning to the original eligibility criteria, and only patients who were not eligible for haematopoietic stem cell transplantation as assessed by the treating physician, were subsequently enrolled.

The primary outcome of the study was progression‑free survival in the intention–to–treat (ITT) population, based on independent review committee assessment of progression. Median progression‑free survival was 751 days (24.7 months) in people randomised to VR‑CAP compared with 437 days (14.4 months) in people randomised to R‑CHOP (hazard ratio [HR]=0.63, p<0.001).

The company presented results for a number of secondary clinical endpoints:

• Based on independent review committee assessment of progression in the ITT population, median time to progression was 929 days (30.5 months) in people randomised to VR‑CAP compared with 490 days (16.1 months) in people randomised to R‑CHOP (HR=0.58; p<0.001).

• In the ITT population, median time to next anti-lymphoma treatment was 1353 days (44.5 months) for people randomised to the VR‑CAP group compared with 756 days (24.8 months) for those randomised to the R‑CHOP group (HR=0.50; p<0.001).

• Median treatment-free interval in the safety analysis set was 1236 days (40.6 months) for people randomised to VR‑CAP compared with 624 days (20.5 months) for those randomised to R‑CHOP (HR=0.50; p<0.001).

• Based on independent review committee assessment, complete response rates (complete response plus complete response unconfirmed) were 53.3% in the VR‑CAP group compared with 41.7% in the R‑CHOP group (odds ratio [OR]=1.688; p=0.007), and the median duration of complete response was 42.1 months compared with 18.0 months for people treated with VR‑CAP. The median time to initial response based on independent review committee assessment was 42 days (1.4 months) in people randomised to VR‑CAP compared with 50 days (1.6 months) in people randomised to R‑CHOP (HR=1.54; p<0.001).

At the time of the company's submission, overall survival data were not mature in the LYM‑3002 trial. In an interim analysis based on a median duration of 40 months' follow-up (in which 158 deaths had been observed: 71 in the VR‑CAP group [29%] and 87 in the R‑CHOP group [36%]), the estimated hazard ratio for death is 0.80 (95% confidence interval [CI] 0.59 to 1.10, in favour of VR‑CAP).

Three different patient-reported outcome tools were used to assess health-related quality of life in the LYM‑3002 trial: the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ‑C30); the Brief Fatigue Inventory ; and the EuroQol Dimension Questionnaire (EQ-5D). The company reported that utility values, translated from the EQ-5D taken at day 1 of every treatment cycle and at the end-of-treatment visit, were not statistically significantly different between treatment groups at baseline and throughout the LYM‑3002 treatment. The company highlighted that as the study design did not include patient-reported outcome collection after the end of treatment, it was not possible to assess the dimension of clinical benefit derived by people from the prolonged progression‑free survival and prolonged disease control provided by VR‑CAP. However, the company stated that such improvement in long-term prognosis would be likely to positively affect patient health-related quality of life in practice.

A de novo cost‑effectiveness model was developed by the company to assess the cost effectiveness of VR‑CAP in England and Wales. The model included 5 states: progression‑free survival from first‑line treatment; progressed from first‑line treatment; progression‑free survival from second‑line treatment; progressed from second‑line treatment; and death.

The company's base-case model time horizon was 20 years. The company considered this to be essentially a lifetime time horizon for patients, given that the mean age assumed in the model was 69 years. Both costs and health outcomes were discounted at an annual rate of 3.5%. The company stated that costs were based on 2013 to 2014 figures (NHS Reference Costs and Personal Social Services Research Unit) as these were the most recent cost data available at the time the model was developed.

The key clinical data used within the economic model were taken from the LYM‑3002 trial. The ITT population of the LYM‑3002 trial was used to assess the effectiveness and safety of VR‑CAP compared with R‑CHOP in the de novo cost-effectiveness model. Based on advice from UK haematologists, the company considered that people included in the LYM‑3002 trial were similar to those expected to be seen in UK clinical practice. However, baseline demographics from only the Western European and North American subgroup were used in the model because the company considered that subgroup to be more similar to people in UK clinical practice in terms of age and weight.

Economic comparison was conducted primarily with R‑CHOP because the company were of the opinion that R‑CHOP induction therapy is the established standard of care for patients with previously untreated mantle cell lymphoma (for whom haematopoietic stem cell transplantation is unsuitable). The company stated that no maintenance treatment with rituximab was assumed in the model base case because it was not identified as a comparator in the decision problem. However, the company highlighted that as R‑maintenance is used in clinical practice in people with a response to induction, the potential impact of induction therapy with VR‑CAP compared with R‑CHOP followed by R‑maintenance was investigated in exploratory analyses.

Instead of using the primary outcome of the LYM‑3002 trial, progression‑free survival assessed by an independent review committee, the company chose to use an alternative assessment (by an independent review committee member) in the base case of the model because it was felt this reflected clinical practice while retaining the blinded assessment.

The company fitted the following parametric models to estimate progression‑free survival in the 2 treatment groups: exponential; Weibull; lognormal; log‑logistic; gamma; and Gompertz. The company used the log‑logistic model in the base case based on the goodness of fit of the progression‑free survival curves (that is, using the Akaike information criterion and the Bayesian information criterion, and visual fit and long‑term fit).

Survival was modelled with parametric models fitted using the LYM 3002 patient level data for people having VR CAP and R CHOP. However, overall survival data from the LYM 3002 trial are still immature; median overall survival for VR CAP has not been reached. Because of the a wide range of potential outcomes when attempting to fit survival curves directly to the overall survival data, the company modelled survival using progression as a surrogate marker for overall survival.

For the base case, parametric curves were fitted for 3 categories of patients: all patients who progressed from VR‑CAP or R‑CHOP during the trial, all patients who did not progress from VR‑CAP, and all patients who did not progress from R‑CHOP. This method assumed that patients who progressed had the same survival regardless of what treatment they had in first line (that is, post‑progression survival was the same, regardless of the first‑line therapy that had been had).

The company added non‑disease‑specific mortality, based on age and sex, to the model to better capture long‑term survival (using UK life tables from the Office for National Statistics). It was assumed that all deaths in the pre‑progression survival curves (before adjustment for background mortality) in the trial were deaths from mantle cell lymphoma.

The mean duration of second‑line treatment and progression‑free survival from second‑line treatment were derived from the LYM‑3002 trial. In the company base case, model treatment duration (90 days) and progression‑free survival (231 days) were assumed to be the same for both groups, using data from both LYM‑3002 trial groups combined.

The company highlighted that there were limited data available for the other comparators included in the scope. The company stated that the indirect comparison to R‑bendamustine was too unreliable given the heterogeneity described previously, particularly for progression‑free survival, to be used to assess comparative efficacy within the cost‑effectiveness model. Instead, the company assumed equal efficacy (progression‑free survival and overall survival) to R‑CHOP, which was based on clinician feedback. Similarly, the limitations of the R‑FC indirect comparison meant that an assumption of equal efficacy with R‑CHOP was also made for R‑FC.

The company used EQ‑5D data from the LYM‑3002 trial for health‑related quality‑of‑life estimates during and on progression from first‑line treatment. Utility decrements for adverse events were included in addition to the health‑state utilities while patients were on treatment, based upon LYM‑3002 trial data. No long‑term utility values were available from the LYM‑3002 trial so instead, the company assumed equal utility while progression free during first- and second‑line treatments (based on UK clinician feedback and previous non‑Hodgkin's lymphoma modelling), utility associated with post‑progression from second‑line treatment was taken from the most relevant source related to aggressive non‑Hodgkin's lymphoma, which the company stated was the most similar condition to mantle cell lymphoma in terms of expected effect on health status.

In the company's base-case deterministic analysis, VR‑CAP was estimated to generate 0.75 incremental life years, 0.80 incremental quality-adjusted life years (QALYs) and an incremental cost of £16,213 compared with R‑CHOP, leading to an incremental cost-effectiveness ratio (ICER) of £20,362 per QALY gained. In the probabilistic analyses the ICERs for VR‑CAP ranged between £13,725 (compared with R‑bendamustine) and £20,264 (compared with R‑CHOP) per QALY gained.

Cost‑effectiveness acceptability curves (generated by the ERG from the company model) showed that R‑CHOP has the highest probability of being cost‑effective (51.3%) followed by VR‑CAP (48.7%). The probabilities of being cost‑effective for R‑FC and R‑bendamustine were 0.0%. VR‑CAP has the highest probability (86.5%) of being cost‑effective at a maximum acceptable ICER of £30,000, followed by R‑CHOP (13.5%), R‑FC (0.0%) and R‑bendamustine (0.0%).

The ICERs were most sensitive to the survival functions used to model progression‑free survival and overall survival the utility value for patients progressed from second‑line treatment, intravenous administration costs and the duration of second‑line treatment.

The company performed a large number of scenario analyses for the comparison between VR‑CAP and R‑CHOP. The most influential scenario analyses were those incorporating different parametric distributions for progression‑free survival; using Weibull, gamma and Gompertz distributions increased the ICER from £20,362 to £25,849, £27,697 and £30,452 respectively. Changing the utility value for patients progressed from second‑line treatment to 0.693 (equal to patients progressing from first‑line treatment) increased the ICER to £26,241 per QALY gained. Changing all health state utility values to correspond with those from Doorduijn et al. 2005 (that is, 0.61 for progression free in the first and second line and 0.45 for progressed patients in the first and second line) did increase the ICER to £28,746 per QALY gained. The company stated that cost‑effectiveness results were generally robust under the sensitivity and scenario analyses conducted, with no scenarios bringing the ICER of VR‑CAP compared with R‑CHOP above £30,000 per QALY gained.

In light of a number of issues highlighted in the ERG report, the ERG made a number of amendments. The ERG corrected a number of errors and changed a number of assumptions in the company's model as follows:

• 1. Corrected the unit prices that were different in the reference price list.

• 2. Corrected an error in the calculation of adverse events.

• 3. Corrected calculation of costs of concomitant medication.

• 4. Inclusion of half‑cycle correction.

• 5. Age, weight and unit prices were made fixed instead of being stochastic (that is, instead of having distributions applied to them).

• 6. Proportion of patients having treatment during a cycle and proportion of patients having concomitant medication were made stochastic to reflect second order uncertainty.

• 7. Adjusted progression‑free survival according to the HR of the European Union population.

• 8. Start second‑line treatment at time of progression.

• 9. Utility for progression from second‑line treatment is calculated by subtracting the disutility as found in Doorduijn et al. (2005) from the baseline utility in the LYM‑3002 trial for progression‑free survival from first line treatment. Therefore, the ERG used a utility of 0.624, instead of the company's value of 0.45.

• 10. Excluded end‑of‑life costs.

• 11. Used per‑protocol dosage instead of observed dosage reductions because it is unknown whether the dosage reduction is applicable to UK patients.

• 12. The primary assessment of progression is used instead of the alternative assessment.

• 13. Indirect treatment comparison is used for the effectiveness of R‑FC and R‑bendamustine instead of assuming equal effectiveness as R‑CHOP.

• 14. Overall survival is not differentiated between patients with and without progression, but between treatments instead.

• 15. Excluded all‑cause mortality as this is already incorporated in the overall survival estimate.

• 16. The exponential distribution is used for the extrapolation of progression‑free survival in the VR‑CAP group and the log‑logistic distribution is used for the extrapolation of progression‑free survival in the R‑CHOP group.

The ERG stated that the ICERs compared to R‑FC and R‑bendamustine were minimally influenced by the ERG changes and so the results presented focused on the comparison with R‑CHOP. Including all of the ERG's amendments at the same time increased the company's base case ICER of VR‑CAP compared with R‑CHOP by £14,000 to £34,039 compared to the company base case. The large difference between the company base case and the ERG's ICER was caused mainly by changing the distribution for progression‑free survival in the VR‑CAP group to the exponential distribution, while keeping the distribution for R‑CHOP progression‑free survival a log‑logistic distribution.

The ERG performed probabilistic sensitivity analyses for all comparators to capture the uncertainty in the estimation of input parameters in their additional analyses. The probability that VR‑CAP is cost effective at a threshold of £20,000 and £30,000 is smaller in the ERG analyses compared to the company's base case (11% versus 49% and 39% versus 89% for a threshold of £20,000 and £30,000 respectively). Similar to the company's base case, the probability that R‑FC or R‑bendamustine are cost effective at the usual NICE thresholds are negligible.

The ERG did some additional exploratory analyses that looked at the effect of removing some assumptions from its preferred cumulative ICER estimate of £34,039 per QALY gained. The ERG combined all their preferred assumptions together but removed the following:

• Progression‑free survival adjustment for the European Union subgroup.

• Distinguish survival for patients with and without progression.

• Use the same progression‑free survival distribution (log‑logistic) for all treatment groups.
  
  As survival for patients with and without progression is distinguished in this additional analysis by the ERG, all cause mortality to survival pre progression was included (in other words, analysis 13 from section 3.42 was also removed). The result of removing these 4 assumptions from the ERG base case gave an ICER for VR CAP compared with R CHOP of £31,576 per QALY gained.

The ERG explored the effect of reverting back to the company's original utility value (0.45) and the exclusion of assumption 7 and assumptions 12 to 14 as in section 3.45. The result of this analysis (that is, the ERG base case excluding assumptions 7, 9 and 12 to 14) gave an ICER of £26,647 per QALY gained for VR‑CAP compared with R‑CHOP.

Full details of all the evidence are in the committee papers.