Pixantrone monotherapy for treating multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma

Clinical effectiveness

4.4 The Committee reviewed the suitability of the clinical trial evidence submitted by the manufacturer and expressed several concerns about the PIX301 trial. It considered PIX301 to be underpowered because it had failed to recruit the planned number of patients. It also noted that European regulators prefer a primary end point of overall survival or progression-free survival for clinical trials of anticancer drugs, but the primary end point for PIX301 was complete or unconfirmed complete response. The Committee heard from the clinical specialists that although this end point would have been acceptable when the trial began in 2004, positron emission tomography (PET) scans have made unconfirmed complete response obsolete in trials that have begun more recently. The Committee also heard from the clinical specialists that they considered studies that were powered to detect a difference in overall survival to be more useful for clinical decision-making. The Committee concluded that these fundamental concerns about the design of PIX301 meant that there was considerable uncertainty in the validity and robustness of its results.

4.5 The Committee discussed the relationship between the marketing authorisation, the PIX301 population and clinical practice in England and Wales. The Committee was aware that the intention-to-treat population included around 10% of patients who did not have aggressive B‑cell lymphoma, making them ineligible for treatment with pixantrone according to the terms of the marketing authorisation. The Committee further noted that the marketing authorisation is for multiply relapsed or refractory disease (that is, it is approved for patients who have received at least 2 previous lines of treatment) and that this does not necessarily restrict its use to third- and fourth-line treatment. However, it also noted the comments received during consultation stating that patients receiving fifth-line or further treatment would likely have palliative treatment or participate in a clinical trial. The Committee was persuaded that pixantrone would most likely be used, within its marketing authorisation, as a third- or fourth-line treatment in clinical practice in England and Wales. The Committee concluded that, when assessing the PIX301 results, it would be more appropriate to consider the population with aggressive B‑cell lymphoma who had received third- or fourth-line treatment.

4.6 The Committee discussed how the tumour histologies were determined in the PIX301 population and whether this was generalisable to clinical practice in England and Wales. It was aware that tumour histology in the intention-to-treat population of PIX301 had been determined by onsite review by a single pathologist. The Committee heard from the clinical specialists that this was not representative of clinical practice in England and Wales, in which multidisciplinary team review is routine and specimens are examined by 2 or 3 pathologists. It noted that the Evidence Review Group (ERG) had also been advised by clinical specialists that a population with disease confirmed by central independent pathological review was more relevant to clinical practice in England and Wales. It also noted that a considerable proportion of patients were excluded after the central independent pathological review (for example, if indolent disease had been confirmed). The Committee concluded that it would be more appropriate to consider the PIX301 population with tumour histology confirmed by retrospective central independent pathological review by consensus than by onsite review by a single pathologist.

4.7 The Committee discussed whether the comparator arm (treatment of physician's choice) in PIX301 was relevant to clinical practice in England and Wales. It heard from clinical specialists that, apart from PIX301, there was no evidence base for selecting a third- or fourth-line treatment for multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma and that there was wide variation in the treatments used in clinical practice in England and Wales. The Committee concluded that all of the comparators used in the treatment of physician's choice arm in PIX301 were clinically relevant (although there was some uncertainty in the proportions in PIX301 compared with clinical practice in England and Wales), and the comparator arm was therefore acceptable for decision-making.

4.8 The Committee discussed the generalisability of previous treatments received by the PIX301 population to clinical practice in England and Wales. The Committee heard from the clinical specialists that rituximab is an integral part of standard first-line treatment in the NHS and is also often used as a second-line treatment. The Committee noted that the manufacturer's subgroup analyses showed a reduced benefit of pixantrone in patients who had previously received rituximab, and that many of the results showed no statistically significant difference between treatment arms (see sections 3.11 and 3.16–3.18). It also noted a clinical specialist's concern that statistical significance was not reached for the parameters complete or unconfirmed complete response, progression-free survival and overall survival for this subgroup. The Committee accepted the non statistically significant results because of the positive trend in all 3 outcomes for this subgroup. It was aware from comments received during consultation that this reduced benefit applied to other drugs in clinical development and was not specific to pixantrone. It was also aware of the obligation to the European Medicines Agency in pixantrone's European marketing authorisation requiring a trial to confirm the clinical benefit in patients who have previously received rituximab. However, the Committee acknowledged the comments received in response to consultation that the complete response rates with pixantrone in PIX301 were among the highest reported to date in trials for patients with diffuse large B‑cell lymphoma who had previously received rituximab. The Committee concluded that it was appropriate to evaluate the subgroup of patients in PIX301 who had previously received rituximab because this would apply to almost all patients with multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma in England and Wales.

4.9 The Committee considered the clinical-effectiveness results for the whole intention-to-treat trial population and all the post-hoc subgroups. It noted that in the intention-to-treat population, PIX301 was inadequately powered to detect a difference between treatment groups because it had accrued less than half of the planned 320 patients. It noted that the difference in response rates, progression-free survival and overall survival between treatment groups did not always reach statistical significance in the intention-to-treat population (see section 3.17) and the post-hoc subgroups, and that there was no statistically significant difference in overall survival between treatment arms for any groups presented by the manufacturer. The Committee had reservations about whether superior efficacy of pixantrone had been shown for the intention-to-treat trial population.

4.10 The Committee then discussed the clinical effectiveness for the subgroup of patients it considered to be most appropriate for decision making (those receiving third- or fourth-line treatment and who had previously received rituximab [see section 3.18]). It concluded that there was an increase in response rates, progression-free survival, and overall survival for pixantrone compared with treatment of physician's choice, and that the mean survival advantage of pixantrone compared with treatment of physician's choice was 2.0 months. However, these results were not statistically significant (see section 3.18). The Committee also concluded that there was limited and non-robust evidence to show that pixantrone was more clinically effective than treatments currently used in the Committee's preferred subgroup.

4.11 The Committee discussed the adverse events associated with pixantrone. It noted the manufacturer's assertion that pixantrone was associated with less cardiotoxicity than anthracyclines. The Committee was aware that the final scope issued by NICE did not include any anthracyclines as comparators and that mitoxantrone was the only anthracenedione out of the 6 comparators. It heard from clinical specialists that doxorubicin (an anthracycline) was used as first-line treatment, and that none of the comparators for third- or fourth-line treatment were associated with the similarly raised cardiovascular risk associated with anthracyclines. The Committee was aware that there were more cardiac adverse events in the pixantrone group than in the comparator group, who received treatment of physician's choice (35% compared with 21%). However, it heard from the clinical specialists that efficacy is considered key in this patient population and that, because of its cardiovascular safety profile compared with anthracyclines, pixantrone offered an opportunity for response in patients who had previously shown sensitivity to anthracyclines but who could not receive further lines of anthracycline treatment after relapse because they had reached the maximum lifetime dose. It concluded that pixantrone had an acceptable adverse-effect profile although it was associated with more cardiotoxicity than treatments such as oxaliplatin and gemcitabine that are routinely used in this population in clinical practice in England and Wales.

Cost effectiveness

4.12 The Committee discussed the manufacturer's general approach to developing the submitted pixantrone economic models. It noted that the ERG considered the manufacturer's approach to follow current best practice and was largely transparent. The Committee concluded that the outlined structure of the models adhered to the NICE reference case for economic analysis and was acceptable for assessing the cost effectiveness of pixantrone.

4.13 The Committee considered the manufacturer's cost-effectiveness analyses that included the patient access scheme for the Committee's preferred patient subgroup (that is, the subgroup with aggressive B‑cell lymphoma confirmed by central independent pathological review for third- or fourth-line treatment and who had previously received rituximab [see section 4.10]). In particular the Committee discussed how quality of life had been incorporated into the manufacturer's economic modelling. It was aware that the base-case analysis in the manufacturer's patient access scheme submitted in November 2013 used utility values for patients receiving second- and subsequent-line treatment for renal cell carcinoma (0.76 for the pre-progression health state and 0.68 for the post-progression health state). It noted the absence of published utility values in the relevant patient population and that the manufacturer intends to fund additional research in this area. The Committee noted that the utility value for the pre-progression health state (0.76) was similar to that expected for a healthy older population in the UK, and it considered that the quality of life of patients receiving third- or fourth-line treatment for aggressive non-Hodgkin's B‑cell lymphoma could be lower than this. The Committee then reviewed the utility values selected by the ERG for its exploratory analyses using the manufacturer's original model and the revised model supplied with the patient access scheme submission, which were for patients receiving final-line treatment for chronic lymphocytic leukaemia (0.428 for the pre-progression health state and 0.279 for the post-progression health state). The Committee heard from the clinical specialists that there were differences between the 2 conditions that could mean these utility values were too low, and decided that the ERG's utility values were likely to underestimate the quality of life for this population. Having excluded the ERG's low utility values, the Committee considered that the manufacturer's deterministic sensitivity analysis on the base case in the patient access scheme submission using various utility values (see section 3.37) showed that utility values were not a key driver of cost effectiveness. The Committee concluded that, although there was some uncertainty as to the true utility value, the utility values used in the manufacturer's revised model with the patient access scheme were acceptable for use in the Committee's decision-making.

4.14 The Committee considered the incremental cost-effectiveness ratios (ICERs) and considered those presented in the manufacturer's most recent cost-effectiveness analyses, which included the patient access scheme for the Committee's preferred patient subgroup. For the comparison of pixantrone with treatment of physician's choice, it noted that the manufacturer's deterministic and mean probabilistic ICERs incorporating the patient access scheme for this population were £18,500 and £22,000 per quality-adjusted life year (QALY) gained respectively. The Committee noted that the ERG had validated the changes made to the manufacturer's model as part of the patient access scheme submission in November 2013. The Committee concluded that the manufacturer's analysis was appropriate for its decision-making.

4.15 The Committee discussed the amount of uncertainty in the cost-effectiveness estimates for the Committee's preferred subgroup of patients, that is people with aggressive B‑cell lymphoma confirmed by central pathological review receiving third- or fourth-line treatment and who have previously received rituximab. The Committee was persuaded that the manufacturer's mean probabilistic ICER of £22,000 per QALY gained could overestimate the uncertainty associated with the survival modelling and that the true value of the ICER might be lower. It was aware that the median probabilistic ICER was £14,700 per QALY gained and that the probabilistic ICER reduced to £10,000 per QALY gained when assuming that progression-free survival and overall survival did not change independently of each other. The Committee noted that the manufacturer's exploratory probabilistic sensitivity analysis showed that the probability of pixantrone being cost effective compared with treatment of physician's choice was 56% at a maximum acceptable ICER of £30,000 per QALY gained, and approximately 50% at a maximum acceptable ICER of £20,000 per QALY gained. Additionally, although pixantrone was less clinically effective in 32% of simulations, it was less expensive than treatment of physician's choice in a high proportion of these at a maximum acceptable ICER of £20,000 per QALY gained. The Committee therefore agreed that the probability of pixantrone being cost-effective compared with treatment of physician's choice was acceptable. The Committee concluded that the most plausible ICER was likely to be less than £22,000 per QALY gained, and it concluded that pixantrone was recommended as a cost-effective use of NHS resources.

4.16 The Committee discussed whether pixantrone was innovative in its potential to make a significant and substantial impact on health-related benefits. It observed that pixantrone is the first drug that has been tested in a randomised phase III trial in patients with multiply relapsed or refractory aggressive non-Hodgkin's lymphoma. It examined whether pixantrone had the potential to make a significant and substantial impact on health-related benefits but heard from the clinical specialists that it was uncertain whether pixantrone could be considered a step change in treatment. On the basis of currently available evidence, the Committee did not consider pixantrone to be a step change in managing multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma. The Committee observed that there were no additional gains in health-related quality of life over those already included in the QALY calculations. The Committee concluded that there were no additional QALYs that had not been incorporated into the economic model and the cost-effectiveness estimates.

4.17 The Committee understood that pixantrone's conditional marketing authorisation is linked to results from the ongoing PIX306 study, which should be available in 2015. It noted that this larger randomised phase III study (n=350) will compare the effectiveness of pixantrone plus rituximab with gemcitabine plus rituximab in patients with relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma who have already received a rituximab-containing regimen. Given the relevance of the patient population (because virtually all patients with multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma in England and Wales will have previously received rituximab [see section 4.8]), the Committee recommended that the technology appraisal guidance on pixantrone for treating multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma should be considered for review by NICE once the PIX306 results are available in 2015.

4.18 The Committee considered whether NICE's duties under the equality legislation required it to alter or to add to its recommendations. It noted that no equality issues had been raised during scoping, in any of the consultees' submissions, during consultation or during the Committee meetings. The Committee concluded that its decision on the use of pixantrone does not have a particular impact on any group with a protected characteristic in the equality legislation and that there was no need to alter or add to its recommendations.

Summary of Appraisal Committee's key conclusions