Tafasitamab with lenalidomide for treating relapsed or refractory diffuse large B-cell lymphoma

3.1 Diffuse large B‑cell lymphoma is an aggressive disease. Symptoms usually develop rapidly and progress quickly. The disease is treated with the aim of cure, but 10% to 15% of people have primary refractory disease and a further 20% to 30% relapse. A submission from a patient expert explained that the prognosis for people with relapsed or refractory disease is extremely poor. Treatments are very intensive, needing long stays in hospital and potentially involving serious side effects even after treatment has ended. Any treatment delivered in an outpatient setting (that is, that did not require a stay in hospital) would have a significant, positive effect on the quality of life of people with the condition and their families. The psychological, social and economic impact of the disease for both the person and their carers is considerable. The clinical experts explained that relapsed or refractory disease is treated using salvage chemotherapy followed by an autologous stem cell transplant if the person can have intensive therapy. Clinical experts explained that about 10% to 20% of people with relapsed or refractory disease who can have intensive therapy are cured of the disease after an autologous stem cell transplant. People who cannot have a transplant, or whose disease relapses after a transplant, are usually offered polatuzumab vedotin with bendamustine and rituximab or other rituximab-based chemotherapy regimens. The committee concluded that relapsed or refractory diffuse large B‑cell lymphoma is a devastating condition with a poor prognosis, and that people with the condition have a high unmet need for effective treatments with manageable side effects.

3.2 Tafasitamab has a marketing authorisation in combination with lenalidomide for treating relapsed or refractory diffuse large B‑cell lymphoma in adults who cannot have an autologous stem cell transplant. The comparators in the NICE scope were:

3.3 The clinical evidence for tafasitamab with lenalidomide came from the phase 2 L‑MIND study. This is an ongoing multicentre, single-arm, open-label study of tafasitamab with lenalidomide in people with relapsed or refractory diffuse large B‑cell lymphoma who could not have an autologous stem cell transplant. Because the study is open label, people in the trial and their healthcare professionals are aware of treatment allocation. The committee highlighted that the study is small, with 81 people recruited, 5 of whom are from the UK. At the October 2020 data cut, median duration of exposure to tafasitamab with lenalidomide was 9.2 months. The primary endpoint of objective response rate (partial and complete response) was 58%. Median overall survival was 33.5 months, and median progression-free survival was 11.6 months. The ERG highlighted several important differences in the baseline characteristics of people in L‑MIND compared with Northend et al. (2022), a retrospective analysis of real-world data from the UK. For example, the proportion of men in Northend et al. was 69% compared with 54% in L‑MIND. Differences were also identified for the presence of bulky disease, International Prognostic Index scores, number of lines of previous therapy, and refractoriness to previous treatment. The committee considered that the study results were promising. However, it concluded that the lack of a direct comparison with any treatment makes the data difficult to interpret.

3.4 Because L‑MIND is a single-arm study, indirect treatment comparisons were needed to establish the relative efficacy of tafasitamab plus lenalidomide compared with other treatments. The company used 2 indirect treatment comparison approaches: propensity score matching against RE‑MIND2 and matching-adjusted indirect comparisons against published studies. RE‑MIND2 was an observational, retrospective cohort study of 3,454 adults with relapsed or refractory diffuse large B‑cell lymphoma, including 115 people from the UK. The company used nearest neighbour propensity score matching to balance the cohorts for comparator treatments with L‑MIND based on 9 baseline covariates. In the matching-adjusted indirect comparisons the company adjusted the L‑MIND population using propensity score weighting to be comparable to the populations in 4 published trials of comparator treatments, which were selected using a systematic literature review and expert input. The company used RE‑MIND2 for rituximab with gemcitabine and oxaliplatin and the matching-adjusted indirect comparisons for polatuzumab vedotin with bendamustine and rituximab as well as bendamustine and rituximab. The company chose indirect evidence sources based on alignment to published outcomes. This resulted in RE‑MIND2 not being selected for polatuzumab vedotin with bendamustine and rituximab. All the indirect comparisons suggested that tafasitamab with lenalidomide improved progression-free and overall survival compared with the comparators, but this was not always statistically significant. The ERG highlighted that RE‑MIND2 consists of pooled individual participant data and is preferred in principle to the intervention population adjustment done in the matching-adjusted indirect comparisons. Adjusting the L‑MIND population differently for each comparator treatment population may have led to bias. However, there was uncertainty about the methods used for RE‑MIND2 because the baseline characteristics of the tafasitamab with lenalidomide cohort varied depending on the comparator. The ERG suggested that it was unclear what type of treatment effect is estimated in RE‑MIND2. The committee concluded that, because of the complexity in the methods used for the indirect treatment comparisons, and the potential biases, the results of the indirect comparisons were very uncertain.

3.5 The company presented a 3‑state partitioned survival model to estimate the cost effectiveness of tafasitamab plus lenalidomide compared with rituximab plus gemcitabine and oxaliplatin, polatuzumab vedotin plus bendamustine and rituximab, and bendamustine plus rituximab. The committee agreed that the company's model structure was appropriate for decision making.

3.6 The ERG questioned the validity of the company's overall and progression-free survival parametric extrapolations for polatuzumab vedotin with bendamustine and rituximab. The company calculated separate hazard ratios for up to month 4 and after month 4 for both survival outcomes from the matching-adjusted indirect treatment comparison. It applied these hazard ratios to the survival distributions for tafasitamab with lenalidomide to calculate the survival distributions for polatuzumab vedotin with bendamustine and rituximab. The company justified this piecewise approach to estimating hazard ratios by saying that the alternative, a constant hazard ratio, was not possible because the proportional hazards test failed. However, the ERG was concerned that the resulting overall survival extrapolation underestimated survival for polatuzumab vedotin with bendamustine and rituximab compared with NICE's technology appraisal guidance on polatuzumab vedotin with rituximab and bendamustine. The previous NICE appraisal estimated around 3.1 mean life years and 2.1 quality-adjusted life years (QALYs). In contrast, the company's extrapolation estimated 2.2 mean life years and 1.5 QALYs. On this basis, the ERG preferred to apply a constant hazard ratio from the matching-adjusted indirect comparison, leading to 3.4 mean life years and 2.2 QALYs for polatuzumab vedotin with bendamustine and rituximab. The clinical experts considered that the company's estimates were reasonable because they were closer to the published literature estimates of median overall survival for polatuzumab vedotin with bendamustine and rituximab (between 8.2 and 12.5 months) than the ERG's. The company justified its methodology by saying that it was verified by clinical experts, produced the results most aligned with real-world evidence, and avoided unnecessary complexity. However, the committee noted that tests for proportional hazards did not support a constant hazard. So, it considered that it was not appropriate to apply constant hazard ratios to the L‑MIND data, even using the piecewise approach. It also identified that better approaches were needed to handle the time-varying nature of the observed hazard ratio. The committee agreed that the company should have looked at more ways to include the data from Sehn et al. (2022) in the indirect comparisons. For example, the polatuzumab vedotin with bendamustine and rituximab hazard ratio from Sehn et al. could be applied to the survival outcomes for the propensity score-matched bendamustine and rituximab population. Or, independent survival models could be fitted to the Sehn et al. Kaplan–Meier curves, adding a third arm for tafasitamab with lenalidomide against bendamustine and rituximab from the matching-adjusted indirect comparison; this would have created a partially anchored indirect comparison. The committee was disappointed that the company did not provide such additional analyses in response to the appraisal consultation document. In addition to the ERG's arguments about the company's modelling not reflecting the absolute benefits of polatuzumab vedotin with bendamustine and rituximab, the committee considered that the modelling poorly reflected the relative benefit compared with bendamustine and rituximab alone. For example, Sehn et al. reported a hazard ratio for overall survival of 0.42 for polatuzumab vedotin plus bendamustine and rituximab compared with bendamustine and rituximab alone. The clinical experts also confirmed that polatuzumab vedotin plus bendamustine and rituximab improves survival compared with bendamustine and rituximab alone. However, this is not fully reflected in the company's modelling, with only a small difference in survival estimated. The committee concluded that the company's parametric extrapolations for polatuzumab vedotin with bendamustine and rituximab were implausible. However, the committee also took into account feedback from clinical experts on outcomes observed in clinical practice submitted in response to the appraisal consultation document. These suggested that the estimates from the ERG's base case may be overestimated, despite alignment with NICE's technology appraisal guidance on polatuzumab vedotin with rituximab and bendamustine. The committee concluded that it would have preferred to see different modelling approaches that both fitted the underlying hazards of the data and produced outcomes more closely reflecting the absolute and relative benefits of polatuzumab vedotin with bendamustine and rituximab compared with bendamustine and rituximab alone, as seen in NICE's guidance on polatuzumab vedotin with rituximab and bendamustine.

3.7 The company and ERG agreed that the log-normal parametric extrapolation of L‑MIND overall survival data for tafasitamab with lenalidomide was the most appropriate approach. Initially, the company chose a generalised gamma distribution fitted to the data from L‑MIND to model progression-free survival for tafasitamab with lenalidomide, and the ERG preferred a log-normal distribution. However, the ERG noted the resulting hazard profile was inconsistent with the predictions of the clinical experts consulted by the company and overestimated progression-free survival in the long term. The committee noted that there was uncertainty in the modelled progression-free survival extrapolations for tafasitamab with lenalidomide because of heavy patient censoring towards the end of the L‑MIND Kaplan–Meier curve. However, it agreed it was appropriate to consider the log-normal distribution chosen by the ERG. In response to the appraisal consultation document, the company updated its base-case model using the committee's preferred assumption of the log-normal parametric extrapolation of L‑MIND progression-free survival data for tafasitamab with lenalidomide. The committee concluded that the company's approach to modelling tafasitamab with lenalidomide survival was appropriate in its updated base case, while noting the inherent uncertainty.

3.8 The committee considered the criteria for life-extending treatments for people with a short life expectancy in section 6.2.10 of NICE's guide to the methods of technology appraisal 2013. These are:

3.9 The committee considered that the most plausible incremental cost-effectiveness ratio (ICER) in the updated company base case was highly uncertain, because of issues with the indirect comparisons and modelling (see sections 3.4, 3.6 and 3.7). It noted that the company's and ERG's base-case probabilistic ICERs (including all the confidential discounts) for tafasitamab plus lenalidomide compared with polatuzumab vedotin plus bendamustine and rituximab were higher than the range normally considered a cost-effective use of NHS resources, even for end of life treatments. The exact results cannot be reported here because they include confidential discounts for other treatments. The committee considered that the company's base-case ICERs were not plausible, because the model survival outputs were not consistent with NICE's technology appraisal guidance on polatuzumab vedotin. It acknowledged that, although the ERG's base case was more closely aligned with these survival outputs, they may overestimate survival for polatuzumab vedotin with bendamustine and rituximab (see section 3.6). The committee concluded that the most plausible ICER was likely to be between the company's and ERG's base-case estimates. It noted that the ERG's base-case ICER was considerably higher than the company's and considerably higher than the level usually considered cost effective. The committee recognised the need for effective treatments in relapsed or refractory diffuse large B‑cell lymphoma. However, tafasitamab with lenalidomide had not been shown to be a cost-effective use of NHS resources in any analyses presented. So it concluded that tafasitamab with lenalidomide could not be recommended for routine use in the NHS.

3.10 Having concluded that tafasitamab with lenalidomide could not be recommended for routine use, the committee considered if it could be recommended for use within the Cancer Drugs Fund. It 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 recognised that people with relapsed or refractory diffuse large B‑cell lymphoma have a high unmet clinical need, and that the availability of new treatments is very important. The company said that further data cuts for the L‑MIND clinical study are planned for 2022, which will provide further evidence on survival and response outcomes. However, the committee was concerned because the single-arm phase 2 study will not provide additional comparative evidence. The model would still rely on indirect evidence for comparator treatments, so this would not resolve a key uncertainty. In addition, the committee was not presented with any analysis showing that tafasitamab with lenalidomide has the plausible potential to be cost effective at the proposed price. Therefore, it concluded that tafasitamab with lenalidomide did not meet the criteria for inclusion in the Cancer Drugs Fund.

3.11 At the third appraisal committee meeting, the committee considered the appeal panel's decision to uphold 1 appeal point. The upheld appeal point asked the committee to:

3.12 The committee reconsidered its decision that tafasitamab with lenalidomide does not meet the short life expectancy criterion (see section 3.8). It noted that the appeal panel had a different interpretation of section 6.2.10 of NICE's guide to the methods of technology appraisal 2013. The panel considered that the interpretation of the word 'normally' should be what NICE's stakeholders would reasonably expect the word 'normally' to mean. The appeal panel agreed with the appeal panel for NICE's technology appraisal guidance on avelumab that stakeholders would consider it unreasonable to find that life expectancy was not 'normally less than 24 months' if most people in a trial had died before 24 months, even if mean survival was greater than 24 months. The panel concluded that the dominant evidence used to determine this end of life criterion should reflect survival metrics that are the most meaningful to stakeholders. It also concluded that the 'less than 35% alive after 2 years' cited by the appeal panel for NICE's guidance on avelumab was not setting a precedent for a threshold for applying end of life criteria. The committee accepted the appeal panel's conclusion that the short life expectancy criterion was met. The committee therefore concluded that tafasitamab with lenalidomide meets the criteria to be considered a life-extending treatment at the end of life.

3.13 The committee considered that the most plausible ICER in the updated company base case was highly uncertain, because of issues with the indirect comparisons and modelling (see sections 3.4, 3.6 and 3.7). In considering the decision-making ICERs, the committee accounted for all the confidential discounts for comparator and subsequent treatments. This included the impact of the loss of price exclusivity on the price for lenalidomide. During the second committee meeting, it considered the live interim tender price for lenalidomide as provided by the Cancer Drugs Fund lead. It also considered pricing scenarios including the estimated price discount for generic lenalidomide up to and including a 100% discount (that is, no cost for lenalidomide). During the third committee meeting, the committee considered the nationally available tender price for generic lenalidomide as confirmed by the Commercial Medicines Unit. The prices agreed through the framework are commercial in confidence. The committee noted that the company's and the ERG's base-case probabilistic ICERs (accounting for all the confidential discounts including lenalidomide) for tafasitamab with lenalidomide compared with polatuzumab vedotin plus bendamustine and rituximab were higher than the range normally considered a cost-effective use of NHS resources for treatments given at the end of life. The exact results cannot be reported here because they include confidential discounts for other treatments. The committee further considered that accepting the appeal panel's conclusion that the short life expectancy criterion is met created an inconsistency. The modelled survival with polatuzumab vedotin plus bendamustine and rituximab was inconsistent between:

3.14 Having concluded that tafasitamab with lenalidomide could not be recommended for routine use, the committee reconsidered whether it could be recommended for use in the Cancer Drugs Fund. The committee still had the same concerns and conclusion as in section 3.10. It recalled that further evidence collection will not generate additional comparative evidence. The model would still rely on indirect evidence for comparator treatments, so this would not resolve a key uncertainty. Also, the committee was not presented with any analysis showing that tafasitamab with lenalidomide has the plausible potential to be cost effective. This was even taking into account the updated patient access scheme for tafasitamab and the decision that end of life criteria were met. So it concluded that tafasitamab with lenalidomide did not meet the criteria for inclusion in the Cancer Drugs Fund.

3.17 There is a high unmet need for effective treatments in relapsed and refractory diffuse large B‑cell lymphoma. Indirect evidence suggests that tafasitamab with lenalidomide may increase progression-free survival and overall survival compared with polatuzumab vedotin with rituximab and bendamustine. However, there is substantial uncertainty in the modelling and the committee was not presented with any analysis showing that tafasitamab with lenalidomide is cost effective. Therefore, tafasitamab with lenalidomide is not recommended for relapsed or refractory diffuse large B‑cell lymphoma in adults who cannot have an autologous stem cell transplant.