Abemaciclib with fulvestrant for treating hormone receptor-positive, HER2-negative advanced breast cancer after endocrine therapy

3.1 Advanced breast cancer is an incurable condition and the aim of treatment is to delay progression and extend survival. Most people who do not need urgent treatment with chemotherapy are offered endocrine therapy as initial treatment, in line with NICE's guideline on advanced breast cancer. After initial endocrine therapy, people can have exemestane plus everolimus before progressing to chemotherapy, though adverse events limit the use of everolimus. People who have had endocrine therapy and are eligible for exemestane plus everolimus as their next treatment may instead have a cyclin dependent kinase 4 and 6 (CDK4/6) inhibitor (that is, abemaciclib, palbociclib or ribociclib) with fulvestrant. Ribociclib is recommended for routine use (see NICE's technology appraisal guidance on ribociclib) and palbociclib is available through the Cancer Drugs Fund (see NICE's technology appraisal guidance on palbociclib). In NICE's original technology appraisal guidance on abemaciclib for advanced disease after endocrine therapy, the clinical experts explained that CDK4/6 inhibitors would not be used twice in the treatment pathway. This is because of the potential for tumours becoming resistant. The clinical experts said that the main groups of people who could benefit from abemaciclib plus fulvestrant after previous endocrine treatment for advanced disease are those whose:

3.2 The patient and clinical experts explained that CDK4/6 inhibitors were welcomed by patients because they can delay disease progression and so delay or avoid the need for chemotherapy. This is desirable because chemotherapy side effects can substantially reduce quality of life. Extending survival can give people valuable extra time with family and friends. The patient experts explained that exemestane plus everolimus, the comparator, was poorly tolerated and used for only a small number of people, because it has similar effects to chemotherapy on quality of life. They also noted that although abemaciclib plus fulvestrant can cause debilitating diarrhoea and other side effects, these can usually be managed and are preferable to having chemotherapy. The committee concluded that having a choice of treatments that extend how long people live before their disease progresses and delay chemotherapy is valued by people who have already had endocrine therapy.

3.3 The patient and clinical experts explained that they would prefer having a choice of CDK4/6 inhibitors. This is because they have different side effect profiles so it would give people the option to change to a different treatment if needed. The patient experts stated that managing side effects through having different CDK4/6 inhibitor options is crucial to maintaining quality of life and is of great importance to patients. One clinical expert further noted that ribociclib and palbociclib can cause dose limiting neutropenia. This means that people having treatment need a week off treatment after 3 weeks, and need up-to-date blood counts to continue treatment. Abemaciclib is continuously dosed, is associated with less neutropenia and there is less of a need for up-to-date blood counts. However, it may cause diarrhoea that needs treatment. The clinical expert said that timing of treatment and managing adverse effects are factors to consider when choosing between CDK4/6 inhibitors. The committee concluded that having multiple CDK4/6 inhibitors allows adverse effects to be managed, which is of value to patients.

3.4 MONARCH 2 is a phase 3, multinational, placebo‑controlled, double‑blind trial. It enrolled women with hormone receptor‑positive, human epidermal growth factor receptor 2 (HER2)‑negative locally advanced or metastatic breast cancer whose disease had progressed on neoadjuvant or adjuvant endocrine therapy, either:

3.5 In the original NICE technology appraisal guidance for abemaciclib plus fulvestrant, abemaciclib plus fulvestrant statistically significantly improved progression‑free survival compared with placebo plus fulvestrant in the full trial population. The effect of abemaciclib plus fulvestrant on overall survival was not statistically significant. It was concluded that more mature data from MONARCH 2 could resolve uncertainty around this outcome. More data from MONARCH 2 has now been collected and was analysed in June 2019. This analysis included an additional 28 months of data compared with the original appraisal:

3.6 The company presented observational data from the systemic anticancer therapy (SACT) dataset for 876 people who had abemaciclib plus fulvestrant through the Cancer Drugs Fund:

3.7 There were no trials directly comparing abemaciclib plus fulvestrant with exemestane plus everolimus. So, the company presented fractional polynomial network meta‑analyses in line with the committee's preferred assumptions. These meta‑analyses incorporated the updated MONARCH 2 data for progression‑free and overall survival for the full trial population. The results were based on the postamendment group at technical engagement, at the ERG's request. The fractional polynomial network meta‑analyses for progression‑free and overall survival showed that abemaciclib plus fulvestrant improved progression‑free and overall survival compared with exemestane plus everolimus for the full trial population. The ERG highlighted that progression‑free and overall survival with abemaciclib plus fulvestrant were shorter in the postamendment group than for the full trial population. Considering the heterogeneity and uncertainty across the network, the size of these benefits was uncertain. The committee recalled its preference to use the postamendment group data to estimate the clinical effectiveness of abemaciclib with fulvestrant (see more about the group data in section 3.4). It concluded that data from the postamendment group from MONARCH 2 should be used to estimate the clinical effectiveness of abemaciclib plus fulvestrant compared with exemestane plus everolimus.

3.8 In its original submission, the company used fractional polynomial network meta‑analysis data that used the full trial population from MONARCH 2 in its economic model for progression‑free and overall survival (see more about the meta-analyses in section 3.7). The ERG was concerned that this may have overestimated the treatment effects compared with clinical practice. It emphasised that this did not fully reflect the licensed dose that would be used in clinical practice. The ERG preferred to use fractional polynomial network meta‑analysis data that used the postamendment group from MONARCH 2 in the economic model. The committee was aware that the results of the model were highly sensitive to the choice of clinical‑effectiveness data for abemaciclib plus fulvestrant. Also, using only the postamendment group data gave a much lower estimate of abemaciclib's clinical effectiveness compared with using the full trial population data. The committee was not persuaded that the company's approach was more appropriate, since the trial was redesigned and powered to detect an effect in progression‑free survival in the postamendment group (see more about the group data in section 3.4). After consultation, the company used the committee's preferred postamendment data in its network meta‑analysis and revised base case to estimate the clinical- and cost effectiveness of abemaciclib plus fulvestrant compared with exemestane plus everolimus. Although the company used the postamendment data in its revised base case, it maintained the view that the full trial population was also relevant when considering the efficacy of abemaciclib plus fulvestrant. The committee concluded that the postamendment group data should be used in the economic model. But it recognised that the cost‑effectiveness results were highly sensitive to the choice of clinical‑effectiveness data for abemaciclib plus fulvestrant. It further concluded that the uncertainty surrounding why the clinical‑effectiveness estimates differed in the postamendment and full trial population should be considered in its decision making.

3.9 In the original NICE technology appraisal guidance for abemaciclib with fulvestrant there was uncertainty around how long people had treatment with abemaciclib plus fulvestrant (time to treatment discontinuation). Also, the company's model underestimated the treatment duration and therefore the treatment costs of abemaciclib plus fulvestrant. This was because the company used data from the full trial population, including those who were enrolled before the protocol amendment. Also, people on the lower dose stopped treatment less often because they had fewer adverse events. During that appraisal, the committee suggested that discontinuation should be estimated using the postamendment group data. This was because it used the lower licensed dose with fewer side effects, and more data could be collected on this outcome. In the current appraisal, the company used updated discontinuation data from the postamendment group as requested. It calculated a hazard ratio to apply to the progression‑free survival curve for abemaciclib with fulvestrant to extrapolate the time on treatment beyond the available trial data from MONARCH 2. This hazard ratio was estimated by comparing the area under the extrapolated time to treatment discontinuation and progression-free survival curves from MONARCH 2 (a restricted means analysis). It presented hazard ratios estimated at 3 time points: the period covering the trial, 10 years (which it used in its base case) and over a person's lifetime. These hazard ratios are commercial in confidence and cannot be reported here. The ERG preferred the hazard ratio estimated over the trial period but considered the 10‑year estimate was plausible. The committee concluded that both the company's and ERG's preferred hazard ratio estimates were plausible and took these into account in its decision making.

3.10 In the original NICE technology appraisal guidance for abemaciclib with fulvestrant, the company estimated a hazard ratio for the time to treatment discontinuation for exemestane plus everolimus compared with progression‑free survival. To do this, it used the median progression‑free survival and median time to treatment discontinuation from BOLERO‑2, a phase 3 randomised controlled trial comparing exemestane plus everolimus with exemestane alone. The hazard ratio was applied to the progression‑free survival curve for exemestane plus everolimus generated by the fractional polynomial network meta‑analysis, which was used in the model. The company's original model was not set up to model time to treatment discontinuation for exemestane and everolimus separately. This was a limitation because people tended to stop treatment with everolimus because of adverse events but continued to have exemestane. This affected cost effectiveness because everolimus is considerably more expensive than exemestane. In this appraisal, the ERG preferred to use a different approach. It calculated a hazard ratio and applied it to the fractional polynomial network meta‑analysis progression‑free survival curve to estimate the exemestane plus everolimus time to treatment discontinuation curve in the model. Three approaches to estimate the hazard ratio were presented by the company:

3.11 The company's base case used administration costs for fulvestrant based on costs used in NICE's technology appraisal guidance on ribociclib with an aromatase inhibitor for previously untreated, hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer. The company also did a scenario analysis in which it assumed that fulvestrant injections are administered by community nurse specialists at a lower cost rather than in secondary care. It also excluded the initial loading dose. The clinical experts agreed that this does not happen in clinical practice, and people have fulvestrant in secondary care. The committee concluded that the company's base‑case assumptions on fulvestrant administration cost were appropriate.

3.12 The cost‑effectiveness estimates included patient access scheme discounts for abemaciclib and everolimus, and the NHS England price for generic fulvestrant. The exact incremental cost‑effectiveness ratio (ICER) cannot be reported here because of the confidential prices. The committee noted that there were a range of ICERs presented, which reflected the range of assumptions about time on treatment with abemaciclib plus fulvestrant and exemestane plus everolimus. It considered these plausible. The range included estimates that were above and below £30,000 quality‑adjusted life years (QALYs) gained. Also, the ICER was primarily driven by assumptions about time on treatment with exemestane plus everolimus. The committee noted:

3.14 The committee noted that some combinations of plausible assumptions gave ICERs over £30,000 per QALY gained. However, these combinations did not take into account the difference in survival between the whole trial and postamendment populations. Taking into account the whole trial population, survival estimates would have lowered the ICERs. Noting the uncertainty introduced by this issue, the committee concluded that it was likely that abemaciclib plus fulvestrant was a cost‑effective use of NHS resources. It also concluded that it met a need for an alternative CDK4/6 inhibitor treatment. It therefore recommended abemaciclib plus fulvestrant for treating hormone receptor‑positive, HER2‑negative, locally advanced or metastatic breast cancer in adults who have had endocrine therapy, only if exemestane plus everolimus is the most appropriate alternative to a CDK4/6 inhibitor.