Ribociclib with fulvestrant for treating hormone receptor-positive, HER2-negative, advanced breast cancer

People with advanced breast cancer would welcome a new treatment option

3.1 Advanced breast cancer is an incurable condition. Patient experts explained that patients value improvements in progression-free survival and want to delay chemotherapy for as long as possible. First-line treatment for hormone receptor-positive, human epidermal growth factor receptor (HER2)-negative locally advanced or metastatic breast cancer is usually a cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitor, palbociclib, ribociclib or abemaciclib, with an aromatase inhibitor (letrozole or anastrozole). If symptoms are severe or the disease is rapidly progressive, then chemotherapy may be needed in the first instance, and tamoxifen can also be offered to some people in line with NICE's clinical guideline on advanced breast cancer. The committee noted that since the CDK 4/6 inhibitors have been recommended, the number of people being offered an aromatase inhibitors alone is declining. However, there are patients who have only previously had an aromatase inhibitor and so could have a CDK 4/6 inhibitor with fulvestrant as a second-line treatment. The committee concluded that a treatment that would extend how long people live before their disease progresses and delay the need for chemotherapy would be welcomed by people who have already had endocrine therapy.

Population B from the company submission is relevant to NHS clinical practice

3.2 MONALEESA-3 is a multicentre, double blind, placebo-controlled, randomised trial comparing ribociclib and fulvestrant with placebo and fulvestrant in adults with hormone receptor-positive, HER2-negative advanced breast cancer. It enrolled 726 postmenopausal women, and results were presented separately for a subgroup of people who had had previous endocrine therapy (n=345). This subgroup was considered in the company's submission as population B. The committee agreed that population B is relevant to this appraisal, but noted that the MONALEESA-3 trial was not designed to have statistical power to detect treatment effects within subgroups. The committee concluded that this was a concern, but that this approach was preferred to further splitting people into a subpopulation with a disease that has progressed at or within 12 months after neoadjuvant endocrine therapy, and a subpopulation with a disease that has progressed after 1 line of endocrine therapy in the advanced setting, that the company had initially suggested.

Ribociclib with fulvestrant increases progression-free survival compared with fulvestrant alone but overall survival data are immature

3.3 The primary outcome measure of MONALEESA-3 was investigator-assessed progression-free survival. Treatment with ribociclib with fulvestrant increased median progression-free survival compared with fulvestrant alone from 12.8 months to 20.5 months (hazard ratio [HR] 0.593; 95% confidence interval [CI] 0.480 to 0.732). Similar results were found for the subgroup of people who had previous endocrine therapy (population B; HR 0.565; 95% CI 0.428 to 0.802). At the time of the analysis, overall survival data were immature. The company provided interim overall survival data for the trial population (the data are confidential and cannot be presented here), but not for population B. The committee agreed that the progression-free survival benefit from ribociclib with fulvestrant was promising, but the benefit on overall survival was unknown. The committee noted that the results came from a data cut in November 2017, and that an updated analysis is expected after completion of the study in 2020. The committee concluded that ribociclib with fulvestrant increased progression-free survival compared with fulvestrant alone in people who had had previous endocrine therapy but that the effect on overall survival was currently unknown.

Class effect for CDK 4/6 inhibitors with fulvestrant is possible

3.4 The company noted that ribociclib with fulvestrant and abemaciclib with fulvestrant may exhibit similar clinical effectiveness and suggested that a class effect for CDK 4/6 could be considered. The clinical experts explained that CDK 4/6 inhibitors have similar clinical effectiveness, but they highlighted that their adverse effect profiles are different. Ribociclib is associated with an increased incidence of neutropenia and also needs regular electrocardiogram assessments and liver function tests during treatment. Abemaciclib is associated with an increased incidence of diarrhoea. The committee agreed with the experts that a class effect for CDK 4/6 inhibitors with fulvestrant is possible. The committee acknowledged that ribociclib is an additional treatment option that may be preferred by some people.

The results of the network meta-analysis are uncertain

3.5 Because there was no evidence directly comparing ribociclib and fulvestrant with exemestane and everolimus, a network-meta-analysis was done. After technical engagement, the ERG updated the company's network meta-analysis for population B. The meta-analysis included 6 studies comparing progression-free survival across the treatments to allow a comparison between ribociclib with fulvestrant and exemestane with everolimus. No results were presented for overall survival. There were substantial differences in the baseline characteristics of the patients included in the studies. In some trials, patients could have had previous chemotherapy, or more than 1 previous endocrine therapy in the advanced setting and not all the trials were specific to HER2-negative disease. Also, the ERG highlighted that the proportional hazards assumption had not been met in the MONALEESA-3 trial and therefore using a hazard ratio that is dependent on this trial is likely to be unreliable. The committee agreed with the ERG and concluded that the results of the network meta-analysis are highly uncertain. They further noted that the effect of this uncertainty on cost-effectiveness results is likely to be high, and that the direction of the effect is unknown.

Progression-free survival extrapolation is uncertain

3.6 After technical engagement, the company assumed a lognormal distribution for time to progression to extrapolate ribociclib and fulvestrant progression-free survival for population B. The ERG explained that the company's curves had potentially implausible extrapolations and suggested that a 3-knot spline had a better fit to the observed data and also more plausible extrapolation. The clinical experts acknowledged that the company's long-term extrapolation of progression-free survival seemed to be optimistic (results are confidential and cannot be presented here). However, they also acknowledged that there are some patients who remain progression-free for longer than expected. The committee agreed that that the company's model is too optimistic, although the ERG's model could underestimate the number of people progression free at longer follow-up. They agreed that given the extent of the uncertainty in the clinical evidence, the ERG's extrapolation may be more appropriate, although if pessimistic it could overestimate the incremental cost-effectiveness ratios (ICERs). The committee concluded that unless further long-term data were available, the most appropriate extrapolation of progression-free survival was uncertain.

The ERG's unrestricted model is suitable for extrapolation

3.7 Because time on treatment was lower for ribociclib than it was for fulvestrant in the treatment arm, the company modelled time-to-treatment stopping for ribociclib and fulvestrant monotherapy (in the treatment arm) separately. They used restricted models to extrapolate ribociclib and fulvestrant (in the treatment arm). The ERG explained that restricted models assume a common shape parameter across different treatment groups. They further explained that unrestricted models, determined only by the treatment group in which the curves are applied, were a more appropriate method to use in this instance. The committee agreed with the ERG and concluded that unrestricted models were more suitable for the time-to-treatment stopping extrapolation for ribociclib with fulvestrant.

Including placebo data for ribociclib is not appropriate

3.8 The company based the extrapolation of time-to-treatment stopping for ribociclib in people who had ribociclib or placebo. The ERG noted that given the lack of treatment effect, people may stop placebo earlier than ribociclib. The ERG explained that by including the placebo data the company was likely to overestimate rates of stopping compared with using only data from people having ribociclib. Unrealistic rates of stopping would underestimate the cost of ribociclib and the resulting ICERs. The committee agreed with the ERG and concluded that using placebo data for estimating time on treatment with ribociclib is not appropriate and could underestimate the ICER.

Assuming the same post-progression survival is not supported

3.9 The company used data from the MONALEESA-3 trial to estimate post-progression survival for ribociclib and fulvestrant. Because no exemestane with everolimus post-progression survival data were available, the company assumed that post-progression survival for exemestane with everolimus was the same as it was for ribociclib and fulvestrant. However, the ERG noted that if post-progression survival were higher on exemestane with everolimus than ribociclib with fulvestrant, this would reduce the relative overall survival gain for ribociclib with fulvestrant, and increase the ICER comparing ribociclib with fulvestrant with exemestane with everolimus. Conversely, if post-progression survival were lower on exemestane with everolimus than on ribociclib with fulvestrant, the overall survival gain for ribociclib with fulvestrant would increase and the ICER would be reduced. The committee concluded that no evidence had been presented to support the assumption that post-progression survival was the same for exemestane with everolimus and ribociclib with fulvestrant, and that the effect of this assumption on the cost-effectiveness results is uncertain.

The most plausible ICERs for ribociclib with fulvestrant are uncertain, but are above the range considered to be a cost-effective use of NHS resources

3.10 The committee considered the cost effectiveness of ribociclib with fulvestrant in people who could have exemestane with everolimus. The committee recalled its preferred modelling assumptions:

The results all include the patient access schemes for ribociclib and everolimus. The company's base-case ICER compared with exemestane with everolimus was above £30,000 per quality-adjusted life year (QALY) gained, and the committees preferred base-case ICER was significantly above £30,000 per QALY gained. The exact ICERs are commercial-in-confidence and cannot be reported here. The committee recognised that there was a high level of uncertainty in the clinical evidence and that the direction of the effect on cost-effectiveness results is unknown (see section 3.5). It further noted that using the placebo data is likely to underestimate the ICER (see section 3.8). The committee also highlighted that the robustness of the ICER would need further exploration if equal post-progression survival were assumed (see section 3.9). The committee concluded that the most plausible ICERs for ribociclib with fulvestrant are uncertain, but above the range considered to be a cost-effective use of NHS resources.

Ribociclib with fulvestrant did not met the criteria to be considered for inclusion in the Cancer Drugs Fund

3.11 Having concluded that ribociclib with fulvestrant could not be recommended for routine use, the committee then considered if it could be recommended for treating hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer within the Cancer Drugs Fund. The committee 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 was aware that MONALEESA-3 was ongoing and that more data would be available. It agreed that there are several uncertainties:

Some of these uncertainties could be resolved with further data collection. However, the committee was aware that ribociclib with fulvestrant does not have plausible potential to be cost effective at the offered price. The company presented a base-case ICER above £30,000 per QALY gained. The committee's preferred adjustments resulted in an ICER significantly higher than £30,000 per QALY gained and still included substantial unresolved uncertainty. The committee concluded that because there was no plausible potential for this combination to be cost effective, ribociclib with fulvestrant did not met the criteria to be considered for inclusion in the Cancer Drugs Fund.

Ribociclib and fulvestrant is not recommended for use in the NHS

3.12 The committee recognised that there was a high level of uncertainty in the clinical evidence supporting the appraisal and the most plausible ICER was above the range that NICE normally considers an acceptable use of NHS resources. Because of this, the committee concluded that ribociclib with fulvestrant could not be recommended for routine commissioning use and did not meet the criteria to be considered for the Cancer Drugs Fund and therefore ribociclib and fulvestrant is not recommended as an option for people with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer.