Capivasertib with fulvestrant for treating hormone receptor-positive HER2-negative advanced breast cancer after endocrine treatment

The clinical experts explained that initial treatment for HR-positive HER2-negative advanced breast cancer is usually a cyclin-dependent kinase (CDK) 4 and 6 inhibitor plus an aromatase inhibitor (a type of endocrine treatment). After this initial treatment, the main options are alpelisib plus fulvestrant (if the cancer has a PIK3CA alteration) or everolimus plus exemestane (unless chemotherapy is needed because of symptomatic visceral disease; see NICE's technology appraisal guidance on alpelisib with fulvestrant for HR-positive HER2-negative PIK3CA-mutated advanced breast cancer [TA816] and on everolimus with exemestane for treating advanced breast cancer after endocrine therapy [TA421]). The clinical experts explained that there is an unmet need because current endocrine-based treatment is relatively ineffective after initial endocrine treatment plus a CDK 4 and 6 inhibitor. They said alpelisib plus fulvestrant is associated with toxicity that has substantially limited its use in the NHS. And that everolimus plus exemestane has low response rates and exemestane is less effective for ESR1-positive cancer, which is up to 50% of cancers in this population. They said that treatments that make endocrine-based treatment more effective after progression on endocrine treatment plus a CDK 4 and 6 inhibitor are important. The clinical experts explained that if endocrine-based treatment fails, chemotherapy is the main option, but delaying this is highly important for patients because of the toxicity it involves. They added that they believed capivasertib plus fulvestrant is a highly effective and well-tolerated targeted treatment that represents a step change in managing breast cancer with PIK3CA, AKT1 or PTEN alterations. The clinical experts said that the toxicity is much lower with capivasertib plus fulvestrant than alpelisib plus fulvestrant, so quality of life is likely to be better on treatment. The committee noted that side effects including hyperglycaemia, rash and stomatitis (an inflamed and sore mouth) were listed in the summary of product characteristics for capivasertib. The clinical experts explained that these side effects are more significant with alpelisib plus fulvestrant or everolimus plus exemestane. They said that there are substantial challenges with managing hyperglycaemia associated with alpelisib plus fulvestrant. For example, treatment requires learning to use a glucose monitor because of the risk of diabetes. The clinical experts added that rash was a more serious problem with alpelisib and that stomatitis could be a serious problem with everolimus. The patient experts also highlighted the value of having a well-tolerated treatment that delays progression and targets the AKT1 or PTEN gene mutation, noting that there are currently none available. The committee recognised the limitations with existing treatments, the advantages of capivasertib plus fulvestrant, and the importance of having a targeted treatment for HR-positive HER2-negative advanced breast cancer with PIK3CA, AKT1 or PTEN alterations.

The marketing authorisation for capivasertib plus fulvestrant is for people whose cancer has recurred or progressed on or after an endocrine-based regimen. The company submitted evidence for a narrower population: people whose cancer has recurred or progressed after a CDK 4 and 6 inhibitor plus an aromatase inhibitor. The company said that this positioning reflected the anticipated use of capivasertib plus fulvestrant in the current UK treatment pathway. It did not anticipate capivasertib being used for people who had not already had a CDK 4 and 6 inhibitor. The committee noted the clinical experts' comments that a CDK 4 and 6 inhibitor plus an aromatase inhibitor is standard initial treatment for HR-positive HER2-negative advanced breast cancer (see section 3.2). It also noted that the company's positioning of capivasertib plus fulvestrant reflected that of alpelisib plus fulvestrant in TA816. The committee concluded that the company's positioning of capivasertib plus fulvestrant after progression on a CDK 4 and 6 inhibitor plus an aromatase inhibitor was appropriate and in line with expected clinical use.

The company submitted evidence against 2 comparators: alpelisib plus fulvestrant for PIK3CA-altered breast cancer and everolimus plus exemestane. It said that these were the standard treatments after initial endocrine treatment with a CDK 4 and 6 inhibitor plus an aromatase inhibitor, where capivasertib would be used. It said it expected capivasertib plus fulvestrant to be used mainly in place of alpelisib plus fulvestrant because most people with PIK3CA and AKT pathway-altered tumours have PIK3CA alterations. The clinical experts agreed that these are the standard treatments after initial endocrine treatment (see section 3.2). The committee concluded that alpelisib plus fulvestrant for PIK3CA-altered breast cancer and everolimus plus exemestane were the relevant comparators for the evaluation.

The key clinical trial, CAPItello-291, was a randomised, double-blind, placebo-controlled phase 3 trial comparing capivasertib plus fulvestrant with placebo plus fulvestrant. It included people whose HR-positive HER2-negative breast cancer had recurred or progressed on or after treatment with an aromatase inhibitor with or without a CDK 4 and 6 inhibitor. People who had previous fulvestrant were excluded. A subgroup of people in the trial had PI3K and AKT pathway-altered (PIK3CA, AKT1 or PTEN) tumours. Results showed that capivasertib plus fulvestrant significantly improved progression-free survival (median 7.3 months; 95% confidence interval [CI] 5.5 to 9.0) compared with placebo plus fulvestrant (median 3.1 months; 95% CI 2.0 to 3.7) in people with PI3K and AKT pathway-altered tumours. Results were similar for people who had previously had a CDK 4 and 6 inhibitor (the company considers this data confidential, so it is not reported here). For overall survival, there was not enough data for a formal analysis. In people with PI3K and AKT pathway-altered tumours, overall survival was better on capivasertib plus fulvestrant, although this was not statistically significant (hazard ratio 0.69; 95% CI 0.45 to 1.05). The committee concluded that capivasertib plus fulvestrant improved progression-free survival compared with placebo plus fulvestrant.

Because there was no direct evidence comparing capivasertib plus fulvestrant with alpelisib plus fulvestrant or everolimus plus exemestane, the company did indirect treatment comparisons. The network meta-analysis (NMA) included 10 randomised controlled trials. Data for capivasertib plus fulvestrant came from the CAPItello-291 and FAKTION trials; for alpelisib plus fulvestrant from the SOLAR-1 trial, and for everolimus plus exemestane from the BOLERO-2 and BOLERO-5 trials.

To estimate long-term progression-free survival, the company fitted parametric survival models (exponential, log-normal, Weibull, log-logistic, gamma, generalised gamma and Gompertz) to the patient-level data of the placebo plus fulvestrant arm from CAPItello-291 (the common comparator in the NMA). It chose the log-normal distribution in its base case (preferred by 1 out of 5 of the company's clinical experts), based on goodness of fit, visual inspection and clinical opinion. The company explored the log-logistic distribution in a scenario, noting that generalised gamma was also suitable (these 2 were preferred by 3 out of 5 of the company's clinical experts). The EAG preferred the log-logistic distribution for its base case because it had the best fit on the Akaike information criterion (AIC) and Bayesian information criterion (BIC) and it was preferred by most of the company experts. The committee concluded that the log-logistic model was the most appropriate to estimate long-term progression-free survival because it had the best fit to the trial data and was preferred by most of the company's clinical experts.

The company estimated progression-free survival and overall survival for all 3 treatments using the hazard ratios from the NMA. It applied these to the modelled placebo plus fulvestrant progression-free survival curve for people with PI3K and AKT pathway-altered tumours who had previous CDK 4 and 6 inhibitor and endocrine treatment. This was on the assumption that proportional hazards applied for the studies in the network (that is, the assumption that the relative hazards remain constant over time for each treatment comparison). The company analysed the studies for evidence of non-proportional hazards and found that it varied from none to strong:

• for progression-free survival:

  • none, 1 study

  • weak, 4 studies

  • moderate, 2 studies

  • strong, 3 studies

• for overall survival (4 studies did not report this outcome):

  • weak, 4 studies

  • moderate, 2 studies.

The company did not incorporate treatment waning into its model. That is, the model assumed the relative benefits of treatment continued at the same level over time. The company said it believed that the time-varying NMA accounted for treatment waning because of the 3-month (progression-free survival) and 6-month (overall survival) cutoff points, with the hazard ratio increasing at the second time point. The EAG disagreed that the company's time-varying scenario would account for waning in the longer-term period. The EAG noted that there was some indication of treatment effect waning for alpelisib plus fulvestrant and for everolimus plus exemestane, and felt treatment effect waning should be explored. In its base case, the EAG set the hazard ratios for progression-free survival and overall survival to 1 after 24 months for all treatments compared with fulvestrant, and after 36 months in a scenario. It accepted that the time points were arbitrary but considered that they were plausible and useful to explore. The company said the analyses were not reasonable, evidence based, or aligned with TA816, which applied treatment waning at 5 years. The committee noted that setting the hazard ratio to 1 after 24 months had a large impact on the incremental cost-effectiveness ratio (ICER). It agreed with the EAG that the company's time-varying piecewise scenario did not account for treatment waning. It noted the lack of data to inform the period beyond 5 years and so it was not convinced by the company's 6-month cut off for overall survival. It thought that an indefinite duration of treatment effect was unlikely and that the higher hazard ratios at the second time point indicated treatment waning. It also noted that only a small number of people were still on treatment at 2 years, so it was not implausible to set waning at 2 years. It also noted that a hazard ratio of 1 did not imply all treatment benefit disappearing, but that the risk of death was similar for all groups after 2 years. A clinical expert said that it was reasonable to assume the same treatment waning characteristics would apply for capivasertib plus fulvestrant and its comparators. The committee concluded that, unless a time-varying analysis (see section 3.10) showed strong evidence of no treatment waning, it would like to see analyses incorporating treatment waning, including waning at 2 years and 3 years.

Treatment with capivasertib plus fulvestrant requires genomic testing for PIK3CA, AKT1 or PTEN alterations. The company did not include the cost of testing for these alterations in its base case. This is because testing for PIK3CA alterations (the most common PI3K and AKT pathway alteration) is done routinely in UK clinical practice since NICE recommended alpelisib plus fulvestrant in 2022 (see NICE's technology appraisal guidance on alpelisib with fulvestrant). The company did a scenario analysis that showed that including additional testing costs for AKT1 and PTEN alterations had little impact on the estimated ICER. The Cancer Drugs Fund lead said that although PIK3CA alterations are tested for, AKT1 and PTEN are not, so additional costs to test for them needed incorporating into the model. The committee concluded that the costs of testing for AKT1 and PTEN alterations should be included in the model.

In the company's model, people on all treatments were assumed to continue until disease progression, unacceptable toxicity or until they withdrew consent. To model time to treatment discontinuation for capivasertib plus fulvestrant, the company calculated the ratio between time to treatment discontinuation and progression-free survival in CAPItello-291. It applied this ratio to the modelled progression-free survival curve for all treatments. The company considers the figure for the ratio confidential so it is not reported here. This was a pragmatic approach for alpelisib plus fulvestrant and everolimus plus exemestane because there was no publicly available data on time to treatment discontinuation. The EAG noted that discontinuation rates because of disease progression and adverse events differed substantially in the relevant trials:

• capivasertib plus fulvestrant (CAPItello-291); 58.9% disease progression, 13% adverse events

• alpelisib plus fulvestrant (SOLAR-1); 37% disease progression, 25% adverse events

• everolimus plus exemestane (BOLERO-2); 55% disease progression, 19% adverse events.

The company modelled mean relative dose intensity (RDI) for capivasertib plus fulvestrant and everolimus plus exemestane. RDI is a measure of how much of the planned dose of drug a participant actually has in a trial. Someone may not have the full planned dose, for example, because of toxicity, which may mean the dose needs to be reduced or delayed. For alpelisib plus fulvestrant, only the median RDI was available from SOLAR-1 (82.7%), so the company assumed a 100% RDI in its base case, with a scenario analysis applying the median RDI. It said this was because means and medians were not the same; the data could be skewed, so means were preferred. The EAG pointed out that if the median RDI for alpelisib plus fulvestrant was 82.7%, this showed that there were delayed or reduced doses. It said that assuming 100% RDI would overestimate its cost. The committee agreed with the EAG's comments. The company provided a scenario that assumed the same RDI for alpelisib plus fulvestrant as for capivasertib plus fulvestrant, which the EAG used in its base case. The company considers that this value is confidential and so it is not reported. The clinical experts said that a 100% RDI was not plausible and reiterated that alpelisib was the least well tolerated of the treatments (see section 3.2). A clinical expert said that alpelisib was likely to have the lowest RDI of all the treatments. The committee concluded that using a 100% RDI would overestimate costs for alpelisib plus fulvestrant. It also concluded that it would prefer the median RDI of 82.7% to be used in the model, in the absence of any other evidence. But it also said that it would like to see more evidence on the appropriate RDI for alpelisib plus fulvestrant.

Because of confidential commercial arrangements for capivasertib, alpelisib, fulvestrant, and one of the post-progression treatments, the cost-effectiveness results are confidential and cannot be reported here. The committee considered that the cost-effectiveness estimates comparing capivasertib plus fulvestrant with alpelisib plus fulvestrant and with everolimus plus exemestane were highly uncertain. It concluded that further analyses were needed to determine the most plausible estimates for decision making.

NICE's manual on health technology evaluations notes that, above a most plausible ICER of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. But it will also take into account other aspects including uncaptured health benefits. The committee appreciated the high unmet need of people with HR-positive HER2-negative advanced breast cancer. It also recognised that capivasertib is an innovative treatment that the clinical experts considered to be a step change in managing breast cancer with PIK3CA, AKT1 or PTEN alterations. But it was concerned about the high level of uncertainty, specifically:

• whether the differences between the populations in terms of PI3K and AKT pathway status and previous treatment with CDK 4 and 6 inhibitors biased the indirect treatment comparisons (see sections 3.6 and 3.7)

• the modelling of long-term overall and progression-free survival and whether it was more appropriate to use a fully time-varying analysis and incorporate treatment waning (see sections 3.9 to 3.11)

• the most appropriate utility value to use for the post-progression health state (see section 3.12).

The committee requested the following additional analyses:

• using a log-logistic model to estimate long-term progression-free survival (see section 3.9)

• exploring time-varying hazard ratios using fully time-varying analyses to model survival, such as a fractional polynomial model (see section 3.10)

• incorporating treatment waning in the model, including waning at 2 years and 3 years (see section 3.11)

• scenarios using exploratory health state utility values of 0.60, 0.65 and 0.70, and the value of 0.69 from TA816 (Mitre et al. 2016) for the post-progression health state (see section 3.12)

• incorporating the costs of testing for AKT1 and PTEN alterations (see section 3.13)

• incorporating an RDI of 82.7% for alpelisib plus fulvestrant and evidence-based scenarios for alternative RDIs (see section 3.15).

The committee did not identify any equality issues.

The committee considered whether there were any uncaptured benefits of capivasertib. It did not identify additional benefits of capivasertib not captured in the economic modelling. So the committee concluded that all additional benefits of capivasertib had already been taken into account.

The committee recognised that capivasertib plus fulvestrant is an effective treatment after a CDK 4 and 6 inhibitor plus an aromatase inhibitor. But the company's and EAG's cost-effectiveness estimates were very uncertain. The committee concluded that it needed further analyses to agree the most appropriate decision making ICERs. So capivasertib plus fulvestrant is not recommended for HR-positive, HER2-negative advanced breast cancer with PIK3CA, AKT1 or PTEN alterations after endocrine-based treatment.