Systematic literature review of real-world evidence for treatments in HR+/HER2- second-line LABC/mBC after first-line treatment with CDK4/6i.

BACKGROUND: Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) are currently recommended by the National Comprehensive Cancer Network (NCCN) guidelines and the European Society for Medical Oncology (ESMO) guidelines as the first-line (1 L) treatment for patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, locally advanced/metastatic breast cancer (HR+/HER2- LABC/mBC). Although there are many treatment options, there is no clear standard of care for patients following 1 L CDK4/6i. Understanding the real-world effectiveness of subsequent therapies may help to identify an unmet need in this patient population. This systematic literature review qualitatively synthesized effectiveness and safety outcomes for treatments received in the real-world setting after 1 L CDK4/6i therapy in patients with HR+/ HER2- LABC/mBC. METHODS: MEDLINE®, Embase, and Cochrane were searched using the Ovid® platform for real-world evidence studies published between 2015 and 2022. Grey literature was searched to identify relevant conference abstracts published from 2019 to 2022. The review was conducted in accordance with PRISMA guidelines (PROSPERO registration: CRD42023383914). Data were qualitatively synthesized and weighted average median real-world progression-free survival (rwPFS) was calculated for NCCN/ESMO-recommended post-1 L CDK4/6i treatment regimens. RESULTS: Twenty records (9 full-text articles and 11 conference abstracts) encompassing 18 unique studies met the eligibility criteria and reported outcomes for second-line (2 L) treatments after 1 L CDK4/6i; no studies reported disaggregated outcomes in the third-line setting or beyond. Sixteen studies included NCCN/ESMO guideline-recommended treatments with the majority evaluating endocrine-based therapy; five studies on single-agent ET, six studies on mammalian target of rapamycin inhibitors (mTORi) ± ET, and three studies with a mix of ET and/or mTORi. Chemotherapy outcomes were reported in 11 studies. The most assessed outcome was median rwPFS; the weighted average median rwPFS was calculated as 3.9 months (3.3-6.0 months) for single-agent ET, 3.6 months (2.5-4.9 months) for mTORi ± ET, 3.7 months for a mix of ET and/or mTORi (3.0-4.0 months), and 6.1 months (3.7-9.7 months) for chemotherapy. Very few studies reported other effectiveness outcomes and only two studies reported safety outcomes. Most studies had heterogeneity in patient- and disease-related characteristics. CONCLUSIONS: The real-world effectiveness of current 2 L treatments post-1 L CDK4/6i are suboptimal, highlighting an unmet need for this patient population.

Cost-effectiveness of ribociclib versus palbociclib in combination with an aromatase inhibitor as first-line treatment of postmenopausal women with HR+/HER2- advanced breast cancer: analysis based on final OS results of MONALEESA-2 and PALOMA-2.

BACKGROUND AND AIMS: Combination of a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor and an aromatase inhibitor is the standard of care first-line (1L) treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). Updated clinical data have become available from the MONALEESA-2 and PALOMA-2 trials for ribociclib and palbociclib, respectively. This analysis with updated data assessed the cost-effectiveness of ribociclib versus palbociclib, both in combination with letrozole, in the setting of 1L therapy of postmenopausal women with HR+/HER2- ABC, from a United Kingdom (UK) National Health Service perspective. METHODS: A three state (progression-free, progressed disease, and death) partitioned survival model with a 1-month cycle was developed. Clinical data were derived from MONALEESA-2 (NCT01958021) and PALOMA-2 (NCT01740427). The treatment effect was modeled using hazard ratios (HRs) for progression-free survival and overall survival derived through a matched-adjusted indirect comparison. Trial data and published literature were used to derive utility values. Cost inputs included drug acquisition, disease monitoring, subsequent therapies, and adverse events. Costs and outcomes were discounted by 3.5%, over a 40-year lifetime horizon. One-way and probabilistic sensitivity analyses were performed. RESULTS: Ribociclib dominated palbociclib, and was both overall cost saving (-£3,273) and more effective (+1.251 quality-adjusted life years [QALYs]). Ribociclib total drug costs were £17,156 lower than palbociclib. At a £30,000 per QALY willingness-to-pay threshold, the probability of ribociclib being cost-effective was almost 100%. Ribociclib remained cost-effective when varying HRs, utilities, drug cost, and health state costs. CONCLUSIONS: Ribociclib is both cost-saving and cost-effective compared with palbociclib for the 1L treatment of postmenopausal women with HR+/HER2- ABC in the UK.

Effect of ribociclib on productivity losses due to breast cancer in young women in Brazil.

OBJETIVE: To evaluate the effect of ribociclib versus endocrine therapy on productivity losses due to advanced breast cancer. METHODS: Productivity data from the MONALEESA-7 trial, obtained from the results of the application of the Work Productivity and Activity Impairment (WPAI) questionnaire on progression-free survival state (43-month follow-up), were extrapolated to the 10,936 Brazilian prevalent cases of premenopausal women with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer. Productivity loss was determined by quantifying the economic costs of workforce dropout over time in both treatment arms and by discounting the economic costs of absenteeism and presenteeism from workforce retention. A human capital approach was used. RESULTS: Net productivity gains in the ribociclib arm were estimated at USD 4,285,525.00, representing 316,609 added work hours over 43 months and a mean of 2,009 added work weeks per year. CONCLUSIONS: The phase III MONALEESA-7 trial productivity results applied to the Brazilian premenopausal prevalent cases of hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer showed that treatment with ribociclib + endocrine therapy improves workforce participation compared with endocrine therapy alone in premenopausal women with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) metastatic breast cancer, with potential economic gains for the Brazilian society.

Patient experiences with patient-reported outcome measures in metastatic breast cancer trials: qualitative interviews.

BACKGROUND: Patient-reported outcome (PRO) measures are critical for assessing treatment benefit of anticancer treatments. Although PRO measures have been developed with the intention of capturing patient-centric concepts, a gap exists in understanding the patient experience with these tools. We characterized the experience of patients with metastatic breast cancer (mBC) with PRO measures in an oncology clinical trial setting to determine the importance, relevance, barriers, and facilitators for PRO completion. METHODS: The multicenter, qualitative design included semistructured interviews with 18 women with mBC who completed PRO measures in a clinical trial setting within 1 year of screening. Interviews began with concept elicitation to understand symptom characterization, decision to participate in a clinical trial, pre-trial expectations, and thoughts on study-related questionnaires. Cognitive debriefing was conducted to determine if items in a commonly used PRO instrument were relevant to the patient experience. Qualitative data were analyzed using a constant comparative approach. RESULTS: Participants described the need for detailed explanation of PRO measures at study start, including information about how the PRO data will likely be used to support drug development. Respondents who felt connected to clinical trial research were more likely to feel as if the measures adequately captured their experiences. Items that were deemed irrelevant or out of date to the patient experience may cause a respondent to feel marginalized and adds to the overall burden of PRO measure completion. Mode of PRO measure administration (electronic/paper) was important to some, but placement of the instrument completion within a study visit appeared to influence respondent willingness to fully engage with the measures. A lack of any type of feedback loop to allow respondents to learn from the captured PRO data was noted as important but missing from the patient experience. CONCLUSIONS: PRO measures need to include content that is relevant to the patient experience over the course of the clinical trial period to be considered meaningful to respondents, and administration techniques also impact engagement. Robust communication strategies that socialize the intent, use, and results of PRO data may enrich the patient experience and support greater adherence to PRO completion in future studies.

Correlation between work productivity loss and EORTC QLQ-C30 and -BR23 domains from the MONALEESA-7 trial of premenopausal women with HR+/HER2- advanced breast cancer.

BACKGROUND: The phase III MONALEESA-7 trial (NCT02278120) assessed ribociclib + endocrine therapy (ET) versus ET in premenopausal women with HR+/HER2- advanced breast cancer (ABC). The relationship between work productivity loss (WPL) and domains of European Organisation for Research and Treatment of Cancer Quality of Life (EORTC QLQ-C30) and the breast cancer (BC)-specific module (QLQ-BR23) has not been explored in ABC. In this post hoc analysis (data cutoff, November 30, 2018), we assessed the correlation between the WPL component of the Work Productivity and Activity Impairment: General Health (WPAI:GH) questionnaire and EORTC QLQ-C30/BR23 domains. METHODS: We analyzed EORTC and WPAI:GH data from 329 patients in both treatment arms of MONALEESA-7 who were employed during the trial. Separate univariable mixed-model repeated measures (MMRM) regression models were fitted for each domain, with WPL as dependent variable and each EORTC domain score as a single fixed-effect covariate. Linear and quadratic relationships were considered based on the Akaike information criterion. Next, two separate multivariable MMRM regression models were fitted with WPL a dependent variable and all QLQ-C30/BR23 domain scores as fixed-effect covariates. The strength of correlation between WPL and EORTC domains was assessed in terms of minimally important differences for the QLQ-C30/BR23 modules. RESULTS: Our univariable analysis showed that greater WPL was statistically significantly associated with lower levels of overall quality of life (QoL) and other functional domains and with higher levels of all symptomatic domains of the QLQ-C30/BR23 modules. Our multivariable analysis determined that this correlation was primarily driven by changes in QoL; physical, role, social, and future perspective domains; and BC-specific symptomatic domains. CONCLUSION: This analysis determined the QoL domains that correlate with WPL in premenopausal patients with HR+/HER2- ABC. These results may inform prognostic tools to identify and characterize patients with greater risk for WPL and help design interventional strategies to minimize WPL.

Quality-Adjusted Survival with Ribociclib Plus Fulvestrant Versus Placebo Plus Fulvestrant in Postmenopausal Women with HR±HER2- Advanced Breast Cancer in the MONALEESA-3 Trial.

BACKGROUND: MONALEESA-3 demonstrated an overall survival (OS) benefit for ribociclib plus fulvestrant (R+F) in postmenopausal women with hormone receptor (HR) positive, HER2 negative advanced breast cancer (ABC). This study estimated quality-adjusted (QA) survival outcomes for patients receiving R+F vs. placebo (P)+F in MONALEESA-3. METHODS: Kaplan-Meier OS was partitioned into health states: (1) toxicity (TOX)=time spent with grade 3 -4 adverse events before progression (DP); (2) progression (PROG)=time between DP and death; and (3) time without symptoms or toxicity (TWiST)=time not in TOX or PROG. QA time was calculated by combining estimated mean time in each health state with treatment-group specific health-state utility values estimated using EQ-5D-5L questionnaire. Outcomes included QA progression-free survival (QAPFS), QAOS, and QA TWiST (Q-TWiST). Q-TWiST was calculated with health-state utility values for TOX and PROG defined relative to TWiST. RESULTS: Mean PFS and OS were significantly greater with R+F vs. P+F (difference 0.56 and 0.19 years). Mean time in TOX and TWiST were greater with R+F; mean time in PROG was greater with P+F. QAPFS was 0.45 years (95% CI 0.27 -0.63) greater with R+F than P+F (P <.001). QAOS was numerically greater with R+F vs. P+F (0.16 years, 95% CI 0.07 -0.45, P = .0569). Q-TWiST was 0.23 years greater with R+F (95% CI 0.07 -0.45, P = .0069). In a sensitivity analysis using an estimate of disutility for PROG, the difference in QAOS was 0.23 years (95% CI 0.08 -0.41, P = .0022). CONCLUSION: R+F in postmenopausal women with HR+/HER2- ABC improves QAPFS, resulting in clinically important improvements in Q-TWiST and may improve QAOS.

Effect of ribociclib on productivity losses due to breast cancer in young women in Brazil

ABSTRACT OBJETIVE To evaluate the effect of ribociclib versus endocrine therapy on productivity losses due to advanced breast cancer. METHODS Productivity data from the MONALEESA-7 trial, obtained from the results of the application of the Work Productivity and Activity Impairment (WPAI) questionnaire on progression-free survival state (43-month follow-up), were extrapolated to the 10,936 Brazilian prevalent cases of premenopausal women with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer. Productivity loss was determined by quantifying the economic costs of workforce dropout over time in both treatment arms and by discounting the economic costs of absenteeism and presenteeism from workforce retention. A human capital approach was used. RESULTS Net productivity gains in the ribociclib arm were estimated at USD 4,285,525.00, representing 316,609 added work hours over 43 months and a mean of 2,009 added work weeks per year. CONCLUSIONS The phase III MONALEESA-7 trial productivity results applied to the Brazilian premenopausal prevalent cases of hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer showed that treatment with ribociclib + endocrine therapy improves workforce participation compared with endocrine therapy alone in premenopausal women with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) metastatic breast cancer, with potential economic gains for the Brazilian society.

Matching-Adjusted Indirect Comparison of Ribociclib Plus Fulvestrant versus Palbociclib Plus Letrozole as First-Line Treatment of HR+/HER2- Advanced Breast Cancer.

PURPOSE: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) plus endocrine therapy are recommended for first-line treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). However, not all CDK4/6i trials have reported significant overall survival (OS) benefit, and there have been no head-to-head trials. Two trials have reported OS outcomes in first-line patients: MONALEESA-3 reported significant OS benefit with first- or second-line ribociclib plus fulvestrant (RIB+FUL) versus placebo plus fulvestrant (PBO+FUL), while PALOMA-1 reported no significant OS benefit for palbociclib plus letrozole (PAL+LET) versus LET in first-line postmenopausal patients. Matched-adjusted indirect comparisons (MAICs) are an established method for comparing efficacy of treatments from different trials. We used an MAIC to compare first-line patients from MONALEESA-3 and PALOMA-1. PATIENTS AND METHODS: An unanchored MAIC of progression-free survival (PFS) and OS in first-line patients with HR+/HER2- ABC treated with RIB+FUL versus PAL+LET was conducted using individual patient data from MONALEESA-3 and aggregated data from PALOMA-1. To match patients in PALOMA-1, patients in MONALEESA-3 were limited to those with no prior endocrine therapy for ABC and no (neo) adjuvant LET ≤12 months before enrollment. PFS and OS were compared using Kaplan-Meier estimators and Cox regression. RESULTS: A total of 329 and 178 patients from RIB+FUL and PBO+FUL arms, respectively, of MONALEESA-3 were matched to 84 and 81 patients from PAL+LET and LET arms of PALOMA-1. After weighting, OS was significantly longer for RIB+FUL versus PAL+LET (hazard ratio [HR], 0.50; 95% CI, 0.32-0.77; p = 0.0020). PFS favored RIB+FUL versus PAL+LET, although the difference was not statistically significant (HR, 0.77; 95% CI, 0.54-1.10; p = 0.1553). CONCLUSION: Using MAIC to adjust for trial differences, OS comparisons favored RIB+FUL over PAL+LET as first-line treatment in postmenopausal patients with HR+/HER2- ABC. These exploratory results suggest a significant increase in OS benefit with RIB treatment compared with PAL.

Cost Effectiveness of Ribociclib in Combination with Fulvestrant for the Treatment of Postmenopausal Women with HR+/HER2- Advanced Breast Cancer Who Have Received No or Only One Prior Line of Endocrine Therapy: A Canadian Healthcare Perspective.

BACKGROUND: The MONALEESA-3 trial demonstrated the efficacy and safety of ribociclib plus fulvestrant versus placebo plus fulvestrant for patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). This analysis evaluated the cost effectiveness of ribociclib plus fulvestrant versus fulvestrant in patients with HR+/HER2- ABC from a Canadian healthcare payer perspective. METHODS: The incremental cost-effectiveness ratio (ICER), expressed as incremental costs per quality-adjusted life-year (QALY) gained for ribociclib plus fulvestrant versus fulvestrant, was estimated using a semi-Markov cohort model developed in Microsoft Excel, with states for progression-free, post-progression, and dead. A 15-year time horizon was used. Survival distributions for progression-free survival (PFS), post-progression survival (PPS), and time to discontinuation (TTD) were based on parametric survival distributions fit to data from MONALEESA-3. Health-state utilities were estimated using EQ-5D index values collected in MONALEESA-3. Direct costs of ABC treatment (medication and administration costs, follow-up and monitoring, adverse events, subsequent treatments) were based on Canadian-specific values from published sources. Costs (2019 CAN$) and QALYs were discounted at 1.5% annually. RESULTS: In the base case, ribociclib plus fulvestrant was estimated to result in gains of 1.19 life-years and 0.96 QALYs versus fulvestrant, at an incremental cost of $151,371. The ICER of ribociclib plus fulvestrant versus fulvestrant was $157,343 per QALY gained based on the mean of probabilistic analyses. Results were sensitive to parametric distributions used for projecting long-term TTD, PFS, and PPS. CONCLUSIONS: For patients with HR+/HER2- ABC, ribociclib plus fulvestrant is projected to result in substantial gains in QALYs compared with fulvestrant. At its current list price, ribociclib used in combination with fulvestrant is likely to be cost effective in these patients at a threshold ICER of $157,343. These results may be useful in deliberations regarding reimbursement and access to this treatment.

Cost Effectiveness of Ribociclib Plus a Nonsteroidal Aromatase Inhibitor in Pre-/Perimenopausal, HR+ and HER2- Advanced Breast Cancer: A Canadian Healthcare Perspective.

BACKGROUND AND OBJECTIVES: The MONALEESA-7 trial demonstrated the efficacy and safety of ribociclib plus a nonsteroidal aromatase inhibitor (NSAI) [with goserelin] for pre-/perimenopausal women with hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer. This analysis evaluated the cost effectiveness of ribociclib plus NSAI vs NSAI monotherapy and tamoxifen monotherapy from the perspective of the Canadian healthcare system. METHODS: The incremental cost-effectiveness ratio expressed as incremental costs per quality-adjusted life-year (QALY) gained for ribociclib plus an NSAI vs an NSAI and vs tamoxifen was estimated using a semi-Markov cohort model developed in Microsoft Excel with a 15-year time horizon and states for progression-free survival, post-progression survival, and dead. Survival distributions for progression-free survival, post-progression survival, and time to discontinuation as well as health-state utilities were estimated using data from MONALEESA-7. Direct costs of advanced breast cancer treatment were based on Canadian-specific values from published sources. Costs ($CAN 2019) and QALYs were discounted at 1.5% annually. RESULTS: Ribociclib plus an NSAI was estimated to yield gains of 1.42 life-years and 1.17 QALYs vs an NSAI, and 2.61 life-years and 2.12 QALYs vs tamoxifen, at incremental costs of $209,701 and $220,836, respectively. In probabilistic analyses, the incremental cost-effectiveness ratio for ribociclib plus an NSAI was estimated to be $178,872 per QALY gained vs an NSAI and $104,400 per QALY gained vs tamoxifen. Results of deterministic analyses were similar (incremental cost-effectiveness ratios of $177,245 and $103,316 vs NSAI and tamoxifen, respectively). Results were sensitive to parametric distributions used for projecting progression-free survival and the time horizon. CONCLUSIONS: At its current list price, ribociclib used in combination with NSAI is likely to be co-effective relative to an NSAI alone or tamoxifen alone if the willingness-to-pay threshold is less than approximately $178,000 per QALY. These results have informed deliberations regarding reimbursement and access to this treatment in Canada and may be useful for decision makers in other settings.

Effectiveness of Alpelisib + Fulvestrant Compared with Real-World Standard Treatment Among Patients with HR+, HER2-, PIK3CA-Mutated Breast Cancer.

BACKGROUND: The BYLieve trial (NCT03056755) confirmed efficacy and safety of alpelisib with fulvestrant for hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-), PIK3CA-mutated advanced breast cancer (ABC), after cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) with an aromatase inhibitor (AI) as immediate prior therapy. Further analyses were performed to compare efficacy from BYLieve with effectiveness of standard treatment in the real-world setting. MATERIALS AND METHODS: Patients who progressed on a CDK4/6i plus AI and were treated with alpelisib with fulvestrant in BYLieve were matched with a real-world patient cohort who received standard-of-care from a deidentified clinico-genomics database (CGDB). Primary and secondary endpoints were to compare progression-free survival (PFS), estimated by the Kaplan-Meier method, and the proportion of patients remaining progression-free at 6 months, respectively, between the two cohorts. RESULTS: A total of 855 patients with PIK3CA-mutant disease who had prior CDK4/6i plus hormone therapy were selected from the CGDB; further matching to 120 patients from BYLieve selected 95 patients without exposure to HER2-targeting agents, clinical study drug, or alpelisib. In unadjusted and postmatching results, primary and secondary endpoints favored treatment with alpelisib with fulvestrant in BYLieve more than standard treatments in the real-world cohort. Postadjustment, median PFS for patients treated with alpelisib in BYLieve was 7.3 versus 3.7 months in the real-world cohort, and 6-month PFS was 54.6% versus 40.1%, respectively. CONCLUSION: Matched/weighted analysis comparing BYLieve with the real-world setting further supports the clinical benefit of alpelisib with fulvestrant for treatment of HR+, HER2-, PIK3CA-mutant ABC after CDK4/6i treatment. IMPLICATIONS FOR PRACTICE: Approximately 40% of patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC) have PIK3CA-mutated tumors, which have been associated with endocrine therapy resistance. Alpelisib, an α-selective phosphatidylinositol-3-kinase inhibitor, demonstrated significantly improved progression-free survival in SOLAR-1 and demonstrated clinical efficacy in BYLieve when combined with fulvestrant. Data are limited in comparing the efficacy of alpelisib combined with fulvestrant with effectiveness of standard therapy after CDK4/6i treatment. Using real-world data, this is the first analysis comparing alpelisib combined with fulvestrant with standard treatments for HR+, HER2-, PIK3CA-mutant ABC in the post-CDK4/6i setting.

Ribociclib plus fulvestrant for advanced breast cancer: Health-related quality-of-life analyses from the MONALEESA-3 study.

PURPOSE: In the MONALEESA-3 Phase III trial of patients with hormone receptor-positive human epidermal growth factor receptor-negative advanced breast cancer, ribociclib plus fulvestrant significantly improved progression-free survival (PFS) and overall survival (OS). Here, we present patient-reported outcomes from the trial, including health-related quality of life (HRQOL). METHODS: Patients were randomized (2:1) to receive ribociclib plus fulvestrant or placebo plus fulvestrant. Time to definitive 10% deterioration (TTD) from baseline in HRQOL (global health status [GHS] from the EORTC QLQ-C30 questionnaire) and pain (BPI-SF questionnaire) were assessed using Kaplan-Meier estimates; a stratified Cox regression model was used to estimate the hazard ratio (HR) and 95% CIs. RESULTS: Deterioration ≥10% in the EORTC-QLQ-C30 GHS was observed in 33% of patients in the ribociclib group vs 34% of patients in the placebo (reference) group (HR for TTD ≥ 10% = 0.81 [95% CI, 0.62-1.1]). Similar findings were noted for TTD ≥5% (HR = 0.79 [95% CI, 0.61-1.0]) and TTD ≥15% (HR = 0.81 [95% CI, 0.60-1.08]). TTD ≥10% in emotional functioning (HR = 0.76 [95% CI, 0.57-1.01]) trended in favor of the ribociclib group, whereas results for fatigue and pain were similar between arms. TTD ≥10% in BPI-SF pain severity index score (HR = 0.77 [95% CI, 0.57-1.05]) and worst pain item score (HR = 0.81 [95% CI, 0.58-1.12]) trended in favor of ribociclib vs placebo. CONCLUSIONS: In addition to significantly prolonging PFS and OS compared with placebo plus fulvestrant, adding ribociclib to fulvestrant maintains HRQOL.

Health-related quality of life in premenopausal women with hormone-receptor-positive, HER2-negative advanced breast cancer treated with ribociclib plus endocrine therapy: results from a phase III randomized clinical trial (MONALEESA-7).

BACKGROUND: This analysis evaluated patient-reported outcomes (PROs) to assess health-related quality of life (HRQoL) in the phase III MONALEESA-7 trial, which previously demonstrated improvements in progression-free survival (PFS) and overall survival (OS) with ribociclib (cyclin-dependent kinase 4/6 inhibitor) + endocrine therapy (ET) compared with placebo + ET in pre- and perimenopausal patients with hormone-receptor-positive, HER2-negative (HR+/HER2-) advanced breast cancer (ABC). METHODS: The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life questionnaire C30 (QLQ-C30) and the EQ-5D-5L were used to evaluate HRQoL. RESULTS: EORTC QLQ-C30 assessments were evaluable for 335 patients in the ribociclib arm and 337 patients in the placebo arm. Adherence rates at baseline and ⩾1 postbaseline time point were 90% and 83%, respectively. Patients treated with ribociclib + ET had a longer time to deterioration (TTD) ⩾ 10% in global HRQoL {hazard ratio (HR), 0.67 [95% confidence interval (CI), 0.52-0.86]}. TTD ⩾ 10% in global HRQoL was delayed in ribociclib-treated patients without versus with disease progression [HR, 0.31 (95% CI, 0.21-0.48)]. TTD ⩾ 10% in pain was longer with ribociclib + ET than with placebo + ET [HR, 0.65 (95% CI, 0.45-0.92)]. Patients who received a nonsteroidal aromatase inhibitor experienced similar benefits with ribociclib versus placebo in global HRQoL and pain. CONCLUSION: HRQoL was maintained longer in patients who received ribociclib + ET versus placebo + ET. These data, combined with previously reported improvements in PFS and OS, support a strong clinical benefit-to-risk ratio with ribociclib-based treatment in pre- and perimenopausal patients with HR+/HER2- ABC.

Systematic literature review of clinical trials of endocrine therapies for premenopausal women with metastatic HR+ HER2- breast cancer.

Several endocrine-based therapies have recently been evaluated as treatments for premenopausal women with hormone-receptor-positive/human-epidermal-growth-factor-receptor 2 negative (HR+/HER2-) metastatic breast cancer (mBC). We conducted a systematic review and assessed the feasibility of an indirect treatment comparison (ITC) to characterize the comparative efficacy of endocrine-based therapies in this setting. A systematic literature review (SLR) of Medline, EMBASE, Cochrane Library and key conferences was performed to identify randomized clinical trials (RCTs) satisfying the following criteria: (a) included pre/perimenopausal women with HR+/HER2- mBC, (b) included endocrine-based therapies, (c) reported efficacy, safety, or quality of life outcomes, and (d) was published in 2007 or later (when HER2 testing was standardized). The clinical and methodological similarities across trials were assessed to evaluate the feasibility of an ITC. Four RCTs (PALOMA-3, MONARCH-2, KCSG BR10-04 and MONALEESA-7) and eight regimens (palbociclib + fulvestrant + goserelin, fulvestrant + goserelin, abemaciclib + fulvestrant + gonadotropin-releasing hormone agonist [GnRHa], fulvestrant + GnRHa, anastrozole + goserelin, goserelin, ribociclib + NSAI/tamoxifen + goserelin and NSAI/tamoxifen + goserelin) were selected. MONALEESA-7 was the only phase 3 trial investigating endocrine-based therapies as first-line in only pre/perimenopausal women with HR+/HER2- mBC; the other three trials focused on the ET-failure setting and their pre/perimenopausal populations were relatively small. ITCs were methodologically unfeasible due to critical differences in treatment settings and lack of common comparators across trials. Therefore, we were not able to characterize the relative efficacy of the different endocrine-based therapies available in the premenopausal HR+/HER2- mBC setting. This systematic review provides a comprehensive assessment of the available trial evidence on the efficacy and safety of endocrine-based therapies for premenopausal women with HR+/HER2- mBC. Only four trials have reported relevant data in this setting, and MONALEESA-7 is currently the only trial focused on premenopausal HR+ HER2- mBC in the first-line setting.

Cost-effectiveness analysis of ribociclib plus letrozole versus palbociclib plus letrozole in the United Kingdom.

OBJECTIVE: To evaluate the cost-effectiveness of ribociclib plus letrozole versus palbociclib plus letrozole in post-menopausal women with hormone receptor positive (HR+) and human epidermal growth receptor 2 negative (HER2-) advanced breast cancer from a UK payer perspective. METHODS: A cohort-based partitioned survival model was developed to evaluate the cost-effectiveness of ribociclib plus letrozole versus palbociclib plus letrozole in post-menopausal women with HR+/HER2- advanced breast cancer over a lifetime horizon. The analysis was carried out from a National Health Services and Personal Social Services perspective, and results are presented in incremental costs per quality adjusted life years. Clinical data from three randomized controlled trials (MONALEESA-2, PALOMA-1 and PALOMA-2 studies) were used, and supplemented with available real world evidence. Costs categories comprised of drug acquisition, medical management, and treatment of adverse events. Healthcare resource utilization data were identified from literature and unit costs sourced from secondary sources. Utility values were derived from MONALEESA-2 study and were supported with values identified from literature. Both deterministic and probabilistic analyses were carried out to assess uncertainty. RESULTS: In the base case, treatment with ribociclib plus letrozole increased mean progression free survival (PFS) by 4.1 months and overall survival by 5.0 months compared to palbociclib plus letrozole. Further, treatment with ribociclib plus letrozole resulted in cost-savings of £8464 and incremental QALYs of 0.261, demonstrating that treatment with ribociclib plus letrozole is dominant to treatment with palbociclib plus letrozole. The probabilistic analysis also yielded mean cost-savings of £7914 and mean QALY gain of 0.273. At willingness-to-pay threshold of £30 000 per QALY, treatment with ribociclib plus letrozole had a 92% probability of being cost-effective compared to palbociclib and letrozole. CONCLUSIONS: The results of the analysis demonstrate that ribociclib plus letrozole treatment is both cost-saving and a cost-effective option amongst the available cyclin dependent kinase 4/6 inhibitors for the treatment of post-menopausal women with advanced breast cancer. The biggest driver of the cost savings were the lower acquisition costs of ribociclib.

Matching-adjusted indirect treatment comparison of ribociclib and palbociclib in HR+, HER2- advanced breast cancer.

BACKGROUND: Ribociclib (RIBO) and palbociclib (PALBO), combined with letrozole (LET), have been evaluated as treatments for hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in separate Phase III randomized controlled trials (RCTs), but not head-to-head. Population differences can lead to biased results by classical indirect treatment comparison (ITC). Matching-adjusted indirect comparison (MAIC) aims to correct these differences. We compared RIBO and PALBO in hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer using MAIC. METHODS: Patient-level data were available for RIBO (MONALEESA-2), while only published summary data were available for PALBO (PALOMA-2). Weights were assigned to MONALEESA-2 patient data such that mean baseline characteristics matched those reported for PALOMA-2; the resulting matched cohort was used in comparisons. Limited by the results reported in PALOMA-2, progression-free survival (PFS) was the primary comparison. Cox regression models were used to calculate adjusted hazard ratios (HRs) for PFS, before indirect treatment comparison (ITC) was performed with 95% confidence intervals. An exploratory analysis was performed similarly for overall survival using earlier PALBO data (PALOMA-1). Grade 3/4 adverse events were also compared. RESULTS: Racial characteristics, prior chemotherapy setting, and the extent of metastasis were the most imbalanced baseline characteristics. The unadjusted PFS HRs were 0.556 (0.429, 0.721) for RIBO+LET versus LET alone and 0.580 (0.460, 0.720) for PALBO+LET versus LET alone. MAIC adjustment resulted in an HR of 0.524 (0.406, 0.676) for RIBO+LET versus LET. PFS ITC using unadjusted trial data produced an HR of 0.959 (0.681, 1.350) for RIBO versus PALBO, or 0.904 (0.644, 1.268) with MAIC. Unadjusted overall survival HR of RIBO versus PALBO was 0.918 (0.492, 1.710); while exploratory MAIC was 0.839 (0.440, 1.598). ITC of grade 3/4 adverse events yielded a risk ratio of 0.806 (0.604, 1.076). CONCLUSION: MAIC was performed for RIBO and PALBO in the absence of a head-to-head trial: though not statistically significant, the results favored RIBO.

Progression-free survival with endocrine-based therapies following progression on non-steroidal aromatase inhibitor among postmenopausal women with hormone receptor positive, human epidermal growth factor receptor-2 negative metastatic breast cancer: a network meta-analysis.

OBJECTIVE: To quantify the comparative efficacy of currently available endocrine-based therapies (ETs) for postmenopausal women with hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) metastatic breast cancer (mBC) after non-steroidal aromatase inhibitor (NSAI) progression. DESIGN: Network meta-analysis (NMA). METHODS: Randomized clinical trials of ETs for HR+/HER2- mBC were identified via a systematic literature review using MEDLINE, Embase, Cochrane Library and key conference proceedings. All trials met the following inclusion criteria: (1) included women with HR+/HER2- mBC; (2) previous treatment with ETs or chemotherapy as first-line therapy; (3) treatment with ET as monotherapy or in combination with targeted therapy; (4) progression-free survival (PFS) was reported; and (5) published in 2007 (when HER2 testing became standardized) or later. Regimens were compared using pairwise hazard ratios (HRs) and 95% credible intervals (CrIs) of PFS obtained from a Bayesian NMA. Treatments with different approved dosages were pooled into the same arm; anastrozole and exemestane were pooled as aromatase inhibitors (AIs) due to clinical similarities. RESULTS: A total of 4 trials and 6 regimens (palbociclib + fulvestrant, everolimus + fulvestrant, everolimus + AI, fulvestrant + AI, fulvestrant and AI) were eligible for inclusion. Palbociclib + fulvestrant and everolimus + AI had 50% and 55% reduced hazard of progression or death vs. AI (95% CrI upper bound ≤1), respectively. Palbociclib + fulvestrant, everolimus + AI and everolimus + fulvestrant had 54%, 58% and 40% reduced hazard vs. fulvestrant (95% CrI upper bound ≤1), while palbociclib + fulvestrant and everolimus + AI had 52% and 55% reduced hazard vs. fulvestrant + AI (95% CrI upper bound ≤1), respectively. CONCLUSION: Postmenopausal women with HR+/HER2- mBC who had previously failed an NSAI and received palbociclib + fulvestrant, everolimus + AI or everolimus + fulvestrant had longer PFS compared to those who received fulvestrant or AI alone.

Progression-free survival/time to progression as a potential surrogate for overall survival in HR+, HER2- metastatic breast cancer.

BACKGROUND: Several recent randomized controlled trials (RCTs) in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) have demonstrated significant improvements in progression-free survival (PFS); however, few have reported improvement in overall survival (OS). The surrogacy of PFS or time to progression (TTP) for OS has not been formally investigated in HR+, HER2- MBC. METHODS: A systematic literature review of RCTs in HR+, HER2- MBC was conducted to identify studies that reported both median PFS/TTP and OS. The correlation between PFS/TTP and OS was evaluated using Pearson's product-moment correlation and Spearman's rank correlation. Subgroup analyses were performed to explore possible reasons for heterogeneity. Errors-in-variables weighted least squares regression (LSR) was used to model incremental OS months as a function of incremental PFS/TTP months. An exploratory analysis investigated the impact of three covariates (chemotherapy vs hormonal/targeted therapy, PFS vs TTP, and first-line therapy vs second-line therapy or greater) on OS prediction. The lower 95% prediction band was used to determine the minimum incremental PFS/TTP months required to predict OS benefit (surrogate threshold effect [STE]). RESULTS: Forty studies were identified. There was a statistically significant correlation between median PFS/TTP and OS (Pearson =0.741, P=0.000; Spearman =0.650, P=0.000). These results proved consistent for chemotherapy and hormonal/targeted therapy. Univariate LSR analysis yielded an R2 of 0.354 with 1 incremental PFS/TTP month corresponding to 1.13 incremental OS months. Controlling the type of treatment (chemotherapy vs hormonal/targeted therapy), line of therapy (first vs subsequent), and progression measure (PFS vs TTP) led to an improved R2 of 0.569 with 1 PFS/TTP month corresponding to 0.78 OS months. The STE for OS benefit was 5-6 months of incremental PFS/TTP. CONCLUSION: We demonstrated a significant association between PFS/TTP and OS, which may justify the use of PFS/TTP as a surrogate for OS benefit in HR+, HER2- MBC.

Is progression-free survival a more relevant endpoint than overall survival in first-line HR+/HER2- metastatic breast cancer?

BACKGROUND: Hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), metastatic breast cancer (MBC) accounts for 73% of all MBCs. Endocrine therapy (ET) is the basis of first-line (1L) therapy for patients with HR+/HER2- MBC. Novel therapies have demonstrated improvements in progression-free survival (PFS) compared to ET. The clinical relevance of PFS is being debated, as there is no proven direct correlation with overall survival (OS) benefit to date. We reviewed studies of HR+/HER2- MBC to assess PFS and other factors that influence OS and treatment response, and health-related quality of life (HRQoL). METHODS: The Embase®, Medline®, and Cochrane databases were systematically searched to identify studies in adult women with HR+/HER2- MBC, published between January 2006 and January 2017, and written in English. Phase II and III randomized controlled trials (RCTs), observational, and retrospective studies were included. RESULTS: Seventy-nine RCTs were identified: 58 (73%) in the 1L+ setting and 21 (27%) in second-line or greater settings. PFS hazard ratios (HRs) were reported in 61 (77%) studies; 31 (39%) reported significant PFS improvements. OS was reported in 44 (41%) studies; 12 (15%) reported significant OS improvements. Significant improvements in both PFS and OS were reported in only 6 (8%) studies (1 Phase II; 5 Phase III). Patients with HER2- MBC received, on average, ≥5 lines of therapy, with no consistent treatment pathway. Baseline characteristics, prior therapies, and the type and number of post-progression therapies significantly impacted OS. PFS, response rates, and HRQoL decreased with each line of therapy (EuroQol 5 Dimensions: 0.78 1L vs. 0.70 post-progression). CONCLUSION: Few RCTs in HR+/HER2- MBC have demonstrated significant improvements in OS. Factors other than choice of 1L therapy impact OS, including post-progression therapies, which cannot be controlled in RCTs. This study emphasizes the importance of PFS improvement in 1L treatment of HR+/HER2- MBC.