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Indication: In combination with endocrine therapy for the adjuvant treatment of adult patients with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative, node-positive, early breast cancer at high risk of disease recurrence based on clinicopathological features and a Ki-67 score of at least 20%
CADTH recommends that Verzenio in combination with endocrine therapy should be reimbursed by public drug plans for the adjuvant treatment of adult patients with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative, node-positive, early breast cancer at high risk of disease recurrence based on clinicopathological features and a Ki-67 score of at least 20% if certain conditions are met.
Verzenio in combination with endocrine therapy should only be covered in patients whose breast cancer has receptors for the hormones estrogen and progesterone, tests negative for the HER2 protein, has been removed by surgery, and is at high risk of coming back based on certain risk features and the results of a biomarker test (i.e., Ki-67 test score ≥ 20%).
Verzenio in combination with endocrine therapy should only be reimbursed if prescribed by clinicians with expertise in delivering systemic therapy and if the cost is reduced.
Breast cancer begins in the cells of the breasts. Invasive early breast cancer without metastases has spread into the surrounding breast tissue but has not spread to different body parts. Approximately 94% of patients with HR-positive, HER2-negative early breast cancer survive at least 5 years.
Patients with early breast cancer that has been removed by surgery but has a high risk to come back are in need of treatment options that prevent or delay the cancer from returning, prolong survival with an acceptable toxicity profile, and maintain quality of life.
Treatment with Verzenio is expected to cost approximately $5,514 per 28 days.
The CADTH pCODR Expert Review Committee (pERC) recommends that abemaciclib (ABE) in combination with endocrine therapy (ET) be reimbursed for the adjuvant treatment of adult patients with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative, node-positive early breast cancer at high risk of disease recurrence based on clinicopathological features and a Ki-67 score of at least 20% only if the conditions listed in Table 1 are met.
One phase III multi-centre, randomized, open-label trial (monarchE; N = 2,003 for patients in cohort 1 with a Ki-67 score ≥ 20%) demonstrated that adjuvant treatment with ABE-ET resulted in added clinical benefit compared with adjuvant ET alone in adult patients with HR-positive, HER2-negative, node-positive early breast cancer at high risk of disease recurrence based on clinicopathological features and a Ki-67 score of at least 20%. Results from the monarchE trial showed a statistically significant and clinically meaningful improvement in invasive disease-free survival (IDFS) with ABE-ET compared with ET alone with a hazard ratio (HR) of 0.64 (95% confidence interval [CI], 0.48 to 0.87). Although those patients treated with ABE-ET appeared to have more adverse events (AEs) overall than those treated with ET alone, pERC noted that no new safety signals were observed and agreed that most AEs could be managed with dose modifications and best supportive care. Patients identified a need for effective treatments that reduce the risk of recurrence, maintain quality of life, have manageable side effects, and are affordable and accessible. pERC concluded that ABE-ET met some patient needs because it reduces the risk of recurrence, has manageable side effects, and may be more accessible due to the oral route of administration of ABE. Although patients expressed an unmet need for treatments that maintain quality of life, no definitive conclusion could be reached regarding the effects of ABE-ET on health-related quality of life (HRQoL) due to a significant decline in the number of patients available to provide HRQoL assessments over time and the open-label design of the monarchE trial.
Using the sponsor-submitted price for ABE and publicly listed prices for all other drug costs, the incremental cost-effectiveness ratio (ICER) for ABE-ET was $78,438 per quality-adjusted life-year (QALY) gained compared with ET. At this ICER, ABE-ET is not cost-effective at a $50,000 per QALY willingness-to-pay (WTP) threshold for patients with HR-positive, HER2-negative, node-positive early breast cancer at high risk of recurrence and Ki-67 score of at least 20%. A reduction in price is required for ABE-ET to be considered cost-effective at this threshold.
Reimbursement Conditions and Reasons.
Breast cancer is the most commonly diagnosed cancer among women in Canada, and the second most common cancer in men and women combined. In 2020, 27,700 women were diagnosed with breast cancer, representing approximately 25% of new cancer cases in Canada. Breast cancer is the second leading cause of cancer deaths among women, accounting for 14% of all cancer deaths. The 5-year net survival for breast cancer is greater than 85% among women diagnosed before 85 years of age, after which it drops to approximately 73%.
Patients with breast cancer are stratified and treated based on the expression status of certain tumour receptors that serve as important prognostic and predictive biomarkers, including estrogen receptor (ER) and progesterone receptor (PR). HR-positive breast cancers with hormone receptor expression (i.e., ER, PR, or both) are the most prevalent type of breast cancer, accounting for 70% to 80% of all breast cancers. Overexpression of the HER2 oncogene, which belongs to the epidermal growth factor receptor (EGFR/HER) family, enables constitutive activation of growth factor signalling and triggering breast cancer cell survival, proliferation, and invasion is associated with poor prognosis. Approximately 85% of patients with breast cancer do not have tumours that overexpress HER2 and are HER2-negative. HR-positive, HER2-negative tumours are the most common subtype of breast cancer, accounting for approximately 70% of breast cancers. More than 90% of patients with breast cancer are diagnosed with early-stage disease, which is defined as not having spread beyond the breast tissue or nearby lymph nodes. Unlike a diagnosis of distant metastatic disease, early-stage breast cancer is potentially curable. In patients with HR-positive, HER2-negative early breast cancer, the 5-year survival rate is 94.3%.
Although many patients with HR-positive, HER2-negative disease will not experience recurrence or have distant recurrence with standard therapies alone, primarily ET, approximately 7% to 11% of patients with early breast cancer experience a local recurrence during the first 5 years after treatment, and nearly 30% eventually experience disease relapse with metastases following treatment with curative intent, often with distant metastases, at which time their prognosis is poor. Risk factors for recurrence include large tumour size, higher degree of involvement of axillary lymph nodes (ALNs), high histologic grade, positive or close margins, age, HR and HER2 status (positive), and high tumour proliferation rate (Ki-67). Ki-67 immunohistochemistry testing is a prognostic factor for the risk of recurrence. However, the use of immunohistochemistry Ki-67 testing in Canadian clinical practice is currently limited due to variability in routine testing and lack of standardized laboratory assays.
To make their recommendation, the committee considered the following information:
The information in this section is a summary of input provided by the patient and clinician groups who responded to CADTH’s call for input and from clinical experts consulted by CADTH for the purpose of this review.
Two patient groups, Rethink and the CBCN, submitted patient input for this review. Respondents from Rethink stated that a breast cancer diagnosis and treatment had a devasting and traumatic impact on a young person’s life, and many patients express a willingness to take on whatever treatments are needed to lower the chance of recurrence. Patients who had experience with ABE indicated that they were willing to endure the additional side effects of a stronger therapy to ensure they were doing everything they could to treat what they know is an aggressive form of breast cancer. The CBCN respondents reported that the following factors were the most important when considering treatment options: effectiveness of treatment, reducing the risk of recurrence, maintaining quality of life, manageable side effects, and affordable and accessible treatments. Maintaining mobility, productivity, and an ability to continue childcare duties were also highlighted by survey respondents as important when deciding on treatment options. CBCN respondents noted that patients have an expectation that ABE will provide a possibility for improving their rate of IDFS and reduce their risk of recurrence, allowing them to live a better quality of life.
The clinical experts consulted by CADTH noted that very few treatments developed in recent years have improved survival or quality of life in the adjuvant breast cancer setting and therefore there is a need for treatments to reduce recurrence risk and improve survival outcomes. Tolerability issues such arthralgias and mood disturbances are common with ET, particularly in young and premenopausal women. Drugs that can prolong time to recurrence without compromise in quality of life are highly desired. The clinical experts noted that ABE is a new indication in this setting. For eligible patients, ABE would be added to standard adjuvant ET with or without ovarian suppression.
Clinician group input was received from the OH-CCO Breast Cancer Drug Advisory Committee, with 3 clinicians contributing to the submission. The clinician group noted that up to 30% of patients with high-risk clinical and/or pathologic features may experience distant recurrence and stated that there is a need for superior treatment options to prevent early recurrence and improve survival. Patients most likely to benefit from ABE would be those with HR-positive, HER2-negative early breast cancer at high risk of recurrence who are node-positive as per inclusion criteria of the monarchE trial. Patients who are least suitable for ABE would be those excluded from enrolment as per monarchE trial eligibility criteria. Abemaciclib would be used in addition to ET in high-risk patients following surgery and chemotherapy (if applicable). The clinician group input strongly recommended against the inclusion of a high Ki-67 score as the sole criteria for drug eligibility, noting that the Ki-67 score is prognostic and not predictive and that it is not a standard pathology test for breast cancer in Ontario.
Input was obtained from the drug programs that participate in the CADTH reimbursement review process.
Responses to Questions From the Drug Programs.
A single sponsor-submitted pivotal study was included in the systematic review; the monarchE trial is an ongoing phase III open-label randomized controlled trial comparing the efficacy and safety of ABE-ET to ET alone in the adjuvant treatment of patients with HR-positive, HER2-negative, node-positive early breast cancer who completed definitive locoregional therapy and who were at high risk of recurrence based on clinicopathological features or a high (20% or higher) Ki-67 index. The primary efficacy end point was IDFS, and the secondary end points included distant relapse-free survival (DRFS) and OS. A total of 5,637 patients in 38 countries, including 44 patients from Canada, were randomized to treatment with either ABE-ET or ET alone. Patients with at least 1 positive lymph node were recruited into 2 cohorts; patients in cohort 1 (n = 5,120) were eligible based on high-risk clinicopathological features (i.e., ≥ 4 positive ALNs or 1 to 3 positive ALNs and at least 1 of the following: tumour size ≥ 5 cm or histologic grade 3) and cohort 2 (n = 517) included patients based on 1 to 3 positive ALNs and high Ki-67 index (≥ 20%). There were 3,917 (76%) patients in cohort 1 who had Ki-67 testing results available and, of these, 2,003 patients (51%) had a high Ki-67 index; this patient population is aligned with the Health Canada–approved indication and the current reimbursement request. Patients in cohort 1 with a Ki-67 index of at least 20% were predominantly female (99.2%) with a mean age of 51.6 years (standard deviation [SD] = 11.1) and an Eastern Cooperative Oncology Group Performance Score (ECOG PS) of 0 (86.3%); 54.4% of patients were postmenopausal.
At interim analysis 1 for OS (April 1, 2021), OS data were immature. There were 95 deaths (42 in the ABE-ET arm and 53 in the ET arm) in the cohort 1 Ki-67 High population. The hazard ratio (HR) between treatment arms was 0.767 (95% confidence interval [CI], 0.511 to 1.152).
At the interim analysis (March 16, 2020), | | IDFS events were observed (| | in the ABE-ET arm and | | in the ET arm). The HR between treatment arms was ||||| (95% CI, ||||| to |||||; P = ||||||).
At the final IDFS analysis (July 8, 2020), with a median follow-up of 19.1 months, ||| IDFS events were observed (| | in the ABE-ET arm and ||| in the ET arm). The HR between treatment arms was 0.643 (95% CI, 0.475 to 0.872, P = 0.0042). The 2-year IDFS rates in the ABE-ET versus ET arm were 91.3% versus 86.1%.
At the additional follow-up analysis (April 1, 2021) with a median follow-up of 27 months, 262 IDFS events were observed (104 in the ABE-ET arm, and 158 in the ET arm). The HR between treatment arms was 0.63 (95% CI, 0.49 to 0.80). The 3-year IDFS rates in the ABE-ET versus ET arms were 86.1% versus 79.0%.
At the interim analysis (March 16, 2020), a total of ||| events were observed, (| | in the ABE-ET arm, and | | in the ET arm). The HR between treatment arms was ||||| (95% CI, ||||| to |||||). The 2-year DRFS rates in the ABE-ET versus ET arms were ||||| versus ||||||.
At the final primary outcome (IDFS) analysis (July 8, 2020), a total of ||| events were observed (|| in the ABE-ET arm, and | | in the ET arm). The HR between treatment arms was ||||| (95% CI, ||||| to |||||). The 2-year DRFS rates in the ABE-ET versus ET arms were ||||| versus |||||.
At the additional follow-up analysis (April 1, 2021), a total of 220 events were observed (85 in the ABE-ET arm, and 135 in the ET arm). The HR between treatment arms was 0.599 (95% CI, 0.456 to 0.787). The 3-year DRFS rate in the ABE-ET versus ET arms was 87.8% versus 82.6%.
The mean scores for the Functional Assessment of Cancer Therapy – Breast (FACT-B) and EQ-5D-5L scales were similar in the 2 treatment arms, and changes from baseline scores in both arms were less than the minimally important difference of the baseline SD.
As of the final primary outcome (IDFS) analysis (July 8, 2020), ||||| of patients in the ABE-ET arm and ||| | of patients in the ET arm reported at least 1 hospitalization. The majority of patients were hospitalized due to |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||. Transfusions were reported for |||| of patients in the ABE-ET arm and |||| of patients in the ET arm. |||||||||||||||| was the most commonly reported AE requiring a transfusion (|||| of patients in the ABE-ET arm and |||| of patients in the ET arm).
As of the final primary outcome (IDFS) analysis (July 8, 2020), 97.9% of patients in the ABE-ET arm, and 87.2% of patients in the ET arm experienced at least 1 treatment-emergent adverse event (TEAE). The most frequent TEAEs were diarrhea (82.6%), neutropenia (45.2%), and fatigue (39.2%) in the ABE-ET arm, and arthralgia (33.1%), hot flush (21.8%), and fatigue (16.6%) in the ET arm. Serious AEs occurred in 13.3% of patients in the ABE-ET arm, and 7.8% of patients in the ET arm. The most frequently reported serious AEs in both arms were pneumonia (0.9% and 0.5%, respectively). Grade 3 or higher TEAEs occurred in 47.4% of patients in the ABE-ET arm, and 14.2% of patients in the ET arm. The most frequently reported grade 3 or higher TEAEs in the ABE-ET arm were neutropenia (19.1%), leukopenia (10.9%), and diarrhea (7.7%). The most common grade 3 or higher TEAEs in the ET arm were neutropenia (0.7%), arthralgia (0.7%), and lymphopenia (0.5%). A total of 481 patients (17.2%) discontinued ABE due to AEs. The 3 most common reasons for discontinuations of ABE were: diarrhea (5.1%), fatigue (1.9%), and neutropenia (0.9%).
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Diarrhea was reported for 82.6% of patients in the ABE-ET arm and 7.8% of patients in the ET arm.
Neutropenia was reported for 45.2% of patients in the ABE-ET arm and 5.2% of patients in the ET arm. Venous thromboembolic events were reported in 2.4% of patients in the ABE-ET arm and 0.6% of patients in the ET arm.
Interstitial lung disease or pneumonitis was reported for 1.5% of patients in the ABE-ET arm and 0.4% of patients in the ET arm.
The monarchE trial was a randomized, open-label trial. Because Ki-67 index was not a stratification factor, the population of interest (cohort 1 Ki-67 High) cannot be considered to be truly randomized, and analyses of this population are therefore at risk of confounding due potential prognostic imbalances across treatment groups. However, this risk is likely to be low since available baseline characteristics appeared well balanced. Although patient blinding would have been impractical and challenging given the differences in the 2 study treatment regimens and different known toxicity profiles, performance and detection bias that may result from lack of blinding of patients and investigators to assigned study treatments cannot be ruled out. The primary outcome (IDFS) was investigator assessed but based on objective criteria and thus unlikely to be greatly affected by the lack of investigator blinding. The subjective patient-reported outcomes may have been biased due to the open-label design of the trial, a high rate of attrition at later follow-up times, and HRQoL results being analyzed in the overall safety population of the monarchE trial, rather than the population for reimbursement (i.e., patients in cohort 1 with Ki-67 index score of ≥ 20%). OS data remain immature. Given the correlation of disease-free survival surrogates with OS is debatable, it is unclear if improvements in IDFS observed in patients in the ABE-ET arm of the trial would translate into OS benefits.
The trial included a heterogenous population of patients with early breast cancer and a wide range of clinical presentations of high recurrence risk were well-represented. The clinical experts consulted noted that the trial population was approximately a decade younger than patients with early breast cancer encountered in clinical practice, potentially explained by high-risk features being more prevalent in younger patients. The inclusion of younger and healthier patients may have led to a more favourable toxicity profile in which more AEs were manageable and/or reversible. Unlike the monarchE trial that implemented standardized Ki-67 central testing, Ki-67 testing is not routinely performed in clinical practice and its reproducibility is affected by several factors, including time and method of biopsy, specimen preparation, and assay used.
Based on data from the monarchE trial, ABE-ET demonstrated a statistically significant benefit compared with ET alone in improving IDFS in women and men with HR-positive, HER2-negative, node-positive early breast cancer at high risk of disease recurrence based on clinicopathological features and a Ki-67 score of at least 20%. DRFS was tested outside of the statistical hierarchy but appeared to be supportive of the primary efficacy results. It is not yet clear whether IDFS benefits will translate to improved OS because the data remain immature and follow-up is ongoing. The safety profile of ABE was consistent with the known adverse effects profile of ABE. Effects on HRQoL and health resource utilization remain uncertain due to high attrition and a lack of between-group statistical testing for these outcomes. Although a much longer follow-up time will likely be needed to determine the efficacy of ABE-ET in terms of OS, given the slow event rate in this setting, the addition of ABE to ET in this new indication could help optimize adjuvant treatment to improve outcomes in terms of disease recurrence. Uncertainties remain regarding the validity and generalizability of Ki-67 testing and practical considerations for its implementation in clinical practice in determining patient eligibility for treatment with ABE.
Cost and Cost-Effectiveness.
CADTH identified the following key limitations with the sponsor’s analysis, including the number of patients eligible for ABE-ET is uncertain, including the proportion of patients at high risk of recurrence based on clinicopathologic features and Ki-67 score; the market share of comparators is uncertain; and the costs associated with ABE in year 3 are likely underestimated.
In the CADTH reanalysis, it was assumed that all patients who are potentially eligible for ABE-ET based on clinicopathological features will undergo Ki-67 testing. In the CADTH base case, the budget impact of reimbursing ABE for use as adjuvant treatment in combination with ET is expected to be $7,066,272 in year 1, $10,953,457 in year 2, and $12,046,862 in year 3, with a 3-year total of $30,066,591. The budget impact is sensitive to uncertainty in the number of patients deemed to be at high risk based on clinicopathologic features, Ki-67 test positivity rates, and assumptions about the market uptake.
Dr. Maureen Trudeau (Chair), Mr. Daryl Bell, Dr. Jennifer Bell, Dr. Matthew Cheung; Dr. Winson Cheung, Dr. Michael Crump, Dr. Leela John, Dr. Christian Kollmannsberger, Mr. Cameron Lane, Dr. Christopher Longo, Dr. Catherine Moltzan, Ms. Amy Peasgood, Dr. Anca Prica, Dr. Adam Raymakers, Dr. Patricia Tang, Dr. Marianne Taylor, and Dr. W. Dominika Wranik
Meeting date: August 10, 2022
Regrets: 3 of the expert committee members did not attend
Conflicts of interest: None
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Indication: In combination with endocrine therapy for the adjuvant treatment of adult patients with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative, node-positive, early breast cancer at high risk of disease recurrence based on clinicopathological features and a Ki-67 score of at least 20%
Sponsor: Eli Lilly Canada Inc.
Final recommendation: Reimburse with conditions
Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence (CC BY-NC-ND), a copy of which is available at http://creativecommons.org/licenses/by-nc-nd/4.0/
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