CADTH Reimbursement Review

Abemaciclib (Verzenio)

Sponsor: Eli Lilly Canada Inc.

Therapeutic area: Adjuvant treatment of hormone receptor–positive, human epidermal growth factor receptor 2–negative early breast cancer

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Introduction

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 about 25% of new cancer cases in Canada.¹ Breast cancer is the second leading cause of cancer deaths among women, accounting for 14% of all cancer deaths.¹ The 5-year net survival rate for breast cancer is more than 85% among women diagnosed before 85 years of age, after which it drops to approximately 73%.¹

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). Hormone receptor (HR)–positive breast cancers that have ERs or PRs or both are the most prevalent type of breast cancer, accounting for 70% to 80% of all breast cancers.² Overexpression of the human epidermal growth factor receptor 2 (HER2) oncogene — which belongs to the epidermal growth factor receptor (EGFR/HER) family and enables constitutive activation of growth factor that signals and triggers breast cancer cell survival, proliferation, and invasion — is associated with poor prognosis.³ 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.⁴ 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.³ Unlike patients with 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%.⁵

Although many people with HR-positive, HER2-negative disease will not experience recurrence or have distant recurrence with standard therapies alone — mainly endocrine therapy (ET) — around 7% to 11% of people with early breast cancer experience a local recurrence during the first 5 years after treatment. Nearly 30% of patients eventually experience disease relapse with metastases following treatment with curative intent, often with distant metastases, at which time their prognosis is poor.⁶ Risk factors for recurrence include large tumour size, a higher degree of involvement of axillary lymph nodes (ALNs), a high histologic grade, positive or close margins, age, HR and HER2 status (positive), and high tumour proliferation rate (Ki-67).^7-11 Ki-67 immunohistochemistry (IHC) testing is a prognostic factor for the risk of recurrence.^12,13 However, the use of IHC Ki-67 testing in Canadian clinical practice is currently limited due to variability in routine testing and a lack of standardized laboratory assays.

The objective of this review was to evaluate the efficacy and safety of abemaciclib in combination with ET for the adjuvant treatment of adult patients with HR-positive, HER2-negative, node-positive early breast cancer at high risk of disease recurrence based on clinicopathologic features and a Ki-67 test score of 20% or more.

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient and clinician groups that responded to CADTH’s call for input and from clinical experts consulted by CADTH for the purpose of this review.

Patient Input

Two patient groups, Rethink Breast Cancer (Rethink) and the Canadian Breast Cancer Network (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 abemaciclib indicated that they were willing to endure the additional side effects of a stronger therapy to ensure that 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 ones when considering treatment options: having the most effective treatment possible, reducing the risk of recurrence, maintaining quality of life, having manageable side effects, and having 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 abemaciclib will provide a possibility for improving their rate of invasive disease–free survival (IDFS) and reduce their risk of recurrence, allowing them to live a better quality of life.

Clinician Input

Input From Clinical Experts Consulted by CADTH

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; therefore, there is a need for treatments to reduce recurrence risk and improve survival outcomes. Tolerability issues such as arthralgias and mood disturbances are common with ET, particularly in young and premenopausal women. Drugs that can prolong the time to recurrence without compromising quality of life are highly desired. The clinical experts noted that abemaciclib is a new indication in this setting. For eligible patients, abemaciclib would be added to standard adjuvant ET with or without ovarian suppression.

Clinician Group Input

Clinician group input was received from the Ontario Health–Cancer Care Ontario 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 abemaciclib 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 abemaciclib 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 high Ki-67 levels as the sole criteria for drug eligibility, noting that Ki-67 was prognostic and not predictive and that it is not a standard pathology test for breast cancer in Ontario.

Drug Program Input

Input was obtained from the drug programs that participate in the CADTH reimbursement review process. The following were identified as key factors that could potentially impact the implementation of a CADTH recommendation for abemaciclib:

• considerations for the initiation of therapy

• considerations for the discontinuation of therapy

• care provision issues

• system and economic issues.

The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug programs.

Clinical Evidence

Pivotal Studies and Protocol-Selected Studies

Description of Study

A single sponsor-submitted pivotal study was included in the systematic review. The monarchE trial is an ongoing, open-label, phase III randomized controlled trial that compared the efficacy and safety of abemaciclib in combination with 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 were at high risk of recurrence based on clinicopathologic 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 overall survival (OS). A total of 5,637 patients in 38 countries, including |||||||| patients from Canada, were randomized to treatment with either abemaciclib plus 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 clinicopathologic features (i.e., ≥ 4 positive ALNs, or 1 positive ALN 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 at high risk of recurrence based on high levels of Ki-67 (≥ 20%). In Cohort 1, a total of 3,917 (76%) patients 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. Cohort 1 patients with a Ki-67 index of 20% or more were predominantly female (||||||||) with a mean age of |||||||| years (standard deviation [SD] = ||||||||) and an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 (||||||||); |||||||| of patients were postmenopausal.

Efficacy Results

The results of the efficacy outcomes of OS, IDFS, and DRFS included in the main body of this report are for the “Ki-67 High” population, which is aligned with the Health Canada–approved indication and the current reimbursement request.

Overall Survival

At the interim analysis 1 for OS (April 1, 2021), OS data were immature. There were 95 deaths (42 in the abemaciclib + ET arm and 53 in the ET arm) in the Cohort 1 Ki-67 High population. The hazard ratio between treatment arms was 0.767 (95% confidence interval [CI], 0.511 to 1.152).

Invasive Disease–Free Survival

At the interim analysis (March 16, 2020), |||||||| IDFS events were observed (|||||||| in the abemaciclib + ET arm and |||||||| in the ET arm). The hazard ratio 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 abemaciclib + ET arm and ||| in the ET arm). The hazard ratio between treatment arms was 0.643 (95% CI, 0.475 to 0.872; P = 0.0042). The 2-year IDFS rates in the abemaciclib plus ET arm versus the ET arm were 91.3% versus 86.1%, respectively.

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 abemaciclib + ET arm and 158 in the ET arm). The hazard ratio between treatment arms was 0.63 (95% CI, 0.49 to 0.80). The 3-year IDFS rates in the abemaciclib plus ET arm versus the ET arm were 86.1% versus 79.0%, respectively.

Distant Relapse–Free Survival

At the interim analysis (March 16, 2020), a total of |||||||| events were observed (|||||||| in the abemaciclib + ET arm and |||||||| in the ET arm). The hazard ratio between treatment arms was |||||||| (95% CI, ||||||||). The 2-year DRFS rates in the abemaciclib plus ET arm versus the ET arm were |||||||| versus ||||||||, respectively.

At the final primary outcome (IDFS) analysis (July 8, 2020), a total of |||||||| events were observed (|||||||| in the abemaciclib + ET arm and |||||||| in the ET arm). The hazard ratio between treatment arms was |||||||| (95% CI, |||||||| to ||||||||). The 2-year DRFS rates in the abemaciclib plus ET arm versus the ET arm were |||||||| versus ||||||||, respectively.

At the additional follow-up analysis (April 1, 2021), a total of 220 events were observed (85 in the abemaciclib + ET arm and 135 in the ET arm). The hazard ratio between treatment arms was 0.599 (95% CI, 0.456 to 0.787). The 3-year DRFS rate in the abemaciclib plus ET arm versus the ET arm was 87.8% versus 82.6%, respectively.

Health-Related Quality of Life

The mean scores for the Functional Assessment of Cancer Therapy – Breast Cancer (FACT-B) and EQ-5D 5-Level (EQ-5D-5L) scales were similar in the 2 treatment arms and changes from baseline scores, in both arms, were less than the minimal important difference (MID) of the baseline SD.

Health Care Resource Utilization

As of the final primary outcome (IDFS) analysis (July 8, 2020), |||||||| of patients in the abemaciclib plus 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 abemaciclib plus ET arm and |||||||||||||||| of patients in the ET arm. |||||||||||||||||||||||| was the most commonly reported adverse event (AE) requiring a transfusion (|||||||| of patients in the abemaciclib + ET arm and |||||||||||||||| of patients in the ET arm).

Table 2: Summary of Key Efficacy Results From the monarchE Study — Cohort 1 Ki-67 High Population

CI = confidence interval; DRFS = distant relapse–free survival; ET = endocrine therapy; IDFS = invasive disease–free survival; OS = overall survival.

Note: The median estimates were not reached for IDFS, DRFS, and OS due to the corresponding event rates.

^aTreatment effects in terms of hazard ratio estimates and P values are computed based on comparator ET.

^bThis was stratified by geographical region, prior treatment, and menopausal status.

^cA stratified Cox proportional hazards model with treatment as a factor was used to estimate the hazard ratio between treatment arms and corresponding 95% CI.

^dThis was estimated using the log-rank test.

^eThe data cut-off date was March 16, 2020.

^fThe data cut-off date was July 8, 2020.

^gThe data cut-off date was April 1, 2021.

^hThis was tested outside the statistical hierarchy (after the end point was met).

ⁱThis was not pre-specified for this population and unadjusted for multiple comparisons.

Sources: Clinical Study Reports for Verzenio (interim analysis 2), Verzenio (final IDFS [primary outcome] analysis), and Verzenio (overall survival interim analysis 1).^14-16

Table 3: Summary of Key Harms Results From the monarchE Study — Safety Population

AE = adverse event; ET = endocrine therapy; IDFS = invasive disease–free survival; ILD = interstitial lung disease; SAE = serious adverse event; TEAE = treatment-emergent adverse event; VTE = venous thromboembolism.

Source: Clinical Study Report for Verzenio (final IDFS [primary outcome] analysis).¹⁵

Harms Results

As of the final primary outcome (IDFS) analysis (July 8, 2020), 97.9% of patients in the abemaciclib plus 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 abemaciclib plus ET arm, and arthralgia (33.1%), hot flush (21.8%), and fatigue (16.6%) in the ET arm. Serious adverse events (SAEs) occurred in 13.3% of patients in the abemaciclib plus ET arm and 7.8% of patients in the ET arm. The most frequently reported SAEs in both arms were pneumonia (0.9% in the abemaciclib plus ET arm and 0.5% in the ET arm). Grade 3 or higher TEAEs occurred in 47.4% of patients in the abemaciclib plus ET arm and 14.2% of patients in the ET arm. The most frequently reported grade 3 or higher TEAEs in the abemaciclib plus 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 (17.2%) patients discontinued abemaciclib due to AEs. The 3 most common reasons for discontinuations of abemaciclib were diarrhea (5.1%), fatigue (1.9%), and neutropenia (0.9%).

||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.

Diarrhea was reported for 82.6% of patients in the abemaciclib plus ET arm and 7.8% of patients in the ET arm.

Neutropenia was reported for 45.2% of patients in the abemaciclib plus ET arm and 5.2% of patients in the ET arm. Venous thromboembolisms (VTEs) were reported in 2.4% of patients in the abemaciclib plus ET arm and 0.6% of patients in the ET arm.

Interstitial lung disease (ILD) or pneumonitis was reported for 1.5% of patients in the abemaciclib plus ET arm and 0.4% of patients in the ET arm.

Critical Appraisal

The monarchE study was a randomized, open-label trial. Since Ki-67 index was not a stratification factor, the population of interest (Cohort 1 Ki-67 High) cannot be considered to have been truly randomized, and analyses of this population are therefore at risk of confounding due to 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 (PROs) may, however, have been affected by this source of bias, as well as a high rate of attrition at later follow-up times. The primary and secondary efficacy end points of IDFS and DRFS are considered appropriate for the disease setting but OS data remain immature. Given that the correlation of disease-free survival (DFS) surrogates with OS is debatable, it is unclear if improvements in IDFS observed in patients in the abemaciclib plus 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 about 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 where more AEs were manageable, and 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.

Conclusions

Based on data from the monarchE trial, abemaciclib plus ET demonstrated a statistically significant and clinically meaningful benefit compared to ET alone in improving IDFS in people with HR-positive, HER2-negative, node-positive early breast cancer at high risk of disease recurrence based on clinicopathologic features and a Ki-67 score of 20% or more. DRFS was tested outside 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 as the data remain immature; follow-up is ongoing. The safety profile of abemaciclib was consistent with the known adverse effects profile of abemaciclib. Effects on health-related quality of life (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 abemaciclib plus ET in terms of OS, given the slow event rate in this setting, abemaciclib in addition 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 terms of determining patient eligibility for abemaciclib treatment.

Introduction

Disease Background

Breast cancer is the most commonly diagnosed cancer among women in Canada, and the second most common cancer in men and women combined.¹ In 2020, 27,700 women were diagnosed with breast cancer, representing about 25% of new cancer cases in Canada.¹ Breast cancer is the second leading cause of cancer deaths among women, accounting for 14% of all cancer deaths.¹ It is estimated that about 1 in 8 (12%) women living in Canada will develop breast cancer during their lifetime and 1 in 34 (3%) will die of it.¹ The 5-year net survival for breast cancer is more than 85% among women diagnosed before 85 years of age, after which it drops to about 73%.¹ In men, the incidence of breast cancer is less than 1% per year, with 260 new cases diagnosed in 2021 in Canada.¹ Breast cancer risk is influenced by several factors, including aging, family history, reproductive status (e.g., late menopause), hormone exposures (e.g., estrogen), and lifestyle factors such as alcohol intake and physical inactivity.⁵

Patients with breast cancer are stratified and treated based on the expression status of certain tumour receptors that have been shown to be important prognostic and predictive biomarkers. These include ER and PR; HR-positive breast cancers are those that express ER or PR or both.³ These tumours are the most prevalent type of breast cancer, accounting for 70% to 80% of all breast cancers, and can often be treated successfully with a variety of drugs that modulate ER or reduce estrogen, known as ET or anti-estrogen therapy.² Overexpression of the HER2 oncogene — which belongs to the EGFR/HER family and enables constitutive activation of growth factor that signals and triggers breast cancer cell survival, proliferation, and invasion — is associated with poor prognosis.³ Approximately 85% of patients with breast cancer do not have tumours that overexpress HER2 and are HER2-negative.³ HR-positive, HER2-negative tumours are the most common subtype of breast cancer, accounting for approximately 70% of cases.⁴

Anatomical staging of breast cancer is based on the size and extent of the breast tumour (T), the extent of regional lymph node involvement (N), and the presence or absence of distant metastases (M). These features are assigned individual scores and then combined to identify the stage (i.e., TNM staging).¹⁷ 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.³ Early breast cancer includes ductal carcinoma in situ (stage 0) and stage I to stage IIIA, but may also include only invasive cancers within stage I to stage IIIC, excluding stage 0.³ Unlike patients with 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%.⁵

Although many patients with HR-positive, HER2-negative disease will not experience recurrence or have distant recurrence with standard therapies alone, around 7% to 11% of patients with early breast cancer experience a local recurrence during the first 5 years after treatment.⁶ Nearly 30% of patients eventually experience disease relapse with metastases following treatment with curative intent, often with distant metastases, at which time their prognosis is poor.⁶ Larger tumour size (> 2 cm), a higher number of lymph nodes affected, and/or patients receiving ET for a short period of time after surgery are associated with a higher risk of late recurrence (after 5 years).¹⁸ The risk of breast cancer recurrence is frequently predicted based on TNM staging, HR status, and genomic profiling.³ The clinical experts consulted by CADTH noted that some multiparameter gene expression assays such as the Oncotype Dx test may be used to guide adjuvant treatment decisions. Risk factors for recurrence include large tumour size, a higher degree of involvement of ALNs, a high histologic grade, positive or close margins, age, HR and HER2 status (positive), and a high tumour proliferation rate (Ki-67).^7-11 Ki-67 IHC testing is used in diagnostic work-up of a variety of tumours, including breast cancer. Ki-67 is a marker of cellular proliferation and is a prognostic factor for the risk of recurrence during the first 5 years following primary breast cancer treatment.¹⁰ Although there is no uniformly accepted threshold of Ki-67 levels indicative of a high risk of recurrence, the International Ki-67 in Breast Cancer Working Group (IKWG) consensus was that Ki-67 expression of more than 30% can be used to identify high-risk patients.¹⁹ However, the use of IHC Ki-67 testing in Canadian clinical practice is currently limited due to geographical variability in routine testing and a lack of standardized laboratory assays.

Standards of Therapy

Patients diagnosed with HR-positive, HER2-negative early breast cancer are typically treated with curative intent with definitive surgery (lumpectomy and/or mastectomy), which may be preceded by neoadjuvant chemotherapy and/or ET and followed by a combination of adjuvant ET with or without radiotherapy and chemotherapy. Premenopausal women may receive concurrent ovarian suppression or ablation (bilateral salpingo-oophorectomy) to improve outcomes. Adjuvant bisphosphonate may be considered in postmenopausal women.^20,21

Adjuvant ET is the standard of care for the systemic treatment of patients with HR-positive, HER2-negative early breast cancer.^18,20,21 Regimens may include tamoxifen and/or 1 of 3 aromatase inhibitors (AIs): anastrozole, letrozole, or exemestane. The choice of endocrine drug is primarily determined by the patient’s menopausal status.^18,20,21 Following primary local therapy, ET is administered for at least 5 years and for up to 10 years; extended ET (10 years) is recommended for patients with node-positive tumours.^18,20,21 The clinical experts consulted by CADTH noted common tolerability issues with ET, such as low-estrogen symptoms, arthralgias, and mood disturbances, particularly in young or premenopausal women. Based on input received from the clinical experts consulted by CADTH, in patients with breast cancer gene–positive (BRCA-positive) tumours, there may be a future role for adjuvant olaparib; however, this regimen has not been reviewed by CADTH in the suggested setting and is currently not reimbursed. Treatment of men with breast cancer is similar to that of postmenopausal women. In men, the use of androgen suppression with gonadotropin-releasing hormone (GnRH) agonists could be considered.¹⁸

Neoadjuvant treatments have the goal of improving surgical outcomes, while adjuvant treatments are intended to eradicate micrometastatic disease and prevent distant recurrence. Patients considered at high risk of recurrence generally receive more extensive and aggressive adjuvant treatment with ET and chemotherapy. The clinical experts consulted by CADTH noted that most patients with 4 or more positive lymph nodes will receive chemotherapy unless contraindicated. Given the increased risk of recurrence in patients with high-risk clinicopathologic features, the clinical experts consulted by CADTH agreed that optimizing adjuvant therapy to prevent or delay recurrence and prolong survival with an acceptable toxicity profile and improvement in quality of life are the most important treatment goals.

Drug

Abemaciclib (Verzenio) is an orally available, selective, and potent ATP-competitive inhibitor of cyclin-dependent kinases (CDKs) 4 and 6 that blocks retinoblastoma (Rb) protein phosphorylation; this prevents cancer cell proliferation by arresting the cell cycle in the G1 phase, thereby suppressing DNA synthesis and inhibiting cancer cell growth.¹⁸ Longer treatment with abemaciclib can lead to prolonged antitumour effects by inducing senescence, apoptosis, and modification of cellular mechanism.^18,22

Abemaciclib received a Notice of Compliance from Health Canada on January 12, 2022, for use in combination with ET for the adjuvant treatment of adult patients with HR-positive, HER2-negative, node-positive, early breast cancer at high risk of recurrence based on clinicopathological features and a Ki-67 score of at least 20%.¹⁸ The sponsor’s requested reimbursement criteria for abemaciclib are as per the Health Canada–approved indication. Abemaciclib is the first and only CDK4 and CDK6 inhibitor approved for the adjuvant treatment of early breast cancer in Canada.

In October 2021, the US FDA approved abemaciclib with ET (tamoxifen or an AI) for adjuvant treatment of adult patients with HR-positive, HER2-negative, node-positive early breast cancer at high risk of recurrence and with a Ki-67 score of 20% or more, as determined by an FDA-approved test.²³ Abemaciclib is the first CDK4 and CDK6 inhibitor approved for adjuvant treatment of breast cancer in the US.²³ In February 2022, the European Medicines Agency’s Committee for Medicinal Products for Human Use recommended abemaciclib in combination with ET as adjuvant treatment for patients with HR-positive, HER2-negative, node-positive early breast cancer at high risk for recurrence.²⁴

Abemaciclib is supplied as tablets (50 mg, 100 mg, 150 mg, and 200 mg) for oral administration.²⁵ The recommended dosage of abemaciclib in combination with ET for early breast cancer is 150 mg taken orally twice daily until completion of either 2 years of treatment or until disease recurrence or unacceptable toxicity.²⁵

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups.

Two patient groups, Rethink and the CBCN, submitted patient input for this review. Rethink gathered data through general observations and meetings with patients with breast cancer as well as via telephone interviews with 2 patients who had experience taking abemaciclib for HR-positive, HER2-negative, high-risk early breast cancer, and 1 patient to whom abemaciclib had been prescribed, but who had not initiated treatment with it yet. CBCN conducted an online survey, with responses from 103 patients in Canada with early-stage HR-positive, HER2-negative breast cancer. Most participants in the CBCN survey indicated having been diagnosed with stage II cancer, followed by those diagnosed with stage I, and stage III cancer. Few respondents to the survey did not specify their cancer stage. None of the 103 participants had direct experience with abemaciclib treatment.

According to Rethink, a breast cancer diagnosis and treatment has 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. Rethink indicated that most of their patients are diagnosed at a younger age, which can lead to age-specific issues such as fertility or family-planning challenges, diagnosis during pregnancy, childcare, an impact on relationships, body image, dating and sexuality, feeling isolated from peers, career hiatuses, and financial insecurity. Most CBCN survey respondents reported having undergone surgery (91%), radiation therapy (57%), chemotherapy (53%), and ET (77%) as part of their overall breast cancer treatment. According to CBCN, side effects of HR-positive breast cancer and the therapies used to treat this disease include hot flashes, night sweats, vaginal dryness, gastrointestinal symptoms, nausea, vomiting, constipation, weakness, fatigue, and a risk of blood clots.

Rethink indicated that the 2 patients who had experience with abemaciclib 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. Both patients reported an overall positive experience taking abemaciclib and would recommend it to other patients. One patient reported being tired as a side effect of abemaciclib treatment.

According to the CBCN patient input received, survey respondents reported that the following factors were the most important when considering treatment options: having the most effective treatment possible, reducing the risk of recurrence, maintaining quality of life, having manageable side effects, and having 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 noted that patients have an expectation that abemaciclib 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. A copy of the 2 original full patient inputs is presented in the Stakeholder Input section of the CADTH report.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, providing guidance on the potential place in therapy). The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of breast cancer.

Unmet Needs

The clinical experts consulted by CADTH noted that there is a significant recurrence risk in patients with high-risk clinicopathologic features. DFS is prolonged with extended adjuvant ET (though it is largely driven by a decrease in second cancers rather than recurrence), but no clear benefit in OS is observed. It was further noted by the clinical experts 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 that improve survival outcomes. Tolerability issues such as low-estrogen symptoms, arthralgias, and mood disturbances are common with current treatments, particularly in young and premenopausal women. Drugs that can prolong time to recurrence without compromising quality of life are highly desired.

Place in Therapy

The clinical experts indicated that the mechanism of action of abemaciclib is new in this setting. As it is a new indication, abemaciclib is not reserved for patients who are intolerant to other treatments. It was also noted by the clinical experts that for eligible patients, abemaciclib would be added to standard adjuvant ET (tamoxifen or AI such as letrozole, anastrozole, or exemestane with or without ovarian suppression). The experts agreed that it would not be appropriate to try other treatments before initiating abemaciclib treatment because there is no comparable alternative to abemaciclib in this setting.

Patient Population

The clinical experts consulted by CADTH agreed that eligible patients would be those who meet the monarchE trial inclusion criteria. Namely, these are high-risk patients, both male and female, with HR-positive, HER2-negative breast cancer (with “high risk” defined as grade 3, ≥ 4 ipsilateral axillary positive nodes, and tumour ≥ 5 cm or high ki-67 [≥ 20%]), and patients who have had surgery and, as indicated, radiotherapy and/or adjuvant or neoadjuvant chemotherapy. It was noted by the clinical experts that Ki-67 testing required to define high-risk patients is available in most centres but not routinely performed on all cases. The clinical experts noted that problems with Ki-67 test standardization may complicate the composite definition of high risk. The clinical experts highlighted that, based on the monarchE trial data, certain lower-risk patient subgroups — including those with smaller tumour size (2 cm to 5 cm), grade 1 tumours, and stage IIA disease — appear to derive less benefit in terms of IDFS.

Assessing Response to Treatment

The clinical experts consulted by CADTH noted that since the current indication is for the adjuvant setting, where patients are free of detectable tumours, treatment “response” cannot be assessed. It was agreed by the clinical experts that treatment benefit would be measured by the absence of recurrence and death. The clinical experts noted that the primary outcome of IDFS in the monarchE trial is an accepted end point in recent clinical trials in this setting. Importantly, data on OS, HRQoL, and long-term IDFS are needed to determine the efficacy of abemaciclib in this setting.

Discontinuing Treatment

The clinical experts consulted by CADTH noted that disease progression and severe or intolerable toxicity would be factors to consider when deciding to discontinue treatment with abemaciclib.

Prescribing Conditions

The clinical experts consulted by CADTH noted that abemaciclib treatment requires ongoing monitoring and should be prescribed by a medical oncologist or a general practitioner in oncology in an outpatient clinic setting.

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by clinician groups.

Clinician group input was received from the Ontario Health–Cancer Care Ontario 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 abemaciclib would be those with HR-positive, HER2-negative early breast cancer at high risk of recurrence who are node-positive as per the inclusion criteria of the monarchE trial. Patients who are least suitable for abemaciclib would be those excluded from enrolment as per the 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 noted that clinicians with experience treating breast cancer, access to laboratory blood work, and expert pharmacy support would be required to diagnose, treat, and monitor patients. The group also stated that monitoring for hematologic toxicity, diarrhea, and extra visits would be required to assess patients for toxicity. The clinician group input strongly recommended against the inclusion of high Ki-67 as the sole criteria for drug eligibility, noting that Ki-67 was a prognostic factor for recurrence in the target setting and not predictive of treatment effect and that it is not a standard pathology test for breast cancer in Ontario.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 4.

Table 4: Summary of Drug Plan Input and Clinical Expert Response

pERC = CADTH pan-Canadian Oncology Drug Review Expert Review Committee.

Clinical Evidence

The clinical evidence included in the CADTH review of abemaciclib includes the following 3 sections: a systematic review of pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those studies that were selected according to an a priori protocol; indirect evidence from the sponsor (if submitted) and indirect evidence selected from the literature that met the selection criteria specified in the review; and sponsor-submitted long-term extension studies and additional relevant studies that were considered to address important gaps in the evidence included in the systematic review.

Systematic Review (Pivotal and Protocol-Selected Studies)

Objectives

To evaluate the efficacy and safety of abemaciclib in combination with ET for the adjuvant treatment of adult patients with HR-positive, HER2-negative, node-positive early breast cancer at high risk of disease recurrence based on clinicopathologic features and a Ki67 score of 20% or more

Methods

Studies selected for inclusion in the systematic review included pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 5. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

Table 5: Inclusion Criteria for the Systematic Review

AI = aromatase inhibitor; BSO = bilateral salpingo-oophorectomy; ECOG PS = Eastern Cooperative Oncology Group Performance Status; ET = endocrine therapy; HRQoL = health-related quality of life; OFS = ovarian function suppression; SERM = selective estrogen receptor modulator; vs. = versus.

The literature search was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist.²⁶

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946–) via Ovid and Embase (1974–) via Ovid. All Ovid searches were run simultaneously as a multi-file search. Duplicates were removed using Ovid deduplication for multi-file searches, followed by manual deduplication in Endnote. The search strategy comprised both controlled vocabulary, such as the US National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concept was Verzenio (abemaciclib). Clinical trials registries were searched: the US National Institutes of Health’s ClinicalTrials.gov, WHO’s International Clinical Trials Registry Platform search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. Refer to Appendix 1 for the detailed search strategies.

The initial search was completed on April 21, 2022. Regular alerts updated the search until the meeting of the CADTH pan-Canadian Oncology Drug Review Expert Committee on August 10, 2022.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool for Searching Health-Related Grey Literature checklist.²⁷ Included in this search were the websites of regulatory agencies (US FDA and European Medicines Agency). Google was used to search for additional internet-based materials. Refer to Appendix 1 for more information on the grey literature search strategy.

These searches were supplemented by reviewing bibliographies of key papers and through contacts with appropriate experts. In addition, the manufacturer of the drug was contacted for information regarding unpublished studies.

Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion.

Findings From the Literature

A total of 633 studies were identified from the literature for inclusion in the systematic review (Figure 1). Seven reports of a single study (monarchE) were included.^{14-16,18,28-30} The included study is summarized in Table 6.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Table 6: Details of the monarchE Study

AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; DCIS = ductal carcinoma in situ; DRFS = distant relapse–free survival; ECOG PS = Eastern Cooperative Oncology Group Performance Status; ET = endocrine therapy; EQ-5D-5L = EQ-5D Five-Level; FACIT = Functional Assessment of Chronic Illness Therapy; FACIT-F = Functional Assessment of Chronic Illness Therapy – Fatigue; FACT-B = Functional Assessment of Cancer Therapy – Breast; FACT-ES = Functional Assessment of Cancer Therapy – Endocrine Symptoms; GnRH = gonadotropin-releasing hormone; HRQoL = health-related quality of life; ITT = intention to treat; IDFS = invasive disease–free survival; OS = overall survival; RCT = randomized controlled trial; SAE = serious adverse event; TEAE = treatment-emergent adverse event.

Source: Clinical Study Report for Verzenio (interim analysis 2).¹⁴

Description of the monarchE Study

The monarchE study is a multi-centre, randomized, open-label, phase III study that compares the efficacy of abemaciclib plus standard adjuvant ET to ET alone in patients with node-positive, invasive, resected, HR-positive, HER2-negative early breast cancer who completed definitive locoregional therapy, with or without neoadjuvant or adjuvant chemotherapy, and whose cancer was at high risk of disease recurrence. The trial was conducted across 603 sites in 38 countries; || patients were recruited in Canada. The primary outcome was IDFS in the intention-to-treat (ITT) population.

Treatment with abemaciclib was given for up to 2 years or until discontinuation criteria were met, whichever occurred first. The duration of 2 years was selected based on previous studies that showed patients with early breast cancer taking ET experienced an initial peak of recurrence at 2 years of treatment. The goal of monarchE was to treat through the first peak of recurrence. The choice of ET, such as tamoxifen or an AI, was at the investigator’s discretion and was taken as prescribed during the on-study treatment period, year 1 and year 2. In year 3 and beyond, ET was continued for a total duration of at least 5 years and up to 10 years, if deemed medically appropriate.

Randomization and treatment allocation: An interactive web response system was used to randomly assign patients in a 1:1 ratio within each cohort to either up to 2 years of oral abemaciclib at 150 mg twice daily and ET or ET alone using the following stratification factors: prior treatment (neoadjuvant chemotherapy versus adjuvant chemotherapy versus no chemotherapy), menopausal status (premenopausal versus postmenopausal), and region (North America or Europe versus Asia versus other). Patients receiving standard adjuvant ET at the time of study entry may not have received more than 12 weeks of standard adjuvant ET after completion of their last non-ET (surgery, chemotherapy, or radiation) before randomization. Randomization had to occur within a maximum of 16 months following the definitive breast cancer surgery. Patients were randomized into 2 cohorts: Cohort 1 included patients at high risk of recurrence based on high-risk clinicopathologic features and Cohort 2 included patients at high risk of recurrence based on a high Ki-67 index (≥ 20%).

Blinding: This was an open-label study; patients were aware of their assigned treatment group and all staff at each investigative site involved in treating and caring for study patients had full knowledge of the patient’s treatment assignment. An open-label design was chosen because toxicities and laboratory abnormalities related to abemaciclib treatment, such as diarrhea, neutropenia, and creatinine increase, had the potential to unblind the study. The sponsor was blinded to treatment group assignment until the study reached a positive outcome. An independent data monitoring committee was responsible for reviewing the unblinded safety and efficacy analyses.

Study phases: The screening phase was 3 months for Cohort 1 and 6 months for Cohort 2. The treatment phase started with the first dose of treatment following randomization (i.e., abemaciclib and ET or ET alone in the intervention and control arms, respectively). The first dose of abemaciclib plus ET was initiated no later than 3 days following randomization. During year 1 and year 2 (the on-study treatment period), patients returned to a clinic every 2 weeks (15 days ± 3 days) for the first 2 months, monthly (30 days ± 5 days) starting with month 3 to month 6, and every 3 months thereafter (every 90 days ± 10 days until visit 27). After a short-term follow-up visit that took place 30 days after discontinuation or after completion of the on-study treatment period, all patients entered the long-term follow-up period that will continue for up to 10 years or until study completion, with long-term follow-up visits occurring approximately every 6 months until the completion of year 5 and then yearly starting in year 6 (Figure 2).

Protocol Amendments

There were modifications to the statistical analysis plan (SAP) for the study that were documented in the SAP amendments. Amendments (from least to most recent) included the following: the exclusion of patients with a history of VTE and safety guidance in reference to VTEs and increased alanine transaminase (October 11, 2018); the inclusion of dose suspension recommendations for patients undergoing surgery (June 29, 2018); the inclusion of Cohort 2 in the ITT population and updates for the eligibility of patients with positive anterior margins of the primary breast tumours (December 19, 2018); and the addition of ILD or pneumonitis as a new AE (June 29, 2019). The most recent amendment (version 5, June 5, 2020) was made after the database lock for the second interim analysis for efficacy. The most important amendment to the SAP concerned analysis of OS. At the FDA’s request in November 2020, an OS interim analysis was added to the protocol-specified main OS analyses. This additional interim OS analysis with the April 1, 2021, data cut-off date was documented in an SAP addendum approved in December 2020. The number of OS events at final OS analysis was increased from 390 to 650 and an additional OS interim analysis (July 2023) was added to allow a yearly assessment of benefit-risk within the first few years of long-term follow-up. In the originally planned final OS analysis, the median follow-up in the study population would have been less than 4 years; this was later deemed insufficient to adequately characterize OS in patients receiving adjuvant breast cancer therapy as the minimum standard time for follow-up is considered to be 5 years. Therefore, the amendment to the OS analyses was to ensure that OS can be characterized for at least 5 years, consistent with expectations from the medical and scientific community.

Figure 2: monarchE Study Design

BD = twice daily; C1 = Cohort 1; C2 = Cohort 2; CPF = clinical and/or pathological features; HER2– = HER2-negative; HR+ = HR-positive; ITT = intention to treat; pALN = positive axillary lymph node; pt = patient; R = randomization; SOC = standard of care.

Source: Clinical Study Report for Verzenio (interim analysis 2).¹⁴

Populations

Inclusion and Exclusion Criteria

Eligible patients were 18 years or older, with confirmed HR-positive, HER2-negative, resected invasive early breast cancer without metastases, who had undergone definitive surgery of primary breast tumour and randomized within 16 months of surgery, had an ECOG PS of 0 or 1, and adequate organ function. To be enrolled in 1 of the cohorts, patients had to fulfill 1 of the following criteria: 1) pathological tumour involvement in 4 or more positive ipsilateral ALNs, or 2) pathological tumour involvement in 1 ipsilateral ALN to 3 ipsilateral ALNs and either grade 3 disease, or primary tumour size of 5 cm or more. Patients eligible based on 1 to 3 positive ALNs (not grade 3 and not primary tumour size of 5 cm or more) who had a Ki-67 index of 20% or more were also eligible (Cohort 2). Patients were ineligible if they had metastatic disease, node-negative or inflammatory breast cancer, a previous history of breast cancer (with the exception of ipsilateral ductal carcinoma in situ treated by locoregional therapy alone at least 5 years ago), a history of any other cancer (except nonmelanoma skin cancer or carcinoma in situ of the cervix), concurrent exogenous reproductive hormone therapy, prior ET for breast cancer, or raloxifene or previous exposure to CDK4 and CDK6 inhibitors (Table 6).

The inclusion criteria for selecting the patient population at high risk of recurrence were based on unpublished efficacy outcome data from the West German Study Group PlanB trial and the NSABP B-28 trial. Among a subset of the PlanB patient population that satisfied the monarchE criteria for high-risk disease, the estimated 5-year IDFS rate was 82.5% (95% CI, 77.8% to 87.2%), suggesting that approximately 17.5% of those patients who were at high risk of recurrence would develop invasive recurrence events within the first 5 years.²⁹

Patients were enrolled into 2 cohorts.

• Cohort 1 (high risk based on clinicopathologic features): Patients were eligible based on clinicopathologic features such as the degree of ALN involvement, tumour size, grade, or a combination of any of those. This included patients with 4 or more positive ALNs, or 1 positive ALN to 3 positive ALNs and at least 1 of the following: a tumour size of 5 cm or more or histologic grade 3. Patients in Cohort 1 were not required to submit a tissue sample to the study’s central laboratory for Ki-67 testing before randomization, but a sample was requested, where available, to support the secondary analysis related to Ki-67.

• Cohort 2 (high risk based on Ki-67 index): Patients were eligible based on having 1 positive ALN to 3 positive ALNs, and a centrally determined high Ki-67 index (≥ 20%). These patients would not have been eligible based on eligibility requirements for Cohort 1. Patients in Cohort 2 were required to submit an untreated breast tissue sample to the study’s central laboratory for central determination of Ki-67 status to deduce eligibility (tissue was to be submitted within 1 month of signing the consent). The sample was tested using the investigational in vitro diagnostic medical device pharmDx Ki-67 Kit, manufactured by Dako.

The ITT population includes all randomized patients in Cohort 1 and Cohort 2. The Cohort 1 Ki-67 High population includes all randomized patients in Cohort 1 with a centrally assessed Ki-67 score of 20% or more, which is aligned with both the Health Canada–approved indicated population and the current reimbursement request. Therefore, this CADTH clinical review focuses on efficacy results based on Cohort 1 patients with Ki-67 of 20% or more (Cohort 1 Ki-67 High population) in the main body of the report. The study was planned and powered based on the ITT population and the statistical testing hierarchy included the ITT population, the ITT Ki-67 High population (Cohort 1 + Cohort 2), and the Cohort 1 Ki-67 High population for IDFS. Some efficacy data from the ITT and ITT Ki-67 analysis populations are presented in Appendix 2 to provide fuller context.

Baseline Characteristics

Cohort 1 patients with a Ki-67 score of 20% or more (39.1% of the 5,120 patients randomized into Cohort 1) were predominantly female (99.2%) with a mean age of 51.6 years (SD = 11.1) and an ECOG PS of 0 (86.3%). More than half of the patients (54.4%) were postmenopausal. Most patients were diagnosed with invasive ductal breast carcinoma (75.5%) with a primary tumour size of 2 cm or more but less than 5 cm determined by pathology (52.9%). Almost all patients had positive ALNs (99.9%) — 57% of patients had 4 or more ALNs and 42.9% of patients had 1 positive ALN to 3 positive ALNs. The majority of patients (95.2%) had received prior radiotherapy — 36.9% of patients had received neoadjuvant chemotherapy and 60.2% of patients had received adjuvant chemotherapy (Table 7). Despite Ki-67 score (≥ 20% versus < 20%) not being a stratification factor (and therefore the population not being truly randomized), the available baseline characteristics appeared well balanced across groups.

The Cohort 1 Ki-67 High population had a lower incidence of invasive lobular breast carcinoma than the ITT population (6.5% versus 12.8%, respectively), with a corresponding higher incidence of invasive ductal breast carcinoma. The percentage of patients with histopathological grade 3 tumours at diagnosis was also higher in this population compared to the ITT population (58.0% versus 38.2%, respectively).

Table 7: Summary of Baseline Characteristics — Cohort 1 Ki-67 High Population

||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

Interventions

Abemaciclib Plus Endocrine Therapy Arm

Treatment consisted of abemaciclib 150 mg administered orally, twice daily, with at least 6 hours separating doses. Treatment with abemaciclib was given for up to 2 years or until discontinuation criteria were met. Standard adjuvant ET of a physician’s choice, such as letrozole, anastrozole, exemestane, or tamoxifen with or without GnRH agonist, was taken as prescribed during the on-study treatment period (year 1 to year 2). In year 3 and beyond, standard adjuvant ET was continued to complete at least 5 years and up to 10 years if this was medically appropriate. Treatment with ET was given until discontinuation criteria were met. Adjuvant treatment with fulvestrant was not allowed at any time during the study.

If a patient discontinued only 1 of the combination drugs (abemaciclib or ET) before completion of the 2-year on-study treatment period for a reason other than an IDFS event, the patient had to continue the other drug until completion of the 2-year on-study treatment period or until other discontinuation criteria were met, whichever occurred first. The study protocol included instructions for mandated abemaciclib dose modifications (holds and reductions) to manage AEs, with a maximum of 2 dose reductions. Patients requiring more than 2 dose reductions were required to discontinue abemaciclib. Study treatment could be held for up to 28 days to permit sufficient time for recovery from toxicity. For patients not recovering from toxicity within 28 days, a delay of more than 28 days was permitted after agreement with the investigator and the sponsor, abemaciclib dose adjustment was considered. Dose adjustment for ET was determined by the investigator and when applicable. A switch to another ET regimen was permitted per the physician’s choice as part of standard of care.

Endocrine Therapy Arm

Standard adjuvant ET of a physician’s choice, such as letrozole, anastrozole, exemestane, or tamoxifen with or without GnRH agonist, was taken as prescribed during the on-study treatment period (year 1 to year 2). In year 3 and beyond, standard adjuvant ET was continued to complete at least 5 years and up to 10 years if this was medically appropriate. Treatment with ET was given until discontinuation criteria were met. Adjuvant treatment with fulvestrant was not allowed at any time during the study. Dose adjustment for ET was determined by the investigator and when applicable. A switch to another ET regimen was permitted per the physician’s choice as part of standard of care.

Concomitant Treatments

All concomitant medications and supportive care therapies were documented at each visit. In general, the list of prohibited medications that affected patient eligibility or participation in the study were limited to ET for breast cancer prevention, concurrent exogenous reproductive hormone therapy, and recent experimental treatment in a clinical trial. Concurrent treatment with standard of care bone-modifying drugs such as bisphosphonates and denosumab was permitted. With the exception of standard ET for breast cancer, no other anticancer therapy was permitted while patients were on study treatment. Patients could receive full supportive care to maximize quality of life (e.g., antiemetics, standard of care bone-modifying drugs) based on the judgment of the treating physician. Patients in the abemaciclib plus ET arm received instructions on the management of diarrhea and were prescribed antidiarrheal therapy (e.g., loperamide) on their first visit.

Study Treatment Discontinuation

Patients would be discontinued from study treatment in the following circumstances.

• The patient was enrolled in any other clinical trial involving an investigational product or any other type of medical research judged not to be scientifically or medically compatible with this study.

• Investigator decision: If the investigator decided that the patient should be discontinued from the study or study treatment, or if the patient, for any reason, required treatment with another therapeutic drug that had been demonstrated to be effective for treatment of the study indication, discontinuation from the study drug occurred before introduction of the new drug.

• Patient decision: If the patient requested to be withdrawn from the study or study treatment, this was done.

• Sponsor decision: The sponsor could stop the study or the patient’s participation in the study for medical, safety, regulatory, or other reasons consistent with applicable laws, regulations, and good clinical practice.

• The patient became pregnant during the study.

• The patient was significantly non-compliant with study procedures and/or treatment.

• The patient experienced any of the IDFS events as per Standardized Definitions for Efficacy End Points (STEEP) in adjuvant breast cancer trials criteria.

• There was unacceptable toxicity.

Outcomes

The efficacy end points identified in the CADTH review protocol that were assessed in the clinical trial included in this review are summarized as follows.

Efficacy

The primary end point was IDFS in the ITT population. The secondary efficacy end points were DRFS in the ITT population, OS in the ITT population, and IDFS in the Ki-67 High population (Cohort 1 + Cohort 2) and the Ki-67 High population (Cohort 1). Other secondary end points included HRQoL and health care resource utilization assessed in the safety population.

IDFS was defined per the STEEP criteria³³ and measured from the date of randomization to the date of first occurrence of the following factors:

• ipsilateral invasive breast tumour recurrence — local recurrence, defined as invasive breast cancer in the ipsilateral breast parenchyma or invasive breast cancer in the skin of the breast or the chest wall occurring after a lumpectomy and/or mastectomy

• regional invasive breast cancer recurrence — defined as the development of a tumour in the axilla, regional lymph nodes (internal mammary, supraclavicular, infraclavicular), and the soft tissue of the ipsilateral breast following surgery

• distant recurrence — defined as evidence of tumour in all areas other than the ones qualifying for local or regional recurrence as described previously

• death attributable to any cause, including breast cancer, non-breast cancer, or unknown cause

• contralateral invasive breast cancer

• second primary non-breast invasive cancer.

Confirmation by biopsy or imaging was required, when possible. During treatment and follow-up, imaging was to be performed per the investigator’s judgment and according to routine standard practice. All imaging was done locally and, therefore, no central imaging assessments were performed. All patients who experienced local recurrence continued to be followed for distant recurrence. Patients for whom no event had been observed were censored at the date of their last post-baseline assessment for disease recurrence or date of randomization if no post-baseline assessment for disease recurrence had occurred. For patients who experienced an IDFS event other than distant recurrence or death, assessments continued to be performed until there was an event of distant recurrence, death, or study completion, whichever occurred first.

DRFS was defined as the time from randomization to distant recurrence or death attributable to any cause, whichever occurred first. Patients for whom no event was observed were censored on the day of their last assessment for recurrence or date of randomization if no post-baseline assessment for recurrence occurred.

The OS time was measured from the date of randomization to the date of death from any cause. For each patient who was not known to have died as of the data cut-off date for a particular analysis time point, OS was censored for that analysis at the date of the last contact before the data cut-off date.

During year 1 and year 2 (the on-study treatment period), patients returned to a clinic every 2 weeks (15 days ± 3 days) for the first 2 months, monthly (30 days ± 5 days) starting with month 3 to month 6, and every 3 months thereafter (every 90 days ± 10 days until visit 27). Phone visits were conducted monthly between the every 3 month visits. Patients had a short-term follow-up visit that took place approximately 30 days after 1 of the following time points, whichever occurred first: after the completion of the 2-year on-study treatment period, or after discontinuation criteria were met and a decision was made for the patient to discontinue all study treatment before the completion of the 2-year on-study treatment period. After the short-term follow-up visit, all patients entered the long-term follow-up period, which began the day after the short-term follow-up visit and that will continue for up to 10 years or until study completion, whichever occurs first. Long-term follow-up visits occur approximately every 6 months until the completion of year 5 and then yearly starting in year 6.

The PRO assessment aimed at assessing the effects of treatment on patient-reported HRQoL and AEs. The FACT-B 37-item questionnaire was used to evaluate the 2 treatment arms in terms of general oncology and breast cancer self-reported HRQoL. The summary scores are presented for the FACT-B total score (a score range of 0 to 148), physical well-being (a score range of 0 to 28), social well-being (a score range of 0 to 28), emotional well-being (a score range of 0 to 24), and functional well-being (a score range of 0 to 28), as well as the breast cancer subscale (a score range of 0 to 40) and trial outcome index (a score range of 0 to 96).

The EQ-5D-5L questionnaire was used to evaluate patients’ health status to inform decision modelling for health economic evaluation. The EQ-5D-5L index values are summary scores based on a scale anchored at 0 being equivalent to death and 1 being full health. Negative values are deemed health states worse than death. The index values were calculated as per the EQ-5D-5L guidance using the published UK value set. The EQ Visual Analogue Scale (EQ VAS) is a measure of the patients’ self-reported health “today” (i.e., on the day of self-assessment) on a scale of 0 to 100, where 0 is the worst health you can imagine and 100 is the best health you can imagine. The EQ VAS score, based on the patient’s self-rated health today, serves to compliment the EQ-5D-5L single index score.

Health care resource utilization included self-reported hospitalizations and transfusions.

After the baseline assessment, PRO questionnaires were next administered to patients at visit 6, visit 9, visit 15, and visit 21 (18 months). Questionnaires were given at visit 27 (24 months) and follow-up visits but were not included in analyses due to less than 25% of patients having an assessment at those visits. Thus, the timing of assessments did not capture the effects of any AEs the patient might have experienced during the first 3 months.

Safety

AEs were graded according to the Common Terminology Criteria for Adverse Events version 4.0. TEAEs were defined as events that first occurred or worsened in severity while on therapy and until 30 days after treatment discontinuation, or serious events beyond 30 days of treatment discontinuation that were related to study treatment. SAEs were reported as treatment-emergent events on study and during the long-term follow-up period (up to 5 years after randomization). SAEs included AEs with an outcome of death, initial or prolonged hospitalization, or life-threatening events. All SAEs in both arms were and will continue to be collected from randomization through year 5. AEs leading to dose adjustments and discontinuation from study treatment due to AEs or death were also recorded. Second primary non-breast neoplasms were captured as AEs (in addition to being captured within the primary end point). Patients were followed up beyond 30 days post–study treatment discontinuation for SAEs regardless of causality to detect any long-term serious toxicities that are likely to be relevant for the adjuvant setting.

Statistical Analysis

Sample Size Calculations

The study was powered at approximately 85% to detect the superiority of abemaciclib plus ET versus ET alone in terms of IDFS in the ITT population, assuming a hazard ratio of 0.73 at a cumulative 2-sided alpha of 0.05, with a 5-year IDFS rate of 82.5% in the control arm, and a dropout probability rate of 10% over the first 5 years following randomization. This required approximately 390 events in the ITT population at the time of the primary analysis. Notably, the study was not powered for the reimbursement population of interest, which was the Cohort 1 Ki-67 High population.

Analyses of Outcomes

The IDFS analysis to test the superiority of abemaciclib with ET to ET alone was performed on the ITT population and used the log-rank test stratified by randomization factors. The 2 planned efficacy interim analyses and 1 planned final analysis for IDFS were to be performed after approximately 195 events, 293 events, and 390 events had been observed in the ITT population. The second efficacy interim analysis at approximately 293 IDFS events included both an efficacy criterion for statistical significance and a futility boundary. The cumulative 1-sided alpha was controlled at 0.025, with an alpha split of 0.00000001 for the first futility analysis and 0.02499999 for the planned efficacy analyses. The cumulative 1-sided type I error rate of 0.02499999 for the 2 planned efficacy interim analyses and 1 planned final analysis was maintained using the Lan-DeMets method (DeMets and Lan 1994).³⁴ Specifically, the alpha spent at each efficacy interim analysis was based on the exact number of IDFS events observed using the O’Brien-Fleming type stopping boundary.

A sequential gatekeeping strategy was used to control the family-wise type I error at 0.025 (1-sided) for IDFS in the ITT, Ki-67 High, and Cohort 1 Ki-67 High populations. IDFS was tested hierarchically in the order of the ITT, Ki-67 High, then Cohort 1 Ki-67 High populations, each gated after the former population. IDFS in the Ki-67 High population was tested only if IDFS in the ITT population was significant, and IDFS in the Cohort 1 Ki-67 High population was tested only if IDFS in the Ki-67 High population was significant.

The Kaplan-Meier method was used to estimate the IDFS curve for each treatment arm. The difference between IDFS rates for each arm was reported with 95% CIs estimated by normal approximation. A stratified Cox proportional hazards model with treatment as a factor was used to estimate the hazard ratio between the 2 treatment arms and the corresponding CI and Wald P value.

Similar analyses were performed on DRFS but there was no alpha control to account for the risk of type I error.

For OS, a sequential gatekeeping strategy was used to test treatment effect on OS in the ITT population, to maintain the experiment-wise type I error rate. That is, only if the tests of IDFS in the ITT, Ki-67 High, and Cohort 1 Ki-67 High populations were all significant, OS (in the ITT population) would be hierarchically tested. Of note, analyses of OS in other populations (i.e., Ki-67 High population and Cohort 1 Ki-67 High population) were not part of the testing hierarchy and were not planned a priori. Analysis of OS in Cohort 1 Ki-67 High population, which is the focus of this CADTH review, was not controlled for multiplicity. At each analysis, the treatment effect on OS was tested using a 1-sided log-rank test stratified by randomization factors. The Kaplan-Meier method was used to estimate the OS curve for each treatment arm. The OS rates for each arm were compared using a normal approximation for the difference between the rates. A stratified Cox proportional hazards model with treatment as a factor was used to estimate the hazard ratio between the 2 treatment arms and the corresponding CI and Wald P values. The follow-up time for OS was defined from the date of randomization and used the inverse of censoring rules for OS. The median follow-up time was calculated using the Kaplan-Meier method. Per the last addendum to the SAP, the final OS analysis was defined as observing approximately 650 OS events, or 10 years after the last patient is randomized, whichever occurs first. The cumulative 1-sided type I error rate of 0.025 was maintained using the Lan-DeMets method³⁴; the alpha spent at each interim analysis was calculated based on the actual number of events using the O’Brien-Fleming type stopping boundary.

The stratification factors for the analysis of primary and secondary end points were prior treatment (neoadjuvant chemotherapy versus adjuvant chemotherapy versus no chemotherapy), menopausal status (premenopausal versus postmenopausal), and region (North America or Europe versus Asia versus other). If a patient received both neoadjuvant and adjuvant chemotherapy, the patient was stratified as neoadjuvant chemotherapy. Male patients were stratified as postmenopausal at the time of randomization.

For HRQoL scores, a mixed effects model for repeated measures was applied to compare treatment arms by assessment with respect to each of the summary scores and select items. An effect size of one-half SD (SD = 0.5) was used to represent an MID. PRO data were analyzed at the pre-specified primary outcome analysis (data cut-off date: July 8, 2020).

AEs were summarized by maximum toxicity regardless of causality. TEAEs were summarized by system organ class and by decreasing frequency of preferred term within the system organ class. Preferred terms identified as clinically identical or synonymous were grouped together under a single consolidated PT. Descriptive statistics were used to summarize safety data.

With the exception of dates, missing data were not imputed.

Sensitivity Analyses

The following sensitivity analyses were performed on IDFS, DRFS, and OS: a log-rank test without stratification by randomization factors was performed to test the superiority of abemaciclib plus ET to ET alone on the ITT population, an unstratified Cox proportional hazards model with treatment as a factor was used to estimate the hazard ratio between the 2 treatment arms, and censoring for control arm patients receiving a CDK4 and CDK6 inhibitor was done. If a patient in the control arm received a CDK4 and CDK6 inhibitor before their first IDFS event, IDFS was censored at the date of the last disease assessment before the CDK4 and CDK6 inhibitor start date.

Subgroup Analyses

Subgroup analyses of IDFS in the ITT population were performed for preplanned subgroups according to menopausal status, primary tumour size, tumour grade, number of positive lymph nodes, PR status, and ECOG PS at baseline; these were subgroups of interest identified in the CADTH systematic review protocol. A similar statistical analysis approach to the main IDFS analysis was used. There was no multiplicity control. As such, all subgroup analyses were exploratory in nature.

Analyses

There were or are 6 planned interim analyses and 1 final analysis to test the null hypothesis, which occurred or will occur at the following time points:

• IDFS efficacy interim analysis 1 — approximately 195 IDFS events (the data cut-off date: September 27, 2019)

• IDFS efficacy interim analysis 2 — approximately 293 IDFS events (the data cut-off date: March 16, 2020)

• final IDFS analysis — approximately 390 IDFS events (the data cut-off date: July 8, 2020)

• OS interim analysis 1 (an additional follow-up analysis conducted at regulatory request; the data cut-off date: April 1, 2021).

• ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

• ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

Analysis Populations

The ITT population (N = 5,637) includes all randomized patients in Cohort 1 (N = 5,120) and Cohort 2 (N = 517). This was the primary analysis population for all efficacy analyses, including the primary end point (IDFS) and a key gated secondary end point (OS). The study was powered based on this population. The safety population included all patients in Cohort 1 and Cohort 2 who received any quantity of study treatment, regardless of the arm to which they were randomized. The safety population was used for the primary analysis of dosing and/or exposure, safety, and resource utilization. The Ki-67 High population included all randomized patients in Cohort 1 and Cohort 2 with a centrally assessed Ki-67 index of 20% or more and the Cohort 1 Ki-67 High population included all randomized patients in Cohort 1 with a centrally assessed Ki-67 index of 20% or more; gated secondary efficacy analyses were performed on these 2 cohorts. The Ki-67 Low population included all randomized patients in Cohort 1 and Cohort 2 with a centrally assessed Ki-67 index of less than 20%. Cohort 1 Ki-67 Low population included all randomized patients in Cohort 1 with a centrally assessed Ki-67 index of less than 20%; exploratory efficacy analyses were performed on this population. Cohort 2 included patients randomized based on a centrally determined Ki-67 index of 20% or more (Table 8).

In line with the approved Health Canada indication and the current reimbursement request, data from the Cohort 1 Ki-67 High population are reported in the main body of this CADTH report.

Table 8: Analysis Populations

C1 = Cohort 1; C2 = Cohort 2; ET = endocrine therapy; IDFS = invasive disease–free survival; ITT = intention to treat.

Note: Not all patients had a Ki-67 test or available test results.

^aPatients with Ki-67 score ≥ 20%.

^bPatients with Ki-67 score < 20%.

Source: Clinical Study Report for Verzenio (final IDFS [primary outcome] analysis).¹⁵

Results

Patient Disposition

A total of 7,372 patients entered the study at 611 sites in 38 countries. A total of 1,872 patients were not randomized due to screen failures. The main reasons for screen failure were inclusion or exclusion criteria not having been met (n = 1,427; 76.2%), withdrawal by patient (n = 364; 19.4%), physician decision (n = 75; 4.0%), and AEs (n = 6; 0.3%). Per protocol, patients who were screen failures could be rescreened; of these, 151 patients were rescreened, and 141 (93.4%) patients were then randomized into the study. Four patients entered the study with consent but did not complete screening and were not randomized. A total of 5,637 patients were randomized (|| patients in Canada) and included in the ITT population (Cohort 1 and Cohort 2), with 2,808 patients randomized to receive abemaciclib plus ET and 2,829 patients randomized to receive ET alone. A total of 5,120 patients were enrolled into Cohort 1. Of these, 3,917 (76%) patients had Ki-67 testing results available; among these, 2,003 (51%) patients had a Ki-67 score of 20% or more.

The end of the study treatment period was planned at 2 years (27 visits), according to the schedule of assessments. Patients performing the total number of visits of the treatment period were considered to have completed the study treatment period. Patients who discontinued abemaciclib, yet continued on ET, were considered still on study treatment. At the time of the primary outcome analysis (with a data cut-off date of July 8, 2020), 26.9% of patients in the abemaciclib plus ET arm and 28.2% of patients in the ET arm had completed the 2-year on-study treatment period. At the additional follow-up analysis (April 1, 2021), 73% of patients who had remained in the study had completed the study treatment phase (Table 9).

Table 9: Patient Disposition — Cohort 1 Ki-67 High Population

ET = endocrine therapy

Source: ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

Protocol Deviations

At the time of final IDFS analysis, 141 (2.5%) patients were reported to have 1 or more important protocol deviations, which included 74 (2.6%) patients in the abemaciclib plus ET arm and 67 (2.4%) patients in the ET arm (ITT population). The most commonly reported protocol deviations were deviations from inclusion or exclusion criteria, and criteria not met (2.2% in the abemaciclib + ET arm and 2.1% in the ET arm). Protocol deviations were evenly distributed between the 2 treatment arms and were considered unlikely to jeopardize the integrity of the data.

Exposure to Study Treatments

||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. Table 10 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Table 11.

Table 10: Exposure to Study Treatments — Cohort 1 Ki-67 High Population

ET = endocrine therapy; SD = standard deviation.

Note: Based on the safety population within Cohort 1 Ki-67 High (i.e., patients who received at least 1 dose of study treatment)

^aA cycle is defined as every 30 days of treatment.

Source: ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

Table 11: Summary of Endocrine Therapies — Cohort 1 Ki-67 High Population

ET = endocrine therapy; GnRH = gonadotropin-releasing hormone.

Note: Based on the safety population within Cohort 1 Ki-67 High (i.e., patients who received at least 1 dose of study treatment).

Source: ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

Prior and Concomitant Therapy

||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. Table 12 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Table 13.

Subsequent Anticancer Therapy

|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Table 14.

Table 12: Prior Anticancer Therapy for Breast Cancer — Cohort 1 Ki-67 High Population

ET = endocrine therapy.

Source: ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

Table 13: Concomitant Medications — Cohort 1 Ki-67 High Population

ET = endocrine therapy.

Note: Based on the safety population within Cohort 1 Ki-67 High (i.e., patients who received at least 1 dose of study treatment).

Source: ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

Table 14: Post-Discontinuation Therapy — Cohort 1 Ki-67 High Population

ET = endocrine therapy.

Source: ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported as follows. Refer to Appendix 2 for detailed efficacy data.

Overall Survival

At the interim analysis 1 for OS (i.e., additional follow-up analysis, with a data cut-off date of April 1, 2021), data were immature, with a |||||||||||||||| event rate. There were ||||||||| deaths in the Cohort 1 Ki-67 High population (|||||||||||||||| in the abemaciclib + ET arm and |||||||||||||||| in the ET arm). The hazard ratio between treatment arms was |||||||||||||||| (95% CI, ||||||||||||||||) (Table 15 and Figure 3).

Table 15: Overall Survival — Cohort 1 Ki-67 High Population

CI = confidence interval; ET = endocrine therapy; OS = overall survival.

Notes: The data cut-off date: April 1, 2021.

The median estimate for OS was not reached due to low event rates.

^aTested outside the preplanned statistical hierarchy and unadjusted for multiple comparisons.

^bStratified by geographical region, prior treatment, menopausal status.

^cEstimated using a Cox proportional hazards model.

^d95% CIs and 2-sided P values for the difference between rates were calculated based on normal approximation.

^eComputed based on comparator ET.

Source: ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

In its regulatory submission to Health Canada, the sponsor was requested to provide an additional unplanned OS analysis in the Cohort 1 population according to Ki-67 index (i.e., ≥ 20% versus < 20%) at the primary outcome (IDFS) analysis (with a data cut-off date of July 8, 2020). Data provided by the sponsor are presented in Table 30, Appendix 2. These data form the basis for the current approved indication of abemaciclib for early breast cancer (i.e., patients with high-risk clinicopathologic features and a Ki-76 index ≥ 20%). Briefly, although the OS data were highly immature, the OS analysis by Ki-67 index in Cohort 1 showed a hazard ratio of |||||||||||||||| (95% CI, ||||||||||||||||) in the Ki-67 of 20% or more population and a hazard ratio of |||||||||||||||| (95% CI, ||||||||||||||||) in the Ki-67 of less than 20% population (n = 1,913).¹⁸

Figure 3: Kaplan-Meier Plot of Overall Survival — Cohort 1 Ki-67 High Population

Note: This figure has been redacted as per sponsor’s request.

Invasive Disease–Free Survival

At the interim analysis (March 16, 2020) with a median follow-up of 15 months, |||||||||||||||| IDFS events were observed in the Cohort 1 Ki-67 High population (|||||||||| events in the abemaciclib + ET arm and |||||||||||||||| events in the ET arm). ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. The hazard ratio estimate between treatment arms was |||||||||||||||| (95% CI, ||||||||||||||||). The 2-year IDFS rates in the abemaciclib plus ET arm versus the ET arm were |||||||||||||||| versus |||||||||||||||| (Table 16).

At the final IDFS analysis (July 8, 2020), with a median follow-up of 19.1 months, ||| IDFS events were observed (|| events in the abemaciclib + ET arm and ||| events in the ET arm). The hazard ratio between treatment arms was 0.643 (95% CI, 0.475 to 0.872; P = 0.0042). The 2-year IDFS rates in the abemaciclib plus ET arm versus the ET arm were 91.3% versus 86.1%, respectively (Table 17 and Figure 4).

At the additional follow-up analysis (April 1, 2021), IDFS was assessed as post hoc analyses. With a median follow-up of 27 months, 262 IDFS events were observed (104 events in the abemaciclib + ET arm and 158 events in the ET arm). The hazard ratio between treatment arms was 0.63 (95% CI, 0.49 to 0.80). The 3-year IDFS rates in the abemaciclib plus ET arm versus the ET arm were 86.1% versus 79.0%, respectively (Table 18 and Figure 5).

IDFS in the ITT population and the ITT Ki-67 High population at the final IDFS analysis are included in Table 26 and Table 27 in Appendix 2.

Table 16: Invasive Disease–Free Survival, Interim Analysis — Cohort 1 Ki-67 High Population

CI = confidence interval; ET = endocrine therapy; IDFS = invasive disease–free survival.

Note: The data cut-off date was March 16, 2020. Tests were performed after failure of the statistical hierarchy.

^aRestriction time is defined by the latest time where the standard error of the survival estimates is 0.075 or less.

^bTreatment effect, difference, and P values were computed based on comparator ET.

^cThe 2-sided P value was based on normal approximation.

^dStratified by geographical region, prior treatment, and menopausal status.

^eEstimated using a Cox proportional hazards model.

^fThe 95% CIs and 2-sided P values for the difference between rates were calculated based on normal approximation.

Source: ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

Table 17: Invasive Disease–Free Survival, Final Analysis — Cohort 1 Ki-67 High Population

CI = confidence interval; ET = endocrine therapy; IDFS = invasive disease–free survival.

Note: The data cut-off date was July 8, 2020.

^aRestriction time is defined by the latest time where the standard error of the survival estimates is 0.075 or less.

^bTreatment effect, difference, and P values were computed based on comparator ET.

^cThe 2-sided P value was based on normal approximation.

^dStratified by geographical region, prior treatment, and menopausal status.

^eEstimated using a Cox proportional hazards model.

^fThe 95% CIs and 2-sided P values for the difference between rates were calculated based on normal approximation.

Source: ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

Table 18: Invasive Disease–Free Survival, Additional Follow-Up Analysis — Cohort 1 Ki-67 High Population

CI = confidence interval; ET = endocrine therapy; IDFS = invasive disease–free survival.

Note: Date cut-off date: April 1, 2021.

^aStratified by geographical region, prior treatment, menopausal status.

^bTesting was performed outside the statistical hierarchy (after end point was met).

^cEstimated using a Cox proportional hazards model.

^d95% CIs and 2-sided P values for the difference between rates were calculated based on normal approximation.

^eTreatment effect, difference, and P values are computed based on comparator ET.

Source: Clinical Study Report for Verzenio (overall survival interim analysis 1).¹⁶

Figure 4: Kaplan-Meier Plot of Invasive Disease–Free Survival, Final Analysis — Cohort 1 Ki-67 High Population

Note: This figure has been redacted as per sponsor’s request.

Figure 5: Kaplan-Meier Plot of Invasive Disease–Free Survival, Additional Follow-Up Analysis — Cohort 1 Ki-67 High Population

CI = confidence interval; ET = endocrine therapy; HR = hazard ratio.

Notes: Date cut-off date: April 1, 2021.

The P value is based on testing outside of the statistical hierarchy.

Source: Clinical Study Report for Verzenio (overall survival interim analysis 1).¹⁶

Subgroup Analyses

In the subgroup analyses, point estimates for hazard ratio were overall supportive of IDFS benefit with abemaciclib in the ITT population. Some subgroups had small sample sizes and wide overlapping 95% CIs. No statistically significant interactions were observed, suggesting a consistent treatment benefit across all subgroups (Table 28, Appendix 2).

Distant Relapse–Free Survival

At the interim analysis (March 16, 2020), a total of ||||||||||||||| events were observed (|||||||||| patients in the abemaciclib + ET arm and |||||||| patients in the ET arm). The hazard ratio between treatment arms was ||||||||||||||||||||||||||||||||||||||||||||||||. The 2-year DRFS rates in the abemaciclib plus ET arm versus the ET arm were ||||||||||||||||| versus ||||||||||||||||||, respectively (Table 19).

Table 19: Distant Relapse–Free Survival, Interim Analysis — Cohort 1 Ki-67 High Population

CI = confidence interval; DRFS = distant relapse–free survival; ET = endocrine therapy.

Note: Data cut-off date: March 16, 2020. Analyses were not pre-specified and not adjusted for multiple comparisons; therefore, there is an increased risk of type I error.

^aRestricted time is defined by the latest time where the standard error of the survival estimates is ≤ 0.075.

^b2-sided P value based on normal approximation.

^cStratified by geographical region, prior treatment, menopausal status.

^dEstimated using a Cox proportional hazards model.

^e95% CIs and 2-sided P values for the difference between rates were calculated based on normal approximation.

Source: ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

Table 20: Distant Relapse–Free Survival, Final Primary Outcome Analysis — Cohort 1 Ki-67 High Population

CI = confidence interval; ET = endocrine therapy, DRFS = distant relapse–free survival.

Note: The data cut-off date was July 8, 2020.

^aRestricted mean time is defined by the latest time where the standard error of the survival estimates is ≤ 0.075.

^bAnalyses were not pre-specified and not adjusted for multiple comparisons and therefore there is an increased risk of type I error.

^c2-sided P value based on normal approximation.

^dStratified by geographical region, prior treatment, menopausal status.

^eEstimated using a Cox proportional hazards model.

^f95% CIs and 2-sided P values for the difference between rates were calculated based on normal approximation.

Source: ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

At the final primary outcome (IDFS) analysis (July 8, 2020), a total of |||||||||||||| events were observed (|||||||| patients in the abemaciclib + ET arm and |||||||||||| patients in the ET arm). The hazard ratio between treatment arms was ||||||||||||||||||||||||||||||||||||||||||||||||. The 2-year DRFS rates in the abemaciclib plus ET arm versus the ET arm were ||||||||||||| versus ||||||||||||||||||||||||, respectively (Table 20 and Figure 6).

At the additional follow-up analysis (April 1, 2021), a total of 220 events were observed (85 patients in the abemaciclib + ET arm and 135 patients in the ET arm). The hazard ratio between treatment arms was 0.599 (95% CI, 0.456 to 0.787). The 3-year DRFS rates in the abemaciclib plus ET arm versus the ET arm were 87.8% versus 82.6%, respectively (Table 21).

Figure 6: Kaplan-Meier Plot of Distant Relapse–Free Survival, Final Primary Outcome Analysis — Cohort 1 Ki-67 High Population

Note: This figure has been redacted as per sponsor’s request.

Table 21: Distant Relapse–Free Survival, Additional Follow-Up Analysis — Cohort 1 Ki-67 High Population

CI = confidence interval; ET = endocrine therapy; DRFS = distant relapse–free survival.

Note: The data cut-off date was April 1, 2021.

^aAnalyses were not pre-specified and not adjusted for multiple comparisons; therefore, there is an increased risk of type I error.

^bStratified by geographical region, prior treatment, menopausal status.

^cEstimated using a Cox proportional hazards model.

^d95% CIs and 2-sided P values for the difference between rates were calculated based on normal approximation.

^eThe 2-sided P value based on normal approximation.

Source: Clinical Study Report for Verzenio (overall survival interim analysis 1).¹⁶

Health-Related Quality of Life

In the monarchE study, HRQoL data were assessed in the safety population only. As such, the results reported as follows are not based on the population of interest for this CADTH report (i.e., Cohort 1 Ki-67 High population).

FACT-B: At baseline, ||||||||| (|||||||||) patients in the abemaciclib plus ET arm and ||||||||| (|||||||||) patients in the ET arm completed the questionnaire; a total of ||||||||| (|||||||||) patients did not complete the questionnaire due to patient refusal, study site failure to administer, translation not being available, and other or missing reasons. At visit 21, ||||||||| patients in the abemaciclib plus ET arm and the ET arm, respectively, had completed questionnaires, representing ||||||||| and ||||||||| of patients with data at baseline; a total of ||||||||| (|||||||||) patients were non-compliant. The mean scores and changes from baseline scores were similar in both arms. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.

EQ-5D-5L: Questionnaire completion rates were ||||||||| and ||||||||| in the abemaciclib plus ET arm and the ET arm, respectively, at baseline, and ||||||||| and |||||||||, respectively, at visit 21 (of patients who reached visit 21). |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.

Health Care Resource Utilization

As of the final primary outcome (IDFS) analysis (July 8, 2020), a total of ||||||||| patients reported at least 1 hospitalization, including ||||||||| (||||||||| patients in the abemaciclib plus ET arm and ||||||||| (|||||||||) patients in the ET arm. The majority of patients were hospitalized due to ||||||||||||||||||||||||||||||||||||||||||||||||||||||. The median duration of hospitalization was |||||||||||||||||||||||||||||||||||||||||||||||||||||| in both treatment arms.

At least 1 transfusion during the study treatment period and within 30 days of study treatment discontinuation was received by ||||||||| patients, including ||||||||| (|||||||||) patients in the abemaciclib plus ET arm and ||||||||| (|||||||||) patients in the ET arm. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| was the most commonly reported AE requiring a transfusion, with ||||||||| (|||||||||) patients in the abemaciclib plus ET arm and ||||||||| (|||||||||) patients in the ET arm.

Harms

Adverse Events

At the final IDFS analysis (July 8, 2020), a total of 5,174 patients experienced at least 1 TEAE (97.9% in the abemaciclib plus ET arm and 87.2% in the ET arm) (Table 22). TEAEs by maximum Common Terminology Criteria for Adverse Events grade and PT that occurred in 10% or more of patients in either arm are summarized in Table 23. The most frequent TEAEs were diarrhea (82.6%), neutropenia (45.2%), and fatigue (39.2%) in the abemaciclib plus ET arm, and arthralgia (33.1%), hot flush (21.8%), and fatigue (16.6%) in the ET arm. Grade 3 or higher AEs occurred in 47.4% of patients in the abemaciclib plus ET arm, and in 14.2% of patients in the ET arm. The most frequently reported grade 3 or higher TEAEs in the abemaciclib plus 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 and arthralgia (0.7%) and lymphopenia (0.5%).

Serious Adverse Events

At least 1 SAE occurred in 13.3% of patients in the abemaciclib plus ET arm and 7.8% of patients in the ET arm. The most frequently reported SAE in both arms was pneumonia (0.9% and 0.5%, respectively) (Table 24).

The most common SAEs in the abemaciclib plus ET arm by system organ class were infections and infestations (4.5% in the abemaciclib plus ET arm versus 2.5% in the ET arm) followed by gastrointestinal disorders (1.9% in the abemaciclib plus ET arm versus 0.6% in the ET arm).

During the long-term follow-up period, ||||||||| patients with at least 1 SAE were reported (||||||||| [|||||||||] patients in the abemaciclib + ET arm, ||||||||| [|||||||||] patients in the ET arm). The SAEs included |||| fatal cases: ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.

Table 22: Summary of Adverse Events — Safety Population

AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; ET = endocrine therapy; IDFS = invasive disease–free survival; SAE = serious adverse event; TEAE = treatment-emergent adverse event.

Note: Data cut-off date: July 8, 2020. AEs were graded per CTCAE version 4.0.

^aPatients may be counted in more than 1 category.

^bDeaths were also included as SAEs and discontinuations due to AEs.

Source: Clinical Study Report for Verzenio (final IDFS [primary outcome] analysis).¹⁵

Table 23: Treatment-Emergent Adverse Events by Maximum CTCAE Grade Reported in 10% or More of Patients in Either Treatment Arm by Preferred Term — Safety Population

ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = Common Terminology Criteria for Adverse Events; ET = endocrine therapy; IDFS = invasive disease–free survival.

Note: Data cut-off date: July 8, 2020.

Source: Clinical Study Report for Verzenio (final IDFS [primary outcome] analysis).¹⁵

Table 24: Treatment-Emergent Serious Adverse Events Occurring in 5 or More Patients in Any Arm — Safety Population

ET = endocrine therapy; ILD = interstitial lung disease; VTE = venous thromboembolism.

Note: The data cut-off date was July 8, 2020. MedDRA Version 23.0.

^a“Composite terms” are defined as a grouping of terms from 1 or more preferred terms that are treatment-emergent events and are related to a defined medical condition or area of interest.

Source: ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

At the additional follow-up (with a data cut-off date of April 1, 2021), safety results were generally consistent with the safety results reported at the final IDFS analysis. A higher incidence of grade 3 or higher AEs and SAEs was observed in the abemaciclib plus ET arm than in the ET arm (50% versus 15% for grade 3 or higher AEs, respectively, and 15% versus 9% for grade 3 or higher SAEs, respectively). In total, 181 (6.5%) patients in the abemaciclib plus ET arm and 30 (1.1%) patients in the ET arm discontinued from the 2-year treatment period due to AEs.

Dose Modifications of Abemaciclib Due to Adverse Events

Abemaciclib dose modifications due to AEs were common (patients with ≥ 1 dose reduction [42.5%] and omission). ||||||||||||||||||||||||||||||||||||||||| of the patients with a dose omission due to an AE reported only 1 occurrence; |||||||| of the patients with a dose reduction due to an AE reported only 1 occurrence; ||||||||||||||||| had 2 dose reductions due to AEs (up to 2 dose reductions were allowed, per protocol). The most frequent reason for dose modifications of abemaciclib was ||||||||||||||||||||||||||||||||||||||||||||||||||||||.

Most dose reductions occurred early during study treatment, with ||||||||||||||||| of the treated patients in the abemaciclib plus ET arm experiencing dose reductions due to AEs within the second month. Reductions were below || per month after 4 months, and dropped below ||||||||||||||||| after 6 months, and below ||||||||||||||||| after 15 months of treatment. Dose reductions were higher for low-grade events (grade 1 or grade 2) in the first month (|||||||||||||||||) but then ||||||||||||||||| of the dose reductions occurred for events of grade 3 or higher throughout the treatment period, per protocol.

Discontinuation Due to Adverse Events

A total of 481 (17.2%) patients discontinued abemaciclib due to AEs, ||||||||| of whom remained on ET when abemaciclib was discontinued. Of these ||||||||||||| patients, ||||||||||||| patients later also discontinued ET due to an AE before completing the 2-year on-study treatment period. The 3 most common reasons for discontinuation of abemaciclib were diarrhea (5.1%), fatigue (1.9%), and neutropenia (0.9%). Low-grade AEs (grade 1 and grade 2) were the cause of discontinuation in 321 of the 481 (66.7%) patients who discontinued abemaciclib. One-third of the discontinuations (n = 160) were due to AEs of grade 3 or higher. The highest number of discontinuations due to any AE occurred during the first month of treatment (77 of the 481 [16.0%] total abemaciclib discontinuations due to AEs). These were mostly due to low-grade (grade 1 or grade 2) events and the frequency of discontinuations diminished over time. Approximately 40% of total abemaciclib discontinuations due to AEs occurred during the first 3 months of treatment. The majority of discontinuations (60.1%), including those due to diarrhea, fatigue, and neutropenia, occurred within the first 6 months of treatment. The percentage of patients discontinuing each month diminished over time, with 1.0% or fewer patients discontinuing each month after month 6.

Deaths

At the time of final IDFS analysis, there were ||||||||||||| (|||||||||||||) deaths in the abemaciclib plus ET arm and ||||||||||||| (|||||||||||||) deaths in the ET arm in the safety population.

There were ||||||||||||| (|||||||||||||) deaths due to AEs in the abemaciclib plus ET arm compared to ||||||||||||| (|||||||||||||) deaths in the ET arm on-study treatment, or within 30 days of all treatment discontinuation. There were ||||||||||||| (|||||||||||||) deaths due to AEs in the abemaciclib plus ET arm (|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||) and 1 death in the ET arm (||||||||||||||||||||||||||||||||||||||||||||||||||||), which occurred more than 30 days after discontinuation of all study treatment.

Notable Harms

Interstitial Lung Disease or Pneumonitis

The most frequently reported ILD or pneumonitis preferred terms were pneumonitis reported in 1.5% and 0.4% of patients in the abemaciclib plus ET and ET arms, respectively, and radiation pneumonitis reported in ||||||||||||| and ||||||||||||| of patients in the abemaciclib plus ET and ET arms, respectively. ILD and pneumonitis events of grade 3 or higher occurred in 11 (0.4%) patients in the abemaciclib plus ET arm and in 1 (< 0.1%) patient in the ET arm.

Diarrhea

The most frequently reported AE in the abemaciclib arm was diarrhea (82.6%); most of these events were low grade (44.8% = grade 1; 30.1% = grade 2; 7.7% = grade 3 or higher). In all, 6.1% of patients discontinued abemaciclib or all treatment in the abemaciclib plus ET arm due to diarrhea. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. In the ET arm, 7.8% of patients experienced diarrhea.

Increased Aminotransferases

In the abemaciclib plus ET arm, 12.8% of patients experienced a TEAE of elevated transaminases, with 3.1% of patients experiencing events of grade 3 or higher. In the ET arm, 6.5% of patients experienced TEAE elevated transaminases, with 0.9% being grade 3 or higher events. SAEs of elevated transaminases occurred in 0.4% of patients in the abemaciclib plus ET arm and 0.1% of patients in the ET arm.

Neutropenia

In the abemaciclib plus ET arm, 1,262 (45.2%) patients experienced a TEAE of neutropenia, with 552 (19.8%) patients experiencing grade 2 and 533 (19.1%) patients experiencing events of grade 3 or higher. Grade 4 neutropenia events occurred in 18 (0.6%) patients and SAEs in 3 (0.1%) patients. In the ET arm, 145 (5.2%) patients experienced TEAE neutropenia, with the majority being grade 1 or grade 2 events.

Infections and Infestations

The frequency of any grade of infection and grade 3 or higher infections was higher in the abemaciclib plus ET arm (47.7% versus 4.7%, respectively) compared to the ET arm (36.4% versus 2.6%, respectively). The most frequent (> 5%) infections by PT in the abemaciclib plus ET arm and the ET arm were upper respiratory tract infections (10.5% versus 8.1%, respectively), urinary tract infection (11.0% versus 6.8%, respectively), and nasopharyngitis (8.7% versus 7.0%, respectively).

Serious infections were reported for 4.5% of patients in the abemaciclib plus ET arm and 2.5% of patients in the ET arm. Pneumonia was the most frequently reported serious infection in both arms (0.9% in the abemaciclib plus ET arm and 0.5% in the ET arm).

Venous Thromboembolisms

VTE events compromising pulmonary embolism and deep vein thrombi (DVTs) were reported in 2.4% of patients in the abemaciclib plus ET arm and 0.6% of patients in the ET arm. In the abemaciclib plus ET arm, DVT was reported in 1.6% of patients and pulmonary embolism was reported in 1% of patients. In the ET arm, DVT was reported in 0.5% of patients and pulmonary embolism in 0.1% of patients.

Second Malignancy

|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

Fatigue

Fatigue was reported for 39.2% of patients in the abemaciclib plus ET arm and 16.6% of patients in the ET arm. Grade 3 or higher fatigue was reported for 2.8% of patients and 0.1% of patients in the abemaciclib plus ET arm and ET arm, respectively. Fatigue was 1 of the most common reasons for dose modifications of abemaciclib; there were dose omissions in 4.8% of patients and dose reductions in 4.4% of patients.

Critical Appraisal

Internal Validity

In the monarchE study, treatment assignment was based on a central randomization scheme that would ensure concealment of the randomized groups until allocation. However, the Ki-67 index was not a stratification factor; therefore, the population of interest (Cohort 1 Ki-67 High) cannot be considered to have been truly randomized. In addition, Ki-67 status in Cohort 1 was tested retrospectively (thus, this may have been affected by variability in testing times and methods), and data were not available for the full cohort. Analyses of this population subgroup could therefore be subject to confounding due to known or unknown prognostic imbalances across groups. The extent of potential confounding due to unknown prognostic factors or effect modifiers cannot be known, but the balanced available baseline characteristics across treatment arms suggests that concern for potential confounding may be minimal.¹⁸ The clinical experts consulted indicated that the high-risk criteria used in the monarchE study appeared reasonable. However, the 20% threshold for Ki-67 index used to categorize patients into high and low recurrence risk is not the threshold recommended by the recent IKWG guidelines.¹⁹ 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. A discussion of Ki-67 testing and issues surrounding its validity and reliability can be found in Appendix 4.

Following allocation, the trial was open label. 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 have resulted from lack of blinding of patients and investigators to assigned study treatments cannot be ruled out. For example, a patient’s knowledge of their assigned treatment could result in the overestimation or underestimation of safety end points and PROs like symptoms and HRQoL. PROs are particularly susceptible to bias from a lack of blinding of patients to their treatment. Investigator knowledge of the treatment group could have also resulted in different concomitant supportive care being offered to patients in the 2 treatment arms. However, the main difference in concomitant treatments was from more loperamide use in the abemaciclib arm to manage diarrhea; this is a known AE related to abemaciclib treatment. The primary outcome (IDFS) was investigator-assessed but based on objective criteria (STEEP) and, thus, unlikely to be greatly affected by the lack of investigators blinding.

Sample size was adequate, and the study was powered (based on the ITT population) to test its primary end point. The primary end point was met, but the study was not powered for the population of interest in this CADTH review (i.e., the Cohort 1 Ki-67 High population). The statistical approach of gatekeeping to sequentially test the primary and secondary end points was acceptable to account for multiple testing across these analyses. However, some analyses conducted on ITT subpopulations such as DRFS and OS in the Cohort 1 Ki-67 High population that are the focus of this CADTH report were not gated end points. Analyses in the Cohort 1 Ki-67 High population including IDFS at the additional analysis (April 1, 2021) were not preplanned and not controlled for multiple comparisons. As such, the analyses for these end points are at increased risk of type I error (i.e., false-positive findings).

The primary and secondary efficacy end points of IDFS and DRFS are considered appropriate for the disease setting. IDFS is widely used and accepted for regulatory drug approvals, especially in the early breast cancer setting with low event rates.¹⁸ As is common in oncology trials, the results for IDFS are the results of an interim analysis; therefore, there is some risk that the effect is overestimated. However, concern for this is reduced because the observed treatment effect appears to be clearly clinically important and maintained in the later additional analysis. IDFS and DRFS are considered early indicators of a patient’s survival, especially for less advanced conditions in which longer survival is expected. OS data in the monarchE study remain immature, which is expected in this disease setting with longer survival prognosis. An understanding of the efficacy of abemaciclib and ET with regard to OS will require a larger number of events and a longer follow-up. The correlation of DFS surrogates with OS remains debatable and requires further investigation. Evidence from the literature is limited, with some studies suggesting that the correlation between DFS may not be strong enough to be used as a predictor of OS in adjuvant breast cancer trials.³⁵ Moreover, estimates of acceptable correlation from other treatments and disease stages may not be generalizable to treatment with abemaciclib in this setting. Therefore, it is unclear if improvements in IDFS that were observed in patients in the abemaciclib plus ET arm of the monarchE trial would translate into OS benefits. Appendix 3 describes the DFS outcome measure and summarizes evidence that examines the validity of DFS as a surrogate for OS in patients with early-stage breast cancer.

Data for some end points, specifically HRQoL and health care resource utilization, were unavailable for the population of interest in this CADTH review. It is not clear if the findings for these outcomes would be similar to those reported for the overall safety population. Moreover, there was a substantial attrition rate for HRQoL assessments over time, with approximately 50% of patients contributing to these assessments at visit 21. No HRQoL data were captured for the first 3 months; this may have been an important time point in terms of changes in quality of life after initiation of new treatment.

External Validity

The monarchE trial included a heterogenous population of patients with early breast cancer and a wide range of clinical presentations were well represented. The clinical experts consulted by CADTH noted that patients in the trial are about a decade younger than patients with early breast cancer encountered in clinical practice, who are generally diagnosed and treated in their early to mid 60s. This discrepancy, however, may be explained by high-risk features potentially being more prevalent in younger patients. The inclusion of younger and healthier patients may have led to a more favourable toxicity profile where more AEs were manageable, and reversible. In terms of clinicopathologic features used for eligibility, the clinical experts noted that for patients who received neoadjuvant therapy, the monarchE study allowed the tumour size to be based on imaging; however, lymph node involvement could have been assessed cytologically and may have produced different results. If multiple lymph nodes were sampled in the trial to determine eligibility, it should be noted that this is not done in routine clinical practice. The clinical experts noted that the ET regimens used in the trial and their distribution are representative of ET regimens used in the Canadian clinical setting.

The Ki-67 IHC is a marker of cell proliferation and considered an important prognostic factor in early breast cancer. In the monarchE study, Ki-67 assessment was performed by the investigational (central) test using standardized laboratory procedures for tissue handling, preparation, and assays to ensure consistency. The clinical experts consulted by CADTH and the clinician group input stated that Ki-67 testing is not broadly practised in the Canadian clinical setting and expressed concerns regarding the reliability of Ki-67 IHC analyses. Unlike a clinical trial setting with centralized testing, the variability in sample preparation methods between different laboratories and different scoring methods between observers reduce the reproducibility of Ki-67 IHC in clinical practice. The clinical experts noted the many internal and external factors that can impact Ki-67 values. For example, tumour heterogeneity and samples from core biopsy and surgery can produce different Ki-67 test values, particularly in patients who undergo neoadjuvant treatment. There are other uncertainties regarding the use of Ki-67 testing in clinical practice and its implementation as a criterion to select eligible patients for treatment. For example, the clinical experts questioned at what time point to conduct the Ki-67 IHC test as biomarkers can change drastically at different time points, and what to do in case of multiple testing results with different values, or if a patient’s test is borderline for the eligibility cut-off (19% instead of 20%). Whether the 20% cut-off value for Ki-67 to categorize recurrence risk as high or low can meaningfully and consistently distinguish patients’ recurrence risk is also debated, and the extent to which Ki-67 is predictive of treatment response is unclear. It is important to note that in the monarchE study, the Ki-67 index was used only as an additional prognostic factor to determine the risk of recurrence. It was not considered as a companion diagnostic for predicting response to treatment.¹⁸ However, regulatory bodies (the FDA, Health Canada) considered that the benefit-risk ratio of adding abemaciclib to ET was only favourable in patients with a Ki-67 index of 20% or higher, in addition to high-risk clinicopathologic features.^18,23 A detailed discussion of Ki-67 testing is included in Appendix 4.

Indirect Evidence

A focused literature search for indirect treatment comparisons dealing with breast cancer was run in MEDLINE All (1946–) on April 20, 2022. No limits were applied to the search. No indirect evidence was identified from the literature and no indirect treatment comparison was submitted by the sponsor.

Other Relevant Evidence

No other relevant evidence was submitted by the sponsor or identified from the literature.

Discussion

Summary of Available Evidence

The monarchE trial that forms the evidence base for this review is an ongoing, open-label, phase III randomized controlled trial that compared the efficacy and safety of abemaciclib in combination with 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 were at high risk of recurrence based on clinicopathologic features or the Ki-67 index. The primary efficacy end point was IDFS, and the secondary end points included DRFS and OS. A total of 5,637 patients in 38 countries, including ||||||||| patients from Canada, were randomized to treatment with either abemaciclib plus ET or ET alone. Patients with at least 1 positive lymph node were recruited into 2 cohorts: Cohort 1 or Cohort 2. Patients in Cohort 1 (n = 5,120) were eligible based on high-risk clinicopathologic features (i.e., ≥ 4 positive ALNs, or 1 positive ALN to 3 positive ALNs and at least 1 of the following: tumour size ≥ 5 cm or histologic grade 3). Patients in Cohort 2 (n = 517) were patients at high risk of recurrence based on high levels of the Ki-67 index (Ki-67 index ≥ 20%). In Cohort 1, 3,917 (76%) patients had Ki-67 testing information 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. Cohort 1 patients with a Ki-67 index of 20% or more were predominantly female (99.2%) with a mean age of 51.6 years (SD = 11.1) and an ECOG PS of 0 (86.3%); 54.4% were postmenopausal.

Interpretation of Results

Efficacy

In the monarchE trial, abemaciclib combined with ET resulted in an improvement in IDFS in patients with HR-positive, HER2-negative, node-positive early breast cancer at high risk of early recurrence. This treatment benefit extended to the subpopulation of patients with high recurrence risk based on high-risk clinicopathologic features and a Ki-67 index of 20% or more (Cohort 1 Ki-67 High population); this aligns with the Health Canada indication for abemaciclib in the adjuvant treatment of early breast cancer and the current reimbursement request. At the final IDFS primary end point analysis with a median follow-up of 19.1 months, IDFS showed a statistically significant and clinically meaningful difference between the 2 treatment arms in favour of abemaciclib plus ET among the Cohort 1 Ki-67 High population (hazard ratio = 0.643; 95% CI, 0.475 to 0.872; P = 0.0042). The 2-year IDFS rate in the abemaciclib plus ET arm was higher than in the ET arm (91.3% versus 86.1%, respectively). This treatment benefit was maintained at the additional follow-up analysis with a median follow-up of 27 months and 90% of patients having completed or discontinued from the study treatment period (hazard ratio = 0.63; 95% CI, 0.49 to 0.80). The 3-year IDFS rates in the abemaciclib plus ET arm versus the ET arm were 86.1% versus 79.0%, respectively. The DRFS secondary end point was not preplanned for the Cohort 1 Ki-67 High population and was tested outside the statistical hierarchy, precluding definitive conclusions due to the increased risk of false-positive results. However, the findings for DRFS were supportive of the IDFS treatment effect (hazard ratio = 0.571; 95% CI, 0.410 to 0.793); findings at the additional follow-up analysis were similar (hazard ratio = 0.599; 95% CI, 0.456 to 0.787).

OS data remain immature at the most recent analysis in the Cohort 1 Ki-67 High population (and in the ITT population). OS is an event-driven secondary end point with a longer expected maturity in the adjuvant setting. At OS interim analysis 1, there were ||||||||| deaths (||||||||| in the abemaciclib + ET arm and ||||||||| in the ET arm) in the Cohort 1 Ki-67 High population with a hazard ratio of ||||||||||||| (95% CI, |||||||||||||). Therefore, no conclusions can be drawn regarding the efficacy of abemaciclib plus ET with respect to OS at this time and reaching statistical significance for OS will require a considerable number of events and a much longer follow-up. In addition to requiring long follow-up time, interpretation of OS in terms of treatment effect is less clear than in the advanced or metastatic settings. Given these caveats, as Health Canada reviewers have noted, it should be considered that the objective of this trial of demonstrating the benefit in preventing or delaying disease progression in the first 2 years of treatment was achieved.¹⁸

Although the efficacy data from the monarchE study demonstrate consistent treatment benefit of abemaciclib plus ET as measured by IDFS and DRFS across all Ki-67 populations in Cohort 1, the data suggest that patients most likely to develop recurrence (i.e., Cohort 1 with a Ki-67 score ≥ 20%) may draw the greatest benefit from the treatment. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. Health Canada reviewers concluded that the interpretation of the effect of abemaciclib plus ET on OS is limited and it is not possible to anticipate that the preliminary OS benefit observed in Cohort 1 with Ki-67 of 20% or more will precede an OS benefit in the entire population of Cohort 1, as a persistent negative OS effect cannot be ruled out.¹⁸ Consequently, taking into account the benefit-harm-uncertainty assessment, Health Canada recommended that the indication be restricted to those patients in whom the greatest benefit was observed — namely, patients with HR-positive, HER2-negative, node-positive early breast cancer with high risk of disease recurrence based on high-risk clinicopathologic features and a Ki-67 index of 20% or more, despite no significant interaction effects between groups.

HRQoL was identified by both patients and clinical experts as an important aspect of treatment for patients with early breast cancer. Based on the patient group input, most patients are willing to accept treatment side effects if the treatment could lower the risk of disease recurrence. As treatment in the adjuvant setting is with curative intent, it is less amenable than the advanced and/or metastatic setting to improving disease-related symptoms and HRQoL. PRO data suggest that the addition of abemaciclib to ET did not result in any clinically meaningful differences in HRQoL. The interpretation of results (i.e., the ability to assess trends over time [over the treatment period] and to make comparisons across treatment groups) is limited by the significant decline in patients available to provide assessment over time and the lack of formal statistical testing.

Harms

The safety profile of abemaciclib plus ET is well established in the advanced breast cancer setting. Data from the monarchE trial show a similar safety profile of adjuvant abemaciclib in the early breast cancer setting. Overall, the most common AEs experienced on abemaciclib plus ET were predictable and according to the clinical experts consulted, clinically manageable in most patients. Most patients in both treatment arms experienced AEs (97.9% in the abemaciclib + ET arm and 87.2% in the ET arm). A higher proportion of patients in the abemaciclib plus ET arm experienced grade 3 or higher AEs compared to the ET arm (47.4% versus 14.2%, respectively) and SAEs (13.3% versus 7.8%, respectively). The most common AEs in the abemaciclib plus ET arm were diarrhea, neutropenia, fatigue, leukopenia, abdominal pain, nausea, and anemia. Most of these AEs were mild to moderate and the highest incidence of severe events (≥ grade 3) was seen for neutropenia and leukopenia (19.1% and 10.9%, respectively). The most common AEs in the ET arm were arthralgia, hot flush, and fatigue. At the additional follow-up with more than 2 years of follow-up data and more than 90% of patients off the study treatment, the safety results were consistent with the safety results reported at the final IDFS analysis. A higher incidence of grade 3 or higher AEs and SAEs were observed in the abemaciclib plus ET arm than in the ET arm (50% in the abemaciclib plus ET arm versus 15% in the ET arm and 15% in the abemaciclib plus ET arm versus 9% in the ET arm at additional follow-up), with the difference driven mainly by a higher incidence of grade 3 or higher diarrhea, neutropenia, and fatigue in the abemaciclib plus ET population. Similar to the metastatic setting, notable AEs identified in the monarchE study included neutropenia, diarrhea, VTE, and ILD or pneumonitis. Although some AEs — including neutropenia and diarrhea — had faster onset, their incidence and severity decreased over time. The clinical experts consulted indicated that, overall, the type and distribution of AEs observed in the monarchE trial were not unexpected compared to clinical practice.

The proportion of patients who discontinued treatment permanently because of AEs was higher in the abemaciclib plus ET arm compared to the ET arm (6.2% versus 0.8%, respectively). However, the AE profile was notably different in the 2 treatment arms. Most patients in the abemaciclib plus ET arm experienced diarrhea (82.6% in the abemaciclib plus ET arm compared to 7.8% in the ET arm). The majority of patients in the abemaciclib plus ET arm who discontinued abemaciclib or all treatment discontinued due to diarrhea (6.1%). In most cases, discontinuation was due to low-grade events (grade < 2) and occurred during the first 3 months of treatment with no prior dose reduction before discontinuing abemaciclib. After 3 months, the proportion of patients who discontinued treatment decreased monthly and reached 1.0% or less after 6 months. The clinical experts consulted indicated that diarrhea is a known AE experienced by patients on abemaciclib and is managed effectively in most patients in clinical practice. However, given the prolonged duration of adjuvant therapy, persistent AEs such as diarrhea can be particularly bothersome for these young patients with active lives, leading to treatment fatigue and discontinuation of treatment for some. Of note, patient groups indicated that, overall, they were willing to endure the additional side effects of abemaciclib.

Infections were commonly observed in both arms and were mostly low grade, although the incidence of any grade and severe infections was higher in the abemaciclib plus ET arm. The most frequent type of infections reported in both arms were upper respiratory tract infections (abemaciclib + ET arm = 10.5%; ET arm = 8.1%), urinary tract infections (abemaciclib + ET arm = 11.0%; ET arm = 6.8%), and nasopharyngitis (abemaciclib + ET arm = 8.7%; ET arm = 7.0%). However, none of these infections was associated with neutropenia. The incidence of VTE was higher in the abemaciclib plus ET arm (2.4% in the abemaciclib plus ET arm versus 0.6% in the ET arm). The clinical experts noted that VTEs have been reported with other CDK4 and CDK6 inhibitors in combination with ET and the proportion of patients who experienced VTE in the monarchE study is similar to what would be expected in clinical practice. Fatigue was also commonly reported in the monarchE study, with a higher proportion of patients in the abemaciclib arm (39.2% in the abemaciclib plus ET arm versus 16.6% in the ET arm). Although fatigue was mild in most cases, it was 1 of the most common reasons for dose modifications (9.2%) and treatment discontinuation (1.9%). These AEs are well-known for abemaciclib and are labelled in prominent sections of the product monograph.¹⁸

|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. No specific patterns in etiology or a temporal relationship with exposure was reported for deaths caused by AEs and a cause-effect relationship could not be established due to multiple confounding factors.

Conclusions

Based on data from the monarchE trial, abemaciclib plus ET demonstrated a statistically significant and clinically meaningful benefit compared to ET alone in improving IDFS in people with HR-positive, HER2-negative, node-positive early breast cancer at high risk of disease recurrence based on clinicopathologic features and a Ki-67 score of 20% or more. DRFS was not a pre-specified end point for the Cohort 1 Ki-67 High population and tested outside 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 as the data remain immature, and follow-up is ongoing. The safety profile of abemaciclib was consistent with the known adverse effects profile of abemaciclib. 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 abemaciclib plus ET in terms of OS, given the slow event rate in this setting, the addition of abemaciclib 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 abemaciclib treatment.

References

1.Canadian Cancer Statistics Advisory Committee, Canadian Cancer Society, Statistics Canada, Public Health Agency of Canada. Canadian Cancer Statistics 2021. Toronto (ON): Canadian Cancer Society; 2021: https://cancer.ca/Canadian-Cancer-Statistics-2021-EN. Accessed 2022 May 20.

2.Kohler BA, Sherman RL, Howlader N, et al. Annual Report to the Nation on the Status of Cancer, 1975-2011, Featuring Incidence of Breast Cancer Subtypes by Race/Ethnicity, Poverty, and State. J Natl Cancer Inst. 2015;107(6):djv048. PubMed

3.Harbeck N, Penault-Llorca F, Cortes J, et al. Breast cancer. Nat Rev Dis Primers. 2019;5(1):66. PubMed

4.Cardoso F, Spence D, Mertz S, et al. Global analysis of advanced/metastatic breast cancer: Decade report (2005-2015). Breast. 2018;39:131-138. PubMed

5.Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: Female Breast Cancer Subtypes. Bethesda (MD): National Cancer Institute: https://seer.cancer.gov/statfacts/html/breast-subtypes.html. Accessed 2022 May 23.

6.Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Aromatase inhibitors versus tamoxifen in premenopausal women with oestrogen receptor-positive early-stage breast cancer treated with ovarian suppression: a patient-level meta-analysis of 7030 women from four randomised trials. Lancet Oncol. 2022;23(3):382-392. PubMed

7.Pan H, Gray R, Braybrooke J, et al. 20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years. N Engl J Med. 2017;377(19):1836-1846. PubMed

8.Stuart-Harris R, Dahlstrom JE, Gupta R, Zhang Y, Craft P, Shadbolt B. Recurrence in early breast cancer: Analysis of data from 3,765 Australian women treated between 1997 and 2015. Breast. 2019;44:153-159. PubMed

9.Song F, Zhang J, Li S, et al. ER-positive breast cancer patients with more than three positive nodes or grade 3 tumors are at high risk of late recurrence after 5-year adjuvant endocrine therapy. Onco Targets Ther. 2017;10:4859-4867. PubMed

10.Fasching PA, Gass P, Haberle L, et al. Prognostic effect of Ki-67 in common clinical subgroups of patients with HER2-negative, hormone receptor-positive early breast cancer. Breast Cancer Res Treat. 2019;175(3):617-625. PubMed

11.Cefaro GA, Genovesi D, Trignani M, M DIN. Human epidermal growth factor receptor-2 positivity predicts locoregional recurrence in patients with T1-T2 breast cancer. Anticancer Res. 2014;34(3):1207-1212. PubMed

12.Liang Q, Ma D, Gao RF, Yu KD. Effect of Ki-67 Expression Levels and Histological Grade on Breast Cancer Early Relapse in Patients with Different Immunohistochemical-based Subtypes. Sci Rep. 2020;10(1):7648. PubMed

13.Burstein HJ, Curigliano G, Loibl S, et al. Estimating the benefits of therapy for early-stage breast cancer: the St. Gallen International Consensus Guidelines for the primary therapy of early breast cancer 2019. Ann Oncol. 2019;30(10):1541-1557. PubMed

14.Clinical Study Report: I3Y-MC-JPCF. Version 1. monarchE: a randomized, open-label, phase 3 study of abemaciclib combined with standard adjuvant endocrine therapy versus standard adjuvant endocrine therapy alone in patients with high risk, node positive, early stage, hormone receptor positive, human epidermal receptor 2 negative, breast cancer [internal sponsor's report]. Toronto (ON): Eli Lilly Canada Inc.; 2020 Sep 25.

15.Clinical Study Report: I3Y-MC-JPCF. Version 2. monarchE: a randomized, open-label, phase 3 study of abemaciclib combined with standard adjuvant endocrine therapy versus standard adjuvant endocrine therapy alone in patients with high risk, node positive, early stage, hormone receptor positive, human epidermal receptor 2 negative, breast cancer [internal sponsor's report]. Toronto (ON): Eli Lilly Canada Inc.; 2020 Dec 15.

16.Clinical Study Report: I3Y-MC-JPCF. Version 3. monarchE: a randomized, open-label, phase 3 study of abemaciclib combined with standard adjuvant endocrine therapy versus standard adjuvant endocrine therapy alone in patients with high risk, node positive, early stage, hormone receptor positive, human epidermal receptor 2 negative, breast cancer [internal sponsor's report]. Toronto (ON): Eli Lilly Canada Inc.; 2021 Jun 28.

17.Sawaki M, Shien T, Iwata H. TNM classification of malignant tumors (Breast Cancer Study Group). Jpn J Clin Oncol. 2019;49(3):228-231. PubMed

18.Health Canada reviewer's report: Verzenio (abemaciclib) [internal sponsor's report]. In: Drug Reimbursement Review sponsor submission: Verzenio (abemaciclib), 50 mg, 100 mg, 150 mg, or 200 mg oral tablets. Toronto (ON): Eli Lilly Canada Inc.; 2022 Apr 07.

19.Nielsen TO, Leung SCY, Rimm DL, et al. Assessment of Ki67 in Breast Cancer: Updated Recommendations From the International Ki67 in Breast Cancer Working Group. J Natl Cancer Inst. 2021;113(7):808-819. PubMed

20.Guideline Resource Unit. Systemic therapy for early breast cancer - quick reference guide. (Clinical practice guideline BR-014 – version 6). Edmonton (AB): Cancer Care Alberta; 2021: https://www.albertahealthservices.ca/assets/info/hp/cancer/if-hp-cancer-guide-systemic-therapy-early-breast.pdf. Accessed 2022 Jul 19.

21.Breast Disease Site Group. Practice Guideline: Disease Management. Provincial Consensus Recommendations for Adjuvant Systemic Therapy for Breast Cancer. Winnipeg (MB): CancerCare Manitoba; 2017: https://ext-opencms.cancercare.mb.ca/export/sites/default/For-Health-Professionals/.galleries/files/treatment-guidelines-rro-files/practice-guidelines/breast/Adjuvant_Breast_Guideline_July_2017.pdf. Accessed 2022 Jul 19.

22.National Center for Biotechnology Information. PubChem Compound Summary for CID 46220502: abemaciclib. Bethesda (MD): National Library of Medicine; 2022: https://pubchem.ncbi.nlm.nih.gov/compound/Abemaciclib. Accessed 2022 May 23.

23.U.S. Food and Drug Administration (FDA). FDA approves abemaciclib with endocrine therapy for early breast cancer. 2021; https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-abemaciclib-endocrine-therapy-early-breast-cancer. Accessed 2022 May 23.

24.Product information: Verzenios (abemaciclib). (European public assessment report). Amsterdam (NL): European Medicines Agency; 2022: https://www.ema.europa.eu/en/documents/product-information/verzenios-epar-product-information_en.pdf. Accessed 2022 Jun 15.

25.Verzenio (abemaciclib): 50 mg, 100 mg, 150 mg, or 200 mg oral tablets [product monograph]. Toronto (ON): Eli Lilly Canada Inc.; 2022 Jan 10.

26.McGowan J, Sampson M, Salzwedel DM, Cogo E, Foerster V, Lefebvre C. PRESS Peer Review of Electronic Search Strategies: 2015 guideline statement. J Clin Epidemiol. 2016;75:40-46. PubMed

27.Grey matters: a practical tool for searching health-related grey literature. Ottawa (ON): CADTH; 2019: https://www.cadth.ca/grey-matters. Accessed 2022 Apr 08.

28.Rugo HS, O'Shaughnessy J, Boyle F, et al. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: safety and patient-reported outcomes from the monarchE study. Ann Oncol. 2022;33(6):616-627. PubMed

29.Harbeck N, Rastogi P, Martin M, et al. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study. Ann Oncol. 2021;32(12):1571-1581. PubMed

30.Johnston SRD, Harbeck N, Hegg R, et al. Abemaciclib Combined With Endocrine Therapy for the Adjuvant Treatment of HR+, HER2-, Node-Positive, High-Risk, Early Breast Cancer (monarchE). J Clin Oncol. 2020;38(34):3987-3998. PubMed

31.Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology. 1991;19(5):403-410. PubMed

32.Eli Lilly Canada Inc. response to May 27, 2022 DRR request for additional information regarding Verzenio (abemaciclib) DRR review [internal additional sponsor's information]. Toronto (ON): Eli Lilly Canada Inc.; 2022.

33.Hudis CA, Barlow WE, Costantino JP, et al. Proposal for standardized definitions for efficacy end points in adjuvant breast cancer trials: the STEEP system. J Clin Oncol. 2007;25(15):2127-2132. PubMed

34.DeMets DL, Lan KK. Interim analysis: the alpha spending function approach. Stat Med. 1994;13(13-14):1341-1352; discussion 1353-1346. PubMed

35.Gyawali B, Hey SP, Kesselheim AS. Evaluating the evidence behind the surrogate measures included in the FDA's table of surrogate endpoints as supporting approval of cancer drugs. EClinicalMedicine. 2020;21:100332. PubMed

36.Webster K, Cella D, Yost K. The Functional Assessment of Chronic Illness Therapy (FACIT) Measurement System: properties, applications, and interpretation. Health Qual Life Outcomes. 2003;1:79. PubMed

37.Hahn EA, Segawa E, Kaiser K, Cella D, Smith BD. Validation of the Functional Assessment of Cancer Therapy-Breast (FACT-B) quality of life instrument. J Clin Oncol. 2015;33(15_suppl):e17753-e17753.

38.Brady MJ, Cella DF, Mo F, et al. Reliability and validity of the Functional Assessment of Cancer Therapy-Breast quality-of-life instrument. J Clin Oncol. 1997;15(3):974-986. PubMed

39.Eton DT, Cella D, Yost KJ, et al. A combination of distribution- and anchor-based approaches determined minimally important differences (MIDs) for four endpoints in a breast cancer scale. J Clin Epidemiol. 2004;57(9):898-910. PubMed

40.EQ-5D-5L User Guide. Basic information on how to use the EQ-5D-5L instrument. Rotterdam (NL): EuroQol Research Foundation; 2019: https://euroqol.org/publications/user-guides/. Accessed 2022 Jun 02.

41.Lee CF, Ng R, Luo N, et al. The English and Chinese versions of the five-level EuroQoL Group's five-dimension questionnaire (EQ-5D) were valid and reliable and provided comparable scores in Asian breast cancer patients. Support Care Cancer. 2013;21(1):201-209. PubMed

42.Kimman ML, Dirksen CD, Lambin P, Boersma LJ. Responsiveness of the EQ-5D in breast cancer patients in their first year after treatment. Health Qual Life Outcomes. 2009;7:11. PubMed

43.Conner-Spady B, Cumming C, Nabholtz JM, Jacobs P, Stewart D. Responsiveness of the EuroQol in breast cancer patients undergoing high dose chemotherapy. Qual Life Res. 2001;10(6):479-486. PubMed

44.McClure NS, Sayah FA, Xie F, Luo N, Johnson JA. Instrument-Defined Estimates of the Minimally Important Difference for EQ-5D-5L Index Scores. Value Health. 2017;20(4):644-650. PubMed

45.Pickard AS, Neary MP, Cella D. Estimation of minimally important differences in EQ-5D utility and VAS scores in cancer. Health Qual Life Outcomes. 2007;5:70. PubMed

46.Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics: Guidance for Industry. Silver Spring (MD): U.S. Food and Drug Administration (FDA); 2018: https://www.fda.gov/media/71195/download. Accessed 2022 May 25.

47.U.S. Food and Drug Administration (FDA). Table of surrogate endpoints that were the basis of drug approval or licensure. 2022; https://www.fda.gov/drugs/development-resources/table-surrogate-endpoints-were-basis-drug-approval-or-licensure. Accessed 2022 May 04.

48.U.S. Food and Drug Administration (FDA). FDA facts: biomarkers and surrogate endpoints. 2017; https://www.fda.gov/about-fda/innovation-fda/fda-facts-biomarkers-and-surrogate-endpoints. Accessed 2022 May 04.

49.Saad ED, Squifflet P, Burzykowski T, et al. Disease-free survival as a surrogate for overall survival in patients with HER2-positive, early breast cancer in trials of adjuvant trastuzumab for up to 1 year: a systematic review and meta-analysis. Lancet Oncol. 2019;20(3):361-370. PubMed

50.Committee For Medicinal Products For Human Use. Guideline on the clinical evaluation of anticancer medicinal products. Amsterdam (NL): European Medicines Agency; 2019: https://www.ema.europa.eu/documents/scientific-guideline/draft-guideline-evaluation-anticancer-medicinal-products-man-revision-6_en.pdf. Accessed 2022 May 25.

51.Validity of surrogate endpoints in oncology, version 1.1. (IQWiG Reports – Commission No. A10-05). Cologne (DE): Institute for Quality and Efficiency in Health Care (IQWiG); 2011: https://www.iqwig.de/download/a10-05_executive_summary_v1-1_surrogate_endpoints_in_oncology.pdf. Accessed 2022 May 26.

52.Haslam A, Hey SP, Gill J, Prasad V. A systematic review of trial-level meta-analyses measuring the strength of association between surrogate end-points and overall survival in oncology. Eur J Cancer. 2019;106:196-211. PubMed

53.Buyse M, Saad ED, Burzykowski T, Regan MM, Sweeney CS. Surrogacy Beyond Prognosis: The Importance of “Trial-Level” Surrogacy. Oncologist. 2022;27(4):266-271. PubMed

54.Buyse M, Molenberghs G, Burzykowski T, Renard D, Geys H. The validation of surrogate endpoints in meta-analyses of randomized experiments. Biostatistics. 2000;1(1):49-67. PubMed

55.Ng R, Pond GR, Tang PA, MacIntosh PW, Siu LL, Chen EX. Correlation of changes between 2-year disease-free survival and 5-year overall survival in adjuvant breast cancer trials from 1966 to 2006. Ann Oncol. 2008;19(3):481-486. PubMed

56.U.S. Food and Drug Administration (FDA). Ki-67 IHC MIB-1 pharmDx (Dako Omnis) - P210026. 2021; https://www.fda.gov/medical-devices/recently-approved-devices/ki-67-ihc-mib-1-pharmdx-dako-omnis-p210026. Accessed 2022 May 10.

57.Inwald EC, Klinkhammer-Schalke M, Hofstadter F, et al. Ki-67 is a prognostic parameter in breast cancer patients: results of a large population-based cohort of a cancer registry. Breast Cancer Res Treat. 2013;139(2):539-552. PubMed

58.Dowsett M, Nielsen TO, A'Hern R, et al. Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer working group. J Natl Cancer Inst. 2011;103(22):1656-1664. PubMed

59.Yerushalmi R, Woods R, Ravdin PM, Hayes MM, Gelmon KA. Ki67 in breast cancer: prognostic and predictive potential. Lancet Oncol. 2010;11(2):174-183. PubMed

60.Smith I, Robertson J, Kilburn L, et al. Long-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women with hormone-sensitive early breast cancer (POETIC): an open-label, multicentre, parallel-group, randomised, phase 3 trial. Lancet Oncol. 2020;21(11):1443-1454. PubMed

61.Andre F, Ismaila N, Allison KH, et al. Biomarkers for Adjuvant Endocrine and Chemotherapy in Early-Stage Breast Cancer: ASCO Guideline Update. J Clin Oncol. 2022;40(16):1816-1837. PubMed

62.Nielsen TO, Jensen MB, Burugu S, et al. High-Risk Premenopausal Luminal A Breast Cancer Patients Derive no Benefit from Adjuvant Cyclophosphamide-based Chemotherapy: Results from the DBCG77B Clinical Trial. Clin Cancer Res. 2017;23(4):946-953. PubMed

63.Hofmann D, Nitz U, Gluz O, et al. WSG ADAPT - adjuvant dynamic marker-adjusted personalized therapy trial optimizing risk assessment and therapy response prediction in early breast cancer: study protocol for a prospective, multi-center, controlled, non-blinded, randomized, investigator initiated phase II/III trial. Trials. 2013;14:261. PubMed

64.Mengel M, von Wasielewski R, Wiese B, Rudiger T, Muller-Hermelink HK, Kreipe H. Inter-laboratory and inter-observer reproducibility of immunohistochemical assessment of the Ki-67 labelling index in a large multi-centre trial. J Pathol. 2002;198(3):292-299. PubMed

65.Davey MG, Hynes SO, Kerin MJ, Miller N, Lowery AJ. Ki-67 as a Prognostic Biomarker in Invasive Breast Cancer. Cancers (Basel). 2021;13(17):4455. PubMed

66.Owens R, Gilmore E, Bingham V, et al. Comparison of different anti-Ki67 antibody clones and hot-spot sizes for assessing proliferative index and grading in pancreatic neuroendocrine tumours using manual and image analysis. Histopathology. 2020;77(4):646-658. PubMed

67.Parry S, Dowsett M, Dodson A. UK NEQAS ICC & ISH Ki-67 Data Reveal Differences in Performance of Primary Antibody Clones. Appl Immunohistochem Mol Morphol. 2021;29(2):86-94. PubMed

68.Polewski MD, Nielsen GB, Gu Y, et al. A Standardized Investigational Ki-67 Immunohistochemistry Assay Used to Assess High-Risk Early Breast Cancer Patients in the monarchE Phase 3 Clinical Study Identifies a Population With Greater Risk of Disease Recurrence When Treated With Endocrine Therapy Alone. Appl Immunohistochem Mol Morphol. 2022;30(4):237-245. PubMed

69.Coates AS, Winer EP, Goldhirsch A, et al. Tailoring therapies--improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015. Ann Oncol. 2015;26(8):1533-1546. PubMed

70.Leung SCY, Nielsen TO, Zabaglo LA, et al. Analytical validation of a standardised scoring protocol for Ki67 immunohistochemistry on breast cancer excision whole sections: an international multicentre collaboration. Histopathology. 2019;75(2):225-235. PubMed

71.Boyaci C, Sun W, Robertson S, Acs B, Hartman J. Independent Clinical Validation of the Automated Ki67 Scoring Guideline from the International Ki67 in Breast Cancer Working Group. Biomolecules. 2021;11(11):30. PubMed

72.Acs B, Pelekanou V, Bai Y, et al. Ki67 reproducibility using digital image analysis: an inter-platform and inter-operator study. Lab Invest. 2019;99(1):107-117. PubMed

73.Giordano SH, Freedman RA, Somerfield MR, Optimal Adjuvant Chemotherapy and Targeted Therapy Guideline Expert Panel. Abemaciclib With Endocrine Therapy in the Treatment of High-Risk Early Breast Cancer: ASCO Optimal Adjuvant Chemotherapy and Targeted Therapy Guideline Rapid Recommendation Update. J Clin Oncol. 2022;40(3):307-309. PubMed

74.NCCN Guidelines. Breast Cancer, version 2.2022. Plymouth Meeting (PA): National Comprehensive Cancer Network (NCCN); 2021: https://www.nccn.org/. Accessed 2022 Apr 11.

Appendix 1: Literature Search Strategy

Note this appendix has not been copy-edited.

Clinical Literature Search

Overview

Interface: Ovid

Databases

• MEDLINE All (1946 to present)

• Embase (1974 to present)

• Note: Subject headings and search fields have been customized for each database. Duplicates between databases were removed in Ovid.

Date of search: August 30, 2021

Alerts: Biweekly search updates until project completion

Search filters applied: No filters were applied to limit the retrieval by study type.

Limits:

• Publication date limit: none

• Language limit: none

• Conference abstracts: excluded

Table 25: Syntax Guide

Multi-Database Strategy

1. exp breast neoplasms/

2. ((breast* or mamma or mammar* or lobular*) adj5 (cancer* or carcinoid* or carcinoma* or carcinogen* or adenocarcinoma* or adeno-carcinoma* or malignan* or neoplas* or sarcoma* or tumo?r* or mass*)).ti,ab,kf.

3. or/1-2

4. network meta-analysis/

5. (meta-analysis/ or meta-analysis as topic/ or "meta analysis (topic)"/) and network.ti,ab,kf.

6. ((indirect or indirect treatment or mixed treatment or bayesian) adj3 comparison*).ti,ab,kf.

7. (network* adj3 (meta-analy* or metaanaly*)).ti,ab,kf.

8. (multi* adj3 treatment adj3 comparison*).ti,ab,kf.

9. (mixed adj3 treatment adj3 (meta-analy* or metaanaly*)).ti,ab,kf.

10. umbrella review*.ti,ab,kf.

11. nma.ti,ab,kf.

12. (Multi* adj2 paramet* adj2 evidence adj2 synthesis).ti,ab,kf.

13. (Multiparamet* adj2 evidence adj2 synthesis).ti,ab,kf.

14. (multi-paramet* adj2 evidence adj2 synthesis).ti,ab,kf.

15. MPES.ti,ab,kf.

16. or/4-15

17. 3 and 16

Clinical Trials Registries

ClinicalTrials.gov

Produced by the US National Library of Medicine. Targeted search used to capture registered clinical trials.

[Search – Studies with results | Verzenio OR Verzenios OR abemaciclib OR bemaciclib OR ABE OR LY-2835219 OR LY2835219 OR LY-2385219 OR LY2385219 OR LY-2835210 OR LY2835210 OR 60UAB198HK | Breast Cancer]

WHO ICTRP

International Clinical Trials Registry Platform, produced by the World Health Organization. Targeted search used to capture registered clinical trials.

[Search terms – (Verzenio OR Verzenios OR abemaciclib OR bemaciclib OR ABE OR LY-2835219 OR LY2835219 OR LY-2385219 OR LY2385219 OR LY-2835210 OR LY2835210 OR 60UAB198HK) AND breast cancer]

Health Canada’s Clinical Trials Database

Produced by Health Canada. Targeted search used to capture registered clinical trials.

[Search terms – abemaciclib]

EU Clinical Trials Register

European Union Clinical Trials Register, produced by the European Union. Targeted search used to capture registered clinical trials.

[Search terms – (Verzenio OR abemaciclib) AND breast cancer]

Grey Literature

Search dates: April 8, 2022, to April 21, 2022

Keywords: [Verzenio OR abemaciclib OR breast cancer]

Limits: Publication years: 1996–present

Updated: Search updated prior to the meeting of the CADTH pan-Canadian Oncology Drug Review Expert Committee (pERC)

Relevant websites from the following sections of the CADTH grey literature checklist Grey Matters: A Practical Tool for Searching Health-Related Grey Literature were searched:

• Health Technology Assessment Agencies

• Health Economics

• Clinical Practice Guidelines

• Drug and Device Regulatory Approvals

• Advisories and Warnings

• Drug Class Reviews

• Clinical Trials Registries

• Databases (free)

• Internet Search

Appendix 2: Detailed Outcome Data

Note this appendix has not been copy-edited.

Table 26: Invasive Disease–Free Survival, Final Analysis — Intention-to-Treat Population

CI = confidence interval; ET = endocrine therapy; IDFS = invasive disease–free survival; ITT = intention to treat.

Note: Data cut-off date: July 8, 2020.

^aRestriction time is defined by the latest time where the standard error of the survival estimates is ≤ 0.075.

^bTreatment Effect/Difference/P values are computed based on comparator ET.

^c2-sided P value based on normal approximation.

^dStratified by IWRS Geographical Region, IWRS Prior Treatment, IWRS Menopausal Status.

^eEstimated using a Cox proportional hazards model.

^f95% CIs and 2-sided P values for the difference between rates were calculated based on normal approximation.

Source: Clinical Study Report for Verzenio (final IDFS [primary outcome] analysis).¹⁵

Table 27: Invasive Disease–Free Survival, Final Analysis — Ki-67 High Population

CI = confidence interval; ET = endocrine therapy; IDFS = invasive disease–free survival; ITT = intention to treat.

Note: Data cut-off date: July 8, 2020.

^aRestriction time is defined by the latest time where the standard error of the survival estimates is ≤ 0.075.

^bTreatment effect, difference, and P values are computed based on comparator ET.

^c2-sided P value based on normal approximation.

^dStratified by geographical region, prior treatment, and menopausal Status.

^eEstimated using a Cox proportional hazards model.

^f95% CIs and 2-sided P values for the difference between rates were calculated based on normal approximation.

Source: Clinical Study Report for Verzenio (final IDFS [primary outcome] analysis).¹⁵

Table 28: Invasive Disease–Free Survival by Subgroup — Intention-to-Treat Population

CI = confidence interval; ECOG PS = Eastern Cooperative Oncology Group Performance Status; ET = endocrine therapy, IDFS = invasive disease–free survival.

Note: Data cut-off date: July 8, 2020.

Source: Clinical Study Report for Verzenio (final IDFS [primary outcome] analysis).¹⁵

Table 29: Overall Survival — Intention-to-Treat Population