Reimbursement Review

Ribociclib (Kisqali)

Sponsor: Novartis Pharmaceuticals Canada Inc.

Therapeutic area: Adjuvant treatment of hormone receptor–positive, HER2-negative early breast cancer

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Abbreviations

Executive Summary

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

Table 1: Background Information of Application Submitted for Review

HR = hormone receptor; NOC = Notice of Compliance.

Note: The sponsor’s application was filed on a pre-NOC basis. This review was conducted before the confirmation of the Health Canada indication.

Introduction

Breast cancer is the most commonly diagnosed cancer in females and the second leading cause of cancer-related death among females in Canada.¹ In 2022, the 5-year prevalence of breast cancer in females and males was 138,072 in Canada.² Although breast cancer primarily affects women, it can also occur in men.³ In 2024, an estimated 30,500 new cases were projected in females and 290 in males in Canada.¹ The age-standardized mortality rate for breast cancer is 11.8 per 100,000 for both females and males, and 21.8 per 100,000 in females.¹

The most common subtype of breast cancer is hormone receptor (HR)-positive, HER2-negative disease, which accounts for 73% of all breast cancer cases.⁴ Early breast cancer (EBC) refers to cancer that has not spread outside the breast to other parts of the body.⁵

The majority of breast cancer cases are diagnosed in the early stage; stages I to III (nonmetastatic) account for 94% of all new breast cancer diagnoses in Canada.⁶ Generally, breast cancer does not induce symptoms in the early stage and regular mammograms are crucial for the early diagnosis of breast cancer.^7-10 Among symptomatic cases, a painless mass in the breast is the most common sign.^7-10 Other early signs and symptoms of breast cancer may include changes in nipple shape, breast or nipple pain, new breast lumps, nipple retraction, skin changes (such as redness, dryness, flaking, or thickening), nipple discharge, or swelling around the collarbone or under the arm.^7-10 In contrast to advanced or metastatic breast cancer, EBC is potentially curable.¹¹ However, recurrence can occur after the initial treatment, including in cases diagnosed at an early stage.¹²

Curative-intent therapy in EBC aims to prevent recurrence and improve long-term survival. According to the clinical experts consulted for this review, curative-intent treatment options for patients diagnosed with HR-positive, HER2-negative EBC include surgery, which may be preceded or followed by systemic therapy, such as chemotherapy and/or endocrine therapy (ET), depending on other pathological features and genomic testing results. Based on the type of surgery and pathology, radiation therapy may also be offered, typically in the adjuvant setting.

The clinical experts consulted for this review noted that for patients with HR-positive, HER2-negative stage III EBC, systemic therapy includes chemotherapy, ET, and abemaciclib (patients eligible are those whose disease is node-positive and at high risk of recurrence based on clinicopathological features). For patients with stage II EBC, systemic therapy may or may not include chemotherapy, depending on other pathological features and genomic testing results (e.g., Oncotype DX). However, ET is routinely offered in treating patients with stage II EBC. Additionally, the adjuvant use of olaparib is reserved for patients with a (suspected) deleterious germline breast cancer gene mutation.¹³

On June 12, 2025, ribociclib was granted a Notice of Compliance by Health Canada. Ribociclib is indicated in combination with an aromatase inhibitor (AI) for the adjuvant treatment of adult patients with HR-positive, HER2-negative stage II to III EBC at high risk of recurrence. In premenopausal or perimenopausal women, or men, the AI should be combined with a luteinizing hormone–releasing hormone (LHRH) agonist.¹⁴

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of ribociclib, 200 mg, oral tablets in the adjuvant treatment of HR-positive, HER2-negative stage II and III EBC in adults.

Ribociclib has previously been reviewed by Canada’s Drug Agency (CDA-AMC) for breast cancer in the advanced or metastatic settings.

Perspectives of Patients, Clinicians, and Drug Programs

The information in this section is a summary of input provided by the patient and clinician groups who responded to our call for input and from the clinical experts consulted by CDA-AMC for the purpose of this review. The full patient and clinician group submissions received are available in the consolidated patient and clinician group input document for this review on the project website.

Patient Input

CDA-AMC received 4 patient group submissions, 1 each from the Canadian Breast Cancer Network (CBCN), Rethink Breast Cancer, and Quebec Breast Cancer Foundation (QCBF), and a joint submission from Breast Cancer Canada (BCC) and the McPeak-Sirois Group for Clinical Research in Breast Cancer. CBCN is a national health charity dedicated to ensuring the best quality of care for individuals with breast cancer in Canada through information, education, and advocacy. Rethink educates, empowers, and advocates for system changes to improve outcomes for patients with breast cancer, focusing on historically underserved groups. QCBF is committed to defending the interests and well-being of people affected by breast cancer and their loved ones. BCC focuses on saving lives through precision oncology breast cancer research and education, fostering diversity, accelerating research, innovating with technology, promoting patient leadership, and expanding research networks. The McPeak-Sirois Group unites key players in Quebec’s public health sector to make cutting-edge breast cancer research and treatments accessible, supported by breast cancer survivor Susan McPeak and entrepreneur Charles Sirois.

CBCN collected input through online surveys in 2017 (N = 216) and 2022 (N = 981), including 17 patients in 2017 and 111 patients in 2022 with stage II or III HR-positive, HER2-negative breast cancer and through key informant interviews with 2 patients with metastatic breast cancer, and from a review of current studies and grey literature. Rethink gathered input from 24 key patient advisors, 50 blog contributors, 500 virtual support group participants, 2,200 members of private peer support networks , and 43,000 Instagram followers, along with in-depth telephone interviews with 4 patients experienced with ribociclib for high-risk HR-positive, HER2-negative EBC. The QCBF gathered input from members of its private Facebook group “Club stade 4” (French name) and a peer support helpline member, who has been taking the drug for almost 5 years, while also conducting literature research and social media reviews. From November 14 to 18, 2024, BCC and McPeak-Sirois Group surveyed 188 breast cancer survivors from their communities using validated patient-reported outcome measures to capture the lived experiences of individuals with EBC.

Patients across all groups indicated that HR-positive, HER2-negative EBC has significantly impacted their lives, causing emotional, physical, and financial strain. Rethink highlights that younger patients face additional challenges, such as fertility issues and childcare and career disruptions. Despite these difficulties, patients across all groups are motivated to undergo therapy to reduce recurrence, and strive to maintain normal activities and manage disease-related symptoms.

Patients across all groups prioritize effective treatments with manageable side effects, emphasizing quality of life and personal choice. Financial burdens and long-term impacts of treatment are significant concerns, with unique challenges such as the need for personalized treatment decisions (Rethink), managing daily symptoms and potential insurance loss (QCBF), and the necessity for effective adverse event (AE) management support (BCC and McPeak-Sirois Group).

Overall, patients prioritize treatment efficacy, reducing the risk of recurrence, manageable side effects, and maintaining a good quality of life, with many willing to endure additional side effects for better outcomes. According to Rethink, younger patients emphasize the importance of long-term remission to continue their personal and professional lives. QCBF highlighted concerns about long-term medication effects and the significant impact of side effects on daily life.

In the inputs from BCC and McPeak-Sirois Group and Rethink, there were 8 and 4 patients with EBC, respectively, who had experience with ribociclib. In the inputs from CBCN and QBCF, 2 patients and 1 patient, respectively, had experience with ribociclib in the metastatic setting. Across the 4 groups, patients consistently reported positive experiences with ribociclib, emphasizing its efficacy in controlling cancer and the manageable nature of its side effects (e.g., neutropenia, nausea, liver issues, fatigue, dry eyes). They valued the treatment for providing reassurance, hope, and a sense of control over their cancer.

Clinician Input

Input From the Clinical Experts Consulted for This Review

The clinical experts consulted by CDA-AMC emphasized the significant unmet needs in treating stage II and III HR-positive, HER2-negative breast cancer, noting the high rates of recurrence despite aggressive treatments, and indicated that the goal of treatment is to eliminate the disease and reduce the risk of recurrence, minimize side effects and impact on quality of life, maintain employment and independence, and reduce caregiver burden and health care system strain.

For patients with HR-positive, HER2-negative EBC, the clinical experts indicated that ribociclib would be added to existing ET when it is deemed appropriate. Both clinical experts indicated that patients with high risk of recurrence (based on genomic testing, such as Oncotype DX and MammaPrint) are those most in need of new treatments. Currently, there is no evidence or specific biomarkers to predict response, but 1 clinical expert mentioned that patients with poor prognostic features, such as positive lymph nodes, large tumours, and high recurrence scores, are most likely to respond and benefit from ribociclib when added to ET. However, ribociclib is not suitable for patients with severe liver dysfunction, individuals who are pregnant or breastfeeding, or those with a history of QT prolongation or severe neutropenia.

Both clinical experts indicated that for patients with stage II and III HR-positive, HER2-negative EBC, preventing recurrence (measured by recurrence-free survival [RFS]) is considered a clinically meaningful outcome to measure the response to treatment. Other meaningful outcomes to measure responses include improved overall survival (OS), quality of life, and toxicity. The clinical experts indicated that routine surveillance visits are typically conducted every 3 to 6 months during the first 2 to 3 years after treatment, depending on the initial extent of disease, with clinical examinations and/or imaging conducted regularly to check for recurrence, especially for disease that is at high risk of recurrence (e.g., node-positive, large tumours). The clinical experts noted that with ribociclib treatment, frequent toxicity assessments are also required in addition to routine surveillance with frequent bloodwork and electrocardiograms (i.e., every 2 weeks), and increased physician appointments, compared to ET alone. The clinical experts indicated that disease recurrence during ribociclib therapy and severe, unmanageable side effects (e.g., myelosuppression, liver toxicity, QT prolongation, and pulmonary toxicity) necessitate stopping treatment with ribociclib. Additionally, 1 clinical expert mentioned that factors influencing the continuation of therapy include significant impact on quality of life, overall health, and patient preferences. The clinical experts indicated that ribociclib should be prescribed and monitored in a hospital outpatient or community oncology practice, with a medical oncologist or breast oncologist involved in patient care.

Clinician Group Input

Clinician group input for this review was received from 2 clinician groups: the Research Excellence, Active Leadership (REAL) Canadian Breast Cancer Alliance and the Ontario Health (Cancer Care Ontario) (OH [CCO]) Breast Cancer Drug Advisory Committee. A total of 19 clinicians provided input for this submission: 11 clinicians from REAL Canadian Breast Cancer Alliance plus 3 clinicians who agree with the REAL Canadian Breast Cancer Alliance clinician input and are in support of the submission, and 5 clinicians from the OH (CCO) Breast Cancer Drug Advisory Committee.

The input from the clinician groups aligned with that of the clinical experts consulted for this review with regard to treatment goals, the unmet needs of this patient population, assessing treatment response, the drug’s place in therapy, deciding when to discontinue treatment, which specialists should manage these patients, and where patients should be treated with ribociclib. Clinicians from the OH (CCO) Breast Cancer Drug Advisory Committee noted that the duration of treatment with ribociclib is 3 years, which may increase the need for clinical monitoring for patients (e.g., blood work and clinic visits) compared to abemaciclib, which is administered for 2 years.

Drug Program Input

Input was obtained from the drug programs that participate in the reimbursement review process. The following were identified as key factors that could potentially affect the implementation of a recommendation for ribociclib: consideration for initiation of therapy, considerations for discontinuation of therapy, and generalizability. The clinical experts consulted for the purpose of this review provided advice on the potential implementation issues raised by the drug programs. Refer to Table 4 for more details.

Clinical Evidence

Systematic Review

Description of Studies

One phase III, open-label, active-controlled randomized controlled trial (RCT) (NATALEE; N = 5,101) was included that evaluated the efficacy and safety of ribociclib plus AI compared to AI alone as an adjuvant treatment in premenopausal and postmenopausal women, and men, with HR-positive, HER2-negative stage II and III EBC. The primary end point was invasive disease–free survival (iDFS) assessed by the investigator using the Standardized Definitions for Efficacy End Points criteria. Secondary end points included RFS, distant disease–free survival (DDFS), OS, health-related quality of life (HRQoL), and safety. Patients were randomized 1:1 to receive either ribociclib plus AI (n = 2,549) or AI alone (n = 2,552). Randomization was stratified by menopausal status (premenopausal versus postmenopausal, with men grouped in the premenopausal category), anatomical stage (II versus III), prior adjuvant or neoadjuvant chemotherapy (yes versus no), and geographical region (North America, Western Europe, and Oceania versus rest of the world). Eligible patients were recruited in 393 centres in 20 countries. The study enrolled 171 patients across 23 sites in Canada.

Demographic and baseline characteristics were well balanced between treatment groups. The median age of all patients was 52.0 years, with ages ranging from 24 to 90 years. Most patients were postmenopausal (55.8%) and female (99.6%). The majority of the patients were white (73.4%), but the trial also included patients who self-reported as American Indian or Alaska Native, Asian, Black or African American, and Native Hawaiian or other Pacific Islander. Most patients had an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 (83.1). More than half (59.6%) of patients had disease that was American Joint Committee on Cancer (AJCC) stage III, nearly half of patients (41.2%) had 1 to 3 positive axillary lymph nodes (ALNs), and most patients (88.1%) had received prior adjuvant or neoadjuvant chemotherapy. There were 676 patients (13.3%) who had genomic tests; Oncotype DX was the most reported test (249; 4.9% of all patients).

Efficacy Results

Three analysis time points are described in this report. The NATALEE trial met its primary end point (iDFS) at interim analysis 3 (IA3) (data cut-off date: January 11, 2023). At IA3, the median duration of follow-up was 27.7 months (range, 0 to 45 months). At the time of end of ribociclib analysis (data cut-off date: April 29, 2024), the median duration of follow-up was 44.2 months (range, 0 to 63 months). At the time of the 5-year follow-up analysis (data cut-off date: May 28, 2025), the median duration of follow-up was 55.4 months. Results for iDFS were reported at IA3, the end of ribociclib analysis, and the 5-year follow-up analysis. No formal statistical analysis of secondary outcomes was planned at any time point; only the results for the end of ribociclib analysis and the 5-year follow-up analysis are summarized in detail for RFS, DDFS, and OS. Because no results were available at the end of ribociclib analysis, only the results for HRQoL at IA3 are presented for this outcome.

Invasive Disease–Free Survival

At IA3, 189 patients (7.4%) in the ribociclib plus AI group and 237 patients (9.3%) in the AI alone group experienced an iDFS event. Distant recurrence (4.7% versus 6.7%) was the most commonly reported iDFS event for both groups. Though the median iDFS was not estimable for either treatment group, there was a statistically significant improvement in iDFS in the ribociclib plus AI group compared with the AI alone group (hazard ratio = 0.75; 95% confidence interval [CI], 0.62 to 0.91; P = 0.0014). The Kaplan-Meier probability estimate of iDFS at 36 months was 90.4% (95% CI, 88.6% to 91.9%) for the ribociclib plus AI group, and 87.1% (95% CI, 85.3% to 88.8%) for the AI alone group. The between-group difference was 3.3% (95% CI, 0.9% to 5.7%). The iDFS results were consistent across all prespecified and additional sensitivity analyses and subgroups.

At the end of ribociclib analysis, a total of 263 patients (10.3%) in the ribociclib plus AI group and 340 patients (13.3%) in the AI alone group experienced an iDFS event. Distant recurrence (6.9% versus 9.6%) was the most reported iDFS event for both groups. The median iDFS was not estimable at the end of ribociclib analysis for either treatment group. The hazard ratio for the ribociclib plus AI group versus the AI alone group was 0.72 (95% CI, 0.61 to 0.84; nominal P < 0.0001), in favour of ribociclib plus AI. The Kaplan-Meier probability estimate of iDFS at 36 months for both groups was consistent with IA3. At 48 months, the Kaplan-Meier probability estimate of iDFS was 88.5% (95% CI, 87.1% to 89.8%) for the ribociclib plus AI group, and 83.6% (95% CI, 81.8% to 85.2%) for the AI alone group, resulting in a between-group difference of 4.9% (95% CI, 2.7% to 7.1%).

At the 5-year follow-up analysis, the hazard ratio for the ribociclib plus AI group versus the AI alone group was 0.72 (95% CI, 0.62 to 0.83). At 60 months, the Kaplan-Meier probability estimate of iDFS was 85.5% (95% CI, 83.9% to 87.0%) for the ribociclib plus AI group, and 81.0% (95% CI, 79.2% to 82.7%) for the AI alone group, resulting in a between-group difference of 4.5% (95% CI, 2.1% to 6.9%).

The subgroup and sensitivity analyses of iDFS at IA3 and the end of ribociclib analysis time points were generally consistent with the primary analysis across all prespecified subgroups.

Recurrence-Free Survival

At the end of ribociclib analysis, a total of 224 patients (8.8%) in the ribociclib plus AI group and 298 patients (11.7%) in the AI alone group experienced an RFS event. The median RFS was not estimable for either treatment group, although the treatment benefit in RFS favoured ribociclib plus AI (hazard ratio = 0.70; 95% CI, 0.58 to 0.83; nominal P < 0.0001). ███ ████████████ ███████████ ████████ ██ ███ ██ ██ ██████ ███ █████ ████ ███ █████ ██ ██████ ███ ███ ██████████ ████ ██ ██████ ███ ████ █ ████ ███ █████ ██ ██████ ███ ███ ██ ██████ ███ ████ █████ ████████ ██ ████ ███ ███████ ███████ ████ ████████ ██ ███ ██████ █████████ █████████.

Distant Disease–Free Survival

At the end of ribociclib analysis, a total of 240 patients (9.4%) in the ribociclib plus AI group and 311 patients (12.2%) in the AI alone group experienced a DDFS event. The median DDFS was not estimable for either treatment group, though the treatment benefit in DDFS favoured ribociclib plus AI compared with AI alone (hazard ratio = 0.72; 95% CI, 0.60 to 0.85; nominal P < 0.0001). ███ ████████████ ███████████ ████████ ██ ████ ██ ██ ██████ ███ █████ ████ ███ █████ ██ ██████ The between-group difference was 4.5% ████ ███ █. These results were consistent with those observed at IA3 and similar results were observed at the 5-year follow-up analysis.

Overall Survival

At the end of ribociclib analysis, a total of 105 patients (4.1%) in the ribociclib plus AI group and 121 patients (4.7%) in the AI alone group had died. The median OS was not estimable for either treatment group. There was no difference in the risk of death between ribociclib plus AI compared with AI alone (hazard ratio = 0.83; 95% CI, 0.64 to 1.07; nominal P = 0.0766). ███ ████████████ ███████████ ████████ ██ ██ ██ ██ ██████ ███ █████ ████ ███ █████ ██ ██████ ███ ███ ██████████ ███████ █████ ██ ████. These results were consistent with those observed at IA3 and similar results were observed at the 5-year follow-up analysis.

Health-Related Quality of Life

At IA3, the mean global health status and quality of life subscale score of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) was 73.7 points (standard deviation [SD] = 17.7 points) in the ribociclib plus AI group (N = 462; 18.1%), and 73.8 points (SD = 17.8 points) in the AI alone group (N = 497; 19.5%). At end of treatment as of IA3, patients in the ribociclib plus AI group reported a least squares mean decrease (deterioration) from baseline in the global health status and quality of life subscale score of the EORTC QLQ-C30 of –10.40 points (standard error [SE] = 1.36 points) compared to –10.04 points (SE = 1.29 points) in patients in the AI alone group. The between-group difference was –0.36 points (95% CI, –3.12 to 2.39 points; nominal P = 0.7957).

Harms Results

At the time of the end of ribociclib analysis, 2,478 patients (98.1%) in the ribociclib plus AI group and 2,155 patients (88.3%) in the AI alone group experienced at least 1 treatment-emergent adverse event (TEAE). The most common TEAEs, occurring in more than 25% of patients, were neutropenia (41.7% versus 2.9% for ribociclib plus AI versus AI alone), and arthralgia (38.8% versus 44.4%). Grade 3 or higher AEs were reported more frequently in the ribociclib plus AI group than in the AI alone group (64.2% versus 19.7%), with grade 3 or higher neutropenia (27.0% versus 0.5%) and decreased neutrophil count (17.7% versus 0.3%) being the most frequently reported.

Serious adverse events (SAEs) were reported among 14.8% of patients in the ribociclib plus AI group and 10.9% of patients in the AI alone group, with COVID-19 (0.8% versus 0.5%) being the most reported SAE.

A total of 21.1% of patients in the ribociclib plus AI group and 5.3% of patients in the AI alone group had TEAEs leading to discontinuation of study treatment. The most common TEAEs that caused treatment discontinuation were increased ALT (7.2% versus 0.1%) and increased AST (2.9% versus 0).

There were 104 patients (4.1%) in the ribociclib plus AI group and 122 patients (5.0%) in the AI alone group who died before the end of follow-up at the end of ribociclib analysis. Overall, the leading reported cause of death was disease recurrence or progression (3.0% versus 4.1%). AEs were reported as the primary cause of death for 16 patients (0.6%) in the ribociclib plus AI group and 6 patients (0.2%) in the AI alone group. At the 5-year follow-up analysis, 137 patients (5.4%) in the ribociclib plus AI group and 163 patients (6.7%) in the AI alone group had died, primarily due to disease recurrence (101 patients; 4.0%) or progression (133 patients; 5.4%). There were 19 patients (0.8%) and 8 patients (0.3%) in the NATALEE trial who had fatal AEs in the ribociclib plus AI group and AI group, respectively.

The clinical experts consulted by CDA-AMC identified the following notable harms that were reported more frequently in the ribociclib plus AI group than in the AI alone group: hepatobiliary toxicity (26.7% versus 11.4%), QT interval prolongation (5.4% versus 1.6%), and pulmonary toxicity (interstitial lung disease or pneumonitis) (1.6% versus 0.9%).

Critical Appraisal

The Health Canada–approved indication for ribociclib is for patients with HR-positive, HER2-negative EBC at high risk of recurrence. However, the eligibility criteria for the NATALEE trial population were based on disease stage and included a heterogenous population of patients with varying degrees of risk. There was no definition of high risk provided in the trial, nor were there any prespecified subgroup analyses specifically for high-risk patients in the NATALEE trial. As such, it was unclear what proportion of patients in the NATALEE trial were at high risk of recurrence.

The choice of AI as the comparator in the NATALEE trial was clinically relevant because it is reflective of clinical practice in Canada for the treatment of patients with HR-positive and HER2-negative EBC, according to the clinical experts. The NATALEE trial was open label, which may introduce performance and detection bias, particularly for subjective, self-reported outcomes. Additionally, fewer patients discontinued the study in the ribociclib plus AI group compared to the AI alone group at both the end of ribociclib analysis (17.7% versus 22.1%) and the 5-year follow-up (21.5% versus 26.0%).

The median follow-up was 44.2 months at the end of ribociclib analysis, which was considered reasonable by the clinical experts, but longer follow-up is needed for the accurate assessment of treatment effect because recurrence can occur beyond 10 years. The analysis of iDFS was predominately influenced by the initial treatment response, which is represented by an event rate of 10.3% and 13.3% in the ribociclib plus AI group compared to the AI alone group, respectively, at the end of ribociclib analysis, and 12.4% and 16.0%, respectively, at the 5-year follow-up analysis. Though more events had occurred at the 5-year follow-up analysis and the proportion of patients who were censored was generally balanced between treatment groups at previous data cut-off dates, there was still a substantial amount of censoring, with rapid drops in the number of patients at risk, which may introduce uncertainties in the estimates of the treatment effects of ribociclib plus an AI on iDFS, RFS, DDFS, and OS at 36, 48, and 60 months. Additionally, the treatment effect observed over 5 years does not permit definitive conclusions about the long-term effectiveness of ribociclib plus an AI.

Relevant outcomes of RFS, DDFS, OS, and HRQoL were not adjusted for multiple testing, limiting the ability to draw definitive conclusions. There was a high attrition rate in the analysis of HRQoL, which may be due to the limited number of patients who had reached the end-of-treatment stage; there were only █████ patients contributing to the analysis, potentially introducing bias due to differing characteristics between those who continued the trial and those who withdrew. No sensitivity analyses were conducted to evaluate missing data or attrition.

According to the clinical experts consulted for this review, the NATALEE trial’s eligibility criteria were standard, but stricter than clinical practice, excluding patients with significant comorbidities or poorer performance status. However, the clinical experts noted that they would consider patients with an ECOG Performance Status of 2 to be potential candidates for ribociclib based on the extensive experience with ribociclib in the metastatic setting. Most patients in the NATALEE trial were white (73.4%), and 55.9% were postmenopausal. The clinical expert indicated there is a more diversified patient population in their clinical practice compared to the patient population in the NATALEE trial, and that there would be a higher proportion of postmenopausal patients aged 60 to 70 years in their clinical practice who are candidates for ribociclib than were enrolled in the NATALEE trial. Within the NATALEE trial, patients with high genomic risk for the purposes of staging were identified by genomic testing using Oncotype DX. The clinical experts noted that genomic risk testing (e.g., Oncotype DX) is used to determine eligibility for chemotherapy rather than ribociclib, and thus the use of genomic testing in the NATALEE trial may not reflect current clinical practice. More than 88% of patients in the NATALEE trial received prior chemotherapy. The clinical experts noted that most patients with no nodal involvement would have been tested for genomic risk; thus, fewer patients in clinical practice would receive chemotherapy compared to the NATALEE trial. This suggests that the study results may not be generalizable due to differences in pretreatment. More than half of the patients in the NATALEE trial (62.8%) completed the 3-year treatment duration of ribociclib at the time of the end of ribociclib analysis, and no patients were receiving ribociclib treatment at the end of the 5-year follow-up. The clinical experts commented that adherence to treatment is a challenge in the adjuvant setting due to the longer disease-free intervals. The clinical experts noted that patients in the NATALEE trial were predominantly younger women with more aggressive disease, who may be less willing to endure the side effects (e.g., nausea and fatigue) of ribociclib for the full 3 years.

GRADE Summary of Findings and Certainty of the Evidence

For the pivotal NATALEE trial identified in the sponsor’s systematic review, Grading of Recommendations, Assessment, Development and Evaluation (GRADE) was used to assess the certainty of the evidence for outcomes considered most relevant to inform expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group.^15,16 Following the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null. The reference points for the certainty of evidence assessment for iDFS, RFS, DDFS, OS, HRQoL, and harms were set according to the presence of an important effect based on thresholds agreed upon by the clinical experts consulted for this review.

The selection of outcomes for GRADE assessment was based on the sponsor’s Summary of Clinical Evidence, consultation with clinical experts, and input received from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members:

• clinical outcomes (iDFS, RFS, DDFS, and OS)

• HRQoL

• safety.

Table 2: Summary of Findings for Ribociclib Plus AI vs. AI Alone for Patients With Early Breast Cancer

AI = aromatase inhibitor; CI = confidence interval; DDFS = distant disease–free survival; EBC = early breast cancer; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; GHS = global health status; iDFS = invasive disease–free survival; MID = minimal important difference; NA = not applicable; NR = not reported; OS = overall survival; QoL = quality of life; RCT = randomized controlled trial; RFS = recurrence-free survival; vs. versus.

Note: Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

The statistical testing for probabilities of iDFS, RFS, DDFS, and OS at 48 months and the change from baseline in GHS and QoL subscale score of the EORTC QLQ-C30 at the end of treatment were not adjusted for multiplicity in the NATALEE trial and should be considered as supportive evidence.

^aRated down 1 level for serious imprecision. There is no established between-group MID for iDFS, RFS, and DDFS at 36, 48, or 60 months, but the clinical experts suggested that a 5% difference between groups in the probabilities of iDFS, RFS, and DDFS could be considered a threshold of minimal clinical importance. In the review of abemaciclib for a similar population, a between-group difference in the probabilities of iDFS used a threshold range of 3% to 5%. As such, this review adopts the threshold range of 3% to 5% for consistency. Supposing the threshold was 5%, the point estimate and the lower bound of the 95% CI for the between-group difference suggested no minimal clinically important difference between the 2 groups, while the upper bound of the 95% CI suggested a clinically important difference for ribociclib plus AI vs. AI alone based on this threshold. Supposing the threshold was 3%, the point estimate would exceed the threshold of clinical meaningfulness at 36, 48, and 60 months; however, because the 95% CI would continue to suggest both the possibility of no benefit and the possibility of benefit and would be rated down 1 level for serious imprecision, the certainty of evidence would remain “moderate.” However, at 3%, the majority of the effect lies higher than the threshold, which would result in greater confidence that the result is higher than the MID.

^bThe absolute difference in Kaplan-Meier probability estimates of iDFS between study groups at 36 months varied notably across different data cut-offs (3.3% at the data cut-off of January 11, 2023, vs. 2.7% at the data cut-off of April 29, 2024). Additionally, the shapes of the iDFS curves differed notably at different data cut-offs.

^cRated down 1 level for serious risk of bias due to the low number of patients at risk. There were significant uncertainties at 48 and 60 months due to the limited number of patients at risk and the rapid depletion of the risk set. Imprecision was not rated down. There is no established between-group MID for OS at 48 and 60 months, but the clinical experts suggested that a 3% difference between groups in the probabilities of being alive could be considered a threshold of clinical importance. At 48 and 60 months, the point estimate and the 95% CI for the between-group difference suggested no clinically important difference between the 2 groups for ribociclib plus AI vs. AI alone based on a 3% threshold.

^dRated down 2 levels for very serious risk of bias due to the large amount of missing data and for performance and detection biases due to the trial’s open-label design. Imprecision was not rated down. There is no established between-group MID for change from baseline in GHS and QoL subscale score of the EORTC QLQ-C30 in patients with EBC, but the clinical experts considered that a 5-point difference between groups in the change from baseline in GHS and QoL subscale score of the EORTC QLQ-C30 could be considered a threshold of clinical importance in patients with EBC. The point estimate and the upper and lower bounds of the 95% CI for the between-group difference suggested no clinically important difference for ribociclib plus AI vs. AI alone based on a 5-point threshold.

^eThe analyses of incidences of hepatobiliary toxicity, QT interval prolongation, and interstitial lung disease or pneumonitis did not account for the participants lost to follow-up or those who dropped out. This omission may introduce a risk of bias, although the direction of this bias is unknown due to the limited data available. Imprecision was not rated down. There is no established between-group MID for the incidence of hepatobiliary toxicity and the incidence of QT interval prolongation, but the clinical experts suggested that a 5% difference in the incidence of hepatobiliary toxicity, a 2% difference in the incidence of QT interval prolongation, and any difference for the incidence of interstitial lung disease or pneumonitis between groups could be considered a threshold of clinical importance. The point estimate and the 95% CI for the between-group difference suggested a clinically important difference between the 2 groups for ribociclib plus AI vs. AI alone based on a 5% threshold for the incidence of hepatobiliary toxicity, 2% threshold for the incidence of QT interval prolongation, and non-null threshold for incidence of interstitial lung disease or pneumonitis.

Sources: NATALEE Clinical Study Reports for the end of ribociclib analysis (2024)¹⁷ interim analysis 3 (2023),¹⁸ and sponsor-provided additional data.^19,20 Details included in the table are from the sponsor’s Summary of Clinical Evidence.²¹

Long-Term Extension Studies

No long-term extension studies were submitted for this review.

Indirect Comparison

Description of Studies

The sponsor conducted an indirect treatment comparison (ITC) using a matching-adjusted indirect comparison (MAIC) to estimate the relative efficacy of ribociclib plus AI compared with abemaciclib plus ET in the adjuvant treatments of patients with HR-positive, HER2-negative EBC whose disease is at high risk of recurrence based on clinicopathological features.

Efficacy Results

After applying the MAIC weights, the estimated iDFS hazard ratio was 0.901 for ribociclib plus AI versus abemaciclib plus ET (95% CI, 0.677 to 1.197; P = 0.4701). ███ █████ ███ █████████ ██████ █████ ███ █████ ████ ███ █████ ██ ████████████████ ███ ███ ███ █████████ ██████ █████ ██ ██████████ ████ ██ ██████. HRQoL was not assessed in the MAIC.

Harms Results

Grade 3 or higher TEAEs (that occurred in ≥ 5% of patients in either group) were assessed in the MAIC. In the weighted comparison, ribociclib plus AI also had significantly increased odds of neutropenia (odds ratio [OR] = 1.56; 95% CI, 1.23 to 1.97) compared with abemaciclib plus ET and increased ALT (OR = 3.94; 95% CI, 2.56 to 6.05). ORs for diarrhea, leukopenia, and lymphopenia were reduced with ribociclib plus AI versus abemaciclib plus ET, with estimated ORs of 0.11 (95% CI, 0.03 to 0.40), 0.27 (95% CI, 0.16 to 0.46), and 0.14 (95% CI, 0.04 to 0.53), respectively.

Critical Appraisal

Overall, the MAICs were conducted according to accepted methodological guidance. A key limitation of the MAICs was heterogeneity across the included studies. In the primary analysis, the MAIC was adjusted for all baseline characteristics identified in published reports of cohort 1 from the monarchE study, but excluded patients from both studies outside of this subcohort (i.e., excluded patients from cohort 2 of the monarchE study, which included patients with 1 to 3 positive ALNs plus a Ki-67 score of 20% or more if tumour size was < 5 cm and disease was not grade 3). The omission of these patients, who are within the Health Canada indication for ribociclib, leads to uncertainty in the generalizability of the efficacy results to the clinical context. Second, a Bucher analysis of iDFS via common comparator was conducted as a second analysis (subgroup analysis) using data reported for a subgroup of patients receiving AI as the ET component of each treatment arm in cohort 1 of the monarchE trial, but excluding patients who received tamoxifen as the endocrine partner. However, this subgroup analysis was not weighted and not adjusted for the prognostic and treatment-effect modifiers. Overall, the results for iDFS, distant relapse–free survival (DRFS), and OS generally suggested no difference between ribociclib plus AI and abemaciclib plus ET in cohort 1 of the monarchE trial, but the generalizability of the results to the Canadian clinical setting is uncertain. A reduced effective sample size (approximately ███ across various analyses), and wide 95% CIs for the comparative effect estimates (hazard ratios) contributed to imprecision and suggested either benefit or harm in efficacy outcomes.

Studies Addressing Gaps in the Evidence From the Systematic Review

No studies addressing gaps in the evidence from the systematic review were submitted for this review.

Conclusions

The patient and clinician input highlighted the need for new effective treatments for EBC that reduce the risk of recurrence with manageable side effects and that maintain quality of life. Evidence from 1 phase III, open-label, active-controlled RCT (NATALEE) comparing the efficacy and safety of ribociclib plus AI with AI alone as adjuvant treatment in patients with HR-positive, HER2-negative stage II or III EBC, demonstrated that when compared to AI alone, the addition of ribociclib to an AI results in statistically significantly prolonged iDFS, although the magnitude of the benefit was not clinically meaningful based on the 5% threshold suggested by the clinical experts. However, using a threshold of 3%, as has been done previously, the results for iDFS at 48 months and 60 months may be considered clinically meaningful because most of the observed effect lies higher than the threshold, though this remained uncertain. Although results for RFS, DDFS, and OS were consistent with the primary outcome, they were secondary and were not controlled for multiplicity; therefore, they were considered only supportive of the overall effect of ribociclib plus AI. Additionally, the differences between treatment groups for RFS, DDFS, and OS are likely not clinically meaningful based on the thresholds suggested by the clinical experts. The results were uncertain for all time-to-event efficacy outcomes because the medians of these end points were not reached in either study group at the time of the end of ribociclib analysis, indicating the data were immature. There was a decrease in overall quality of life for both ribociclib plus AI and AI alone, though there was little to no difference in HRQoL between treatments, and the results were difficult to interpret due to the large amount of missing data, precluding definitive conclusions.

There is extensive experience with ribociclib, having been available to patients in Canada since 2018. In the NATALEE trial, no new safety signals were identified, and the safety profile was considered manageable based on the clinical experts’ experience with the drug in the metastatic setting.

Indirect evidence via 1 sponsor-submitted MAIC comparing ribociclib plus AI to abemaciclib plus ET suggested no difference between the 2 treatment regimens. However, there were limitations in the indirect evidence, specifically, that the population of patients from the NATALEE study was matched to cohort 1 of the monarchE trial and was not representative of the entire population within the scope of this Reimbursement Review. Additionally, considerable reductions in effective sample size resulting in wide 95% CIs undermined the validity and precision of the results, precluding conclusions on the comparative efficacy of ribociclib plus AI.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of ribociclib, 200 mg, oral tablets in the adjuvant treatment of HR-positive, HER2-negative stage II and III EBC in adults.

Disease Background

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following was summarized and validated by the review team.

Breast cancer is the most commonly diagnosed cancer in females and the second leading cause of cancer-related death among females in Canada.¹ In 2022, the 5-year prevalence of breast cancer in females and males was 138,072 in Canada.² Although breast cancer primarily affects women, it can also occur in men.³ In 2024, an estimated 30,500 new cases were projected in females and 290 in males in Canada.¹ The age-standardized mortality rate for breast cancer is 11.8 per 100,000 for females and males, and 21.8 per 100,000 in females.¹ The most common subtype of breast cancer is HR-positive, HER2-negative disease, which accounts for 73% of all breast cancer cases.⁴ Given its prevalence and impact, early detection and diagnosis of breast cancer are critical.²²

The majority of breast cancer cases are diagnosed in the early stage, with stages I to III (nonmetastatic) accounting for 94% of all new breast cancer cases in Canada.⁶ Early breast cancer refers to cancer that has not spread outside the breast to other parts of the body.⁵ Generally, breast cancer does not induce symptoms in the early stage.^7-10 Among symptomatic cases, a painless mass in the breast is the most common sign.^7-10 Only 5% of patients with a malignant mass experience pain in the breast.^7-10 Other early signs and symptoms of breast cancer may include changes in nipple shape, breast or nipple pain, new breast lumps, nipple retraction, skin changes (such as redness, dryness, flaking, thickening), nipple discharge, or swelling around the collarbone or under the arm.^7-10

Breast cancer can recur after the initial treatment, even when diagnosed at an early stage.¹² Despite efforts to eradicate all cancer cells during the initial treatment, some may remain and be undetected.²³ Over time, these residual cells can multiply and lead to a recurrence of the cancer.²³ Recurrence can happen months or even years after the initial treatment,²³ and can be categorized as local (cancer reappearing at the original site), regional (cancer returning in nearby tissues or lymph nodes), or distant (cancer metastasizing and reappearing in a different part of the body).²⁴ Various risk factors of recurrence have been highlighted in the literature, including, but not limited to, nodal status, primary tumour size, young age at diagnosis, tumour grade, Ki-67 status, or genomic signatures.^12,25 Thus, even in patients with the most favourable prognosis, the risk of breast cancer recurrence remains a significant health concern.¹²

Early cancer detection can prevent the use of more aggressive treatments and improve patient outcomes, including survival rates.²² Regular mammograms are crucial for the early diagnosis of breast cancer. While mammography serves as the primary method for breast cancer screening, other screening methods can be used such as breast exam or ultrasound.²² MRI may be used to screen patients at high risk of breast cancer. Following suspicious findings, a core biopsy, which is sometimes accompanied by clip placement, is conducted to confirm diagnosis.²⁶ Subsequently, biomarker testing, including estrogen receptor, progesterone receptor, and HER2, conducted via immunochemistry or fluorescence in situ hybridization on tumour samples, plays a crucial role in directing personalized treatment pathways.^27,28 Clinical staging is determined using imaging and clinical examination findings. Pathological staging postsurgery involves examining the tumour and lymph nodes to further refine treatment strategies and prognostic assessment.²⁹

Standards of Therapy

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following was summarized and validated by the review team.

In contrast to advanced or metastatic breast cancer, EBC is potentially curable.¹¹ Curative-intent therapy in EBC aims to prevent recurrence and improve long-term survival. According to the clinical experts consulted for this review, curative-intent therapy options for patients diagnosed with HR-positive, HER2-negative EBC include surgery, which may be preceded or followed by systemic therapy (i.e., chemotherapy and/or ET, depending on other pathological features and genomic testing results). Based on the type of surgery and pathology, radiation therapy may also be offered, typically in the adjuvant setting. The clinical experts consulted for this review noted that for patients with HR-positive, HER2-negative stage III EBC, systemic therapy includes chemotherapy, ET, and abemaciclib (for eligible patients whose disease is node-positive and at high risk of recurrence based on clinicopathological features). For patients with stage II EBC, systemic therapy may or may not include chemotherapy, depending on other pathological features and genomic testing results (e.g., Oncotype DX). The clinical experts indicated the typical chemotherapy options can include anthracyclines and taxanes (although anthracyclines may be excluded in certain settings), and ET (e.g., AIs such as anastrozole, letrozole, or exemestane, or tamoxifen), which would be offered as the standard of care for all patients with stage II EBC, presuming no contraindications.^30-33 ET is typically prescribed for 5 to 10 years, depending on the risk of recurrence, patients’ preferences, or menopausal status. Ovarian function suppression or ablation is offered concurrently in premenopausal or perimenopausal patients.^30-33 In men with breast cancer, the treatment regimen is similar to that in postmenopausal patients, and the use of androgen suppression with LHRH agonists is the current standard treatment.³³ Additionally, the adjuvant use of olaparib is reserved for patients with (suspected) deleterious germline breast cancer gene mutation.¹³

Drug Under Review

Key characteristics of ribociclib are summarized in Table 3 with other treatments available for the adjuvant treatment of patients with HR-positive, HER2-negative, stage II and III EBC.

Ribociclib is a cyclin-dependent kinase 4 and kinase 6 (CDK4/6) inhibitor that reduces cell cycle progression and proliferation by decreasing retinoblastoma protein phosphorylation, leading to tumour regression and a senescent phenotype in breast cancer models. In vivo, ribociclib treatment resulted in well-tolerated tumour regressions correlated with retinoblastoma protein phosphorylation inhibition.¹⁴ Ribociclib is available in 200 mg oral tablets. The recommended dosage of ribociclib is 400 mg taken orally once daily for 21 consecutive days followed by 7 days off treatment, resulting in a complete cycle of 28 days.¹⁴

On June 12, 2025, ribociclib received a Health Canada Notice of Compliance in combination with an AI for the adjuvant treatment of adult patients with HR-positive, HER2-negative stage II to III EBC at high risk of recurrence. In premenopausal or perimenopausal women, or men, the AI should be combined with an LHRH agonist.¹⁴ In September 2024, the FDA approved ribociclib in combination with an AI for the adjuvant treatment of adults with HR-positive, HER2-negative, stage II and III EBC at high risk of recurrence, including those with no nodal involvement.³⁴ More recently, in November 2024, the European Commission also approved ribociclib in combination with an AI for the adjuvant treatment of patients with HR-positive, HER2-negative EBC at high risk of recurrence.³⁵ The sponsor is seeking reimbursement for ribociclib as per the proposed Health Canada indication.

Ribociclib was previously reviewed by CDA-AMC for breast cancer in the advanced or metastatic settings:

• On June 4, 2020, a recommendation for reimbursement was issued for ribociclib in combination with an AI and an LHRH agonist for the treatment of premenopausal or perimenopausal patients with HR-positive, HER2-negative advanced or metastatic breast cancer as initial endocrine-based therapy.³⁶

• On April 22, 2020, a recommendation for reimbursement was issued for ribociclib in combination with fulvestrant for the treatment of postmenopausal patients with HR-positive, HER2-negative advanced or metastatic breast cancer as initial therapy or following disease progression.³⁷

• On April 18, 2018, a recommendation for reimbursement was issued for ribociclib in combination with letrozole for the treatment of postmenopausal patients with HR-positive, HER2-negative advanced or metastatic breast cancer as initial ET.³⁸

Table 3: Key Characteristics of Ribociclib, Abemaciclib, Anastrozole, Exemestane, Goserelin Acetate, Letrozole, and Tamoxifen

AI = aromatase inhibitor; BMI = body mass index; CDA-AMC = Canada’s Drug Agency; CDK4/6 = cyclin-dependent kinase 4 and kinase 6; EBC = early breast cancer; ET = endocrine therapy; ER = estrogen receptor; GnRH = gonadotropin-releasing hormone; HR = hormone receptor; INR = international normalized ratio; LHRH = luteinizing hormone–releasing hormone; NA = not applicable.

^aHealth Canada–approved indication.

Sources: Product monographs for ribociclib,¹⁴ abemaciclib,³⁹ anastrozole,⁴⁰ exemestane,⁴¹ goserelin acetate,⁴² letrozole,⁴³ and tamoxifen.⁴⁴

Perspectives of Patients, Clinicians, and Drug Programs

The full patient and clinician group submissions received are available in the consolidated patient and clinician group input document for this review on the project website.

Patient Group Input

This section was prepared by the review team based on the input provided by patient groups.

CDA-AMC received 4 patient group submissions from CBCN, Rethink Breast Cancer, QCBF, and a joint submission from BCC and the McPeak-Sirois Group for Clinical Research in Breast Cancer. CBCN is a national health charity dedicated to ensuring the best quality of care for individuals with breast cancer in Canada through information, education, and advocacy. Rethink educates, empowers, and advocates for system changes to improve outcomes for patients with breast cancer, focusing on historically underserved groups. QCBF is committed to defending the interests and well-being of people affected by breast cancer and their loved ones. BCC focuses on saving lives through precision oncology breast cancer research and education, fostering diversity, accelerating research, innovating with technology, promoting patient leadership, and expanding research networks. The McPeak-Sirois Group unites key players in Quebec’s public health sector to make cutting-edge breast cancer research and treatments accessible, supported by breast cancer survivor Susan McPeak and entrepreneur Charles Sirois.

CBCN collected input through online surveys in 2017 (N = 216) and 2022 (N = 981), including 17 patients in 2017 and 111 patients in 2022 with stage II or III HR-positive, HER2-negative breast cancer, respectively, as well as key informant interviews with 2 patients with metastatic breast cancer, and a review of current studies and grey literature. Rethink gathered input from 24 key patient advisors, 50 blog contributors, 500 virtual support group participants, 2,200 private peer support network members, and 43,000 Instagram followers, along with in-depth telephone interviews with 4 patients experienced with ribociclib for high-risk HR-positive, HER2-negative EBC. The QCBF gathered inputs from members of its Facebook private group “Club stade 4” (French name) and a peer support helpline member, who has been taking the drug for almost 5 years, while also conducting literature research and social media reviews. From November 14 to 18, 2024, BCC and McPeak-Sirois Group surveyed 188 breast cancer survivors from their communities using validated patient-reported outcomes measures to capture the lived experiences of individuals with EBC.

Patients across all groups indicated that HR-positive, HER2-negative EBC significantly impacts their lives, causing emotional, physical, and financial strain. Rethink highlights that younger patients face additional challenges such as fertility issues and disruptions to childcare and career. Despite these difficulties, patients across all groups are motivated to undergo therapy to reduce recurrence and strive to maintain normal activities and manage disease-related symptoms.

Patients across all groups prioritize effective treatments with manageable side effects, emphasizing quality of life and personal choice. Financial burdens and long-term impacts of treatment are significant concerns, with unique challenges such as the need for personalized treatment decisions (Rethink), managing daily symptoms and potential insurance loss (QCBF), and the necessity for effective AE management support (BCC and McPeak-Sirois Group).

Overall, patients prioritize treatment efficacy, reducing the risk of recurrence, manageable side effects, and maintaining a good quality of life, with many willing to endure additional side effects for better outcomes. According to Rethink, younger patients emphasize the importance of long-term remission to continue their personal and professional lives. QCBF highlighted concerns about long-term medication effects and the significant impact of side effects on daily life.

In the joint submission from BCC and McPeak-Sirois Group and the input from Rethink, there were 8 and 4 patients with EBC, respectively, who had experience with ribociclib. In the inputs from CBCN and QBCF, 2 patients and 1 patient, respectively, had experience with ribociclib in the metastatic setting. Across the 4 groups, patients consistently reported positive experiences with ribociclib, emphasizing its efficacy in controlling cancer and the manageable nature of its side effects (e.g., neutropenia, nausea, liver issues, fatigue, dry eyes). They valued the treatment for providing reassurance, hope, and a sense of control over their cancer.

The inputs from CBCN focused on patients with metastatic breast cancer, Rethink's detailed account of side effects, QCBF's concern about long-term access and insurance, and BCC and McPeak-Sirois Group's emphasis on maintaining daily functionality and the importance of clinical support. Additionally, inputs from Rethink and BCC and McPeak-Sirois Group highlight the financial burden on younger patients and the importance of public funding and accessible care to alleviate these challenges. While the input from BCC and McPeak-Sirois Group focuses on the financial burden and the need for public funding, the input from Rethink underscored the positive impact of CDK4/6 inhibitors and the necessity of addressing barriers to care for younger patients.

Clinician Input

Input From Clinical Experts Consulted for This Review

All CDA-AMC 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, and 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 HR-positive, HER2-negative stage II and III EBC.

Unmet Needs

The clinical experts consulted by CDA-AMC emphasized the significant unmet needs in treating stage II and III HR-positive, HER2-negative breast cancer, noting the high rates of recurrence despite aggressive treatments. According to the clinical experts, the estimated recurrence rates are 10% to 30% for patients with stage II disease and 30% to 50% for patients with stage III disease over 10 years. Over 20 years after diagnosis, the clinical experts estimated the recurrence rates to be 27% to 37% for patients with stage II disease and 46% to 57% for patients with stage III disease. The clinical experts underscored the necessity for improved long-term management strategies to enhance patient outcomes and reduce the chances of recurrence. The clinical experts highlighted that considering that treatment for HR-positive, HER2-negative, EBC is with curative intent, the goal is to eliminate the disease and reduce the risk of recurrence, minimize side effects and impact on quality of life, maintain employment and independence, and reduce caregiver burden and health care system strain.

Place in Therapy

For patients with HR-positive, HER2-negative EBC, the clinical experts indicated that ribociclib would be added to existing ET when it is deemed appropriate. One clinical expert noted that ribociclib works synergistically with ET (e.g., AIs or tamoxifen) by targeting cancer cell proliferation while ET blocks estrogen-driven tumour growth. The clinical experts expect ribociclib to shift the treatment paradigm for high-risk HR-positive, HER2-negative EBC, replacing abemaciclib when appropriate, particularly for patients at high risk of recurrence who benefit from the combination of ET and a CDK4/6 inhibitor. According to the clinical experts, the choice between ribociclib and abemaciclib would depend on differences in trial eligibility, patient comorbidities, patient preferences, and potential toxicities.

Patient Population

Both clinical experts indicated that patients with a high risk of recurrence (based on genomic testing, such as Oncotype DX and MammaPrint) are those most in need of new treatments. Currently, there is no evidence or specific biomarkers to predict response, but 1 clinical expert mentioned that patients with poor prognostic features, such as positive lymph nodes, large tumours, and high recurrence scores, are most likely to respond and benefit from ribociclib when added to ET. One clinical expert mentioned that patients with minimal contraindications to CDK4/6 inhibitors and good performance status are also ideal candidates. However, 1 expert noted that ribociclib is not suitable for patients with severe liver dysfunction, patients who are pregnant or breastfeeding, those with a history of QT prolongation, or those with severe neutropenia. The clinical experts stated that clinical judgment of tumour size, lymph node involvement, and risk of recurrence, as well as genomic testing and laboratory tests are essential for identifying patients at high risk of recurrence. Additionally, patients’ comorbidities and tolerability should be considered to ensure safety before initiating treatment with ribociclib.

Assessing the Response to Treatment

The clinical experts highlighted that given the early stage of the disease, response to treatment, generally measured by recurrence (i.e., RFS), is a clinically meaningful outcome; however, this takes time and may not be evaluable during the ribociclib treatment period. Other meaningful outcomes to measure responses include improved OS, quality of life, and toxicity, which are assessed frequently during follow-up.

The clinical experts indicated that routine surveillance visits are typically conducted every 3 to 6 months during the first 2 to 3 years after treatment, with clinical examinations and/or imaging conducted regularly to check for recurrence, especially for disease that is at high risk of recurrence (e.g., node-positive, large tumours). Additionally, the clinical experts stated that with ribociclib, close monitoring for treatment toxicity is required, with frequent bloodwork and electrocardiograms (i.e., every 2 weeks) and increased physician appointments, compared to ET alone.

Discontinuing Treatment

The clinical experts indicated that disease recurrence during ribociclib therapy and severe, unmanageable side effects (e.g., myelosuppression, liver toxicity, QT prolongation, and pulmonary toxicity) necessitate stopping treatment with ribociclib. Additionally, 1 clinical expert mentioned that factors influencing the continuation of therapy include significant impacts on quality of life, overall health, and patient preferences.

Prescribing Considerations

The clinical experts indicated that ribociclib should be prescribed and monitored in a hospital outpatient or community oncology practice with a medical oncologist or breast oncologist involved in patient care. The clinical experts highlighted the importance of specialized care, side effect management, and timely treatment adjustments, with nurses and pharmacists with oncology expertise playing crucial roles in patient monitoring and support.

Clinician Group Input

This section was prepared by the review team based on the input provided by clinician groups.

Clinician group input for this review was received from 2 clinician groups: the REAL Canadian Breast Cancer Alliance and OH (CCO) Breast Cancer Drug Advisory Committee. A total of 19 clinicians provided input for this submission: 11 clinicians from REAL Canadian Breast Cancer Alliance plus 3 clinicians who agree with the REAL Canadian Breast Cancer Alliance clinician input and are in support of the submission, and 5 clinicians from the OH (CCO) Breast Cancer Drug Advisory Committee.

The input from the clinician groups aligned with that of the clinical experts consulted for this review with regard to treatment goals, the unmet needs of this patient population, assessing treatment response, the drug’s place in therapy, deciding when to discontinue treatment, which specialists should manage these patients, and where patients should be treated with ribociclib. Clinicians from the OH (CCO) Breast Cancer Drug Advisory Committee noted that the duration of treatment with ribociclib is 3 years, which may increase the need for clinical monitoring for patients (e.g., blood work and clinic visits) compared to abemaciclib, which is given for 2 years.

Drug Program Input

The drug programs provide input on each drug being reviewed through the 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 for this review are summarized in Table 4.

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

AJCC = American Joint Committee on Cancer; CDK4/6 = cyclin-dependent kinase 4 and kinase 6; ECOG = Eastern Cooperative Oncology Group; ET = endocrine therapy; PAG = Provincial Advisory Group; pERC = pan-Canadian Oncology Drug Review Expert Review Committee; QTc = corrected QT.

Clinical Evidence

The objective of this Clinical Review report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of ribociclib, 200 mg tablets, in the treatment of HR-positive, HER2-negative EBC in adults. The focus will be placed on comparing ribociclib to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of ribociclib is presented in 2 sections, with our critical appraisal of the evidence included at the end of each section. The first section, the systematic review, includes pivotal studies and RCTs that were selected according to the sponsor’s systematic review protocol. Our assessment of the certainty of the evidence in this first section using the GRADE approach follows the critical appraisal of the evidence. The second section includes indirect evidence from the sponsor. No long-term extension studies or studies addressing gaps were included in the review.

Included Studies

Clinical evidence from the following is included in the review and appraised in this document:

• one phase III, multicentre, open-label, active-controlled RCT identified in a systematic review (NATALEE)

• one ITC using MAICs.

Systematic Review

Contents within this section have been informed by materials submitted by the sponsor. The following was summarized and validated by the review team.

Description of Studies

Characteristics of the included studies are summarized in Table 5.

Table 5: Details of Studies Included in the Systematic Review

AE = adverse event; AI = aromatase inhibitor; CDK = cyclin-dependent kinase; CTCAE = Common Terminology Criteria for Adverse Events; ctDNA = circulating tumour DNA; ctRNA = circulating tumour ribonucleic acid; DDFS = distant disease–free survival; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; ER = estrogen receptor; ET = endocrine therapy; iDFS = invasive disease–free survival; LRRFS = locoregional recurrence–free survival; NCI = National Cancer Institute; OS = overall survival; PK = pharmacokinetics; p.o. = orally; PR = progesterone receptor; QoL = quality of life; QTcF = QT corrected for heart rate using the Fridericia formula; RCT = randomized controlled trial; RFS = recurrence-free survival; SC = subcutaneous; STEEP = Standardized Definitions for Efficacy End Points.

^aEnd of trial was planned to be declared when 60 months plus 30 days had elapsed from the date the last patient had been randomized.

Source: NATALEE Clinical Study Reports for the end of ribociclib analysis (2024).¹⁷ Details included in the table are from the sponsor’s Summary of Clinical Evidence.²¹

One pivotal trial (NATALEE) was included in the systematic review (Table 5). NATALEE was a phase III, open-label, active-controlled RCT to evaluate the efficacy and safety of ribociclib plus AI compared to AI alone as an adjuvant treatment in premenopausal and postmenopausal women, and men, with HR-positive and HER2-negative EBC. The primary end point was iDFS assessed by the investigator using the Standardized Definitions for Efficacy End Points criteria. Secondary end points included RFS, DDFS, OS, HRQoL, and safety. A total of 5,101 patients were randomized at a 1:1 ratio to receive either ribociclib plus AI (n = 2,549) or AI alone (n = 2,552). Randomization was conducted using an interactive response technology system and stratified by menopausal status (postmenopausal versus premenopausal, with men grouped in the premenopausal category), anatomical stage (II versus III), prior adjuvant or neoadjuvant chemotherapy (yes versus no), and geographical region (North America, Western Europe, and Oceania versus rest of the world). Eligible patients were recruited in 393 centres in 20 countries. The study enrolled 171 patients across 23 sites in Canada.

The NATALEE trial consisted of 3 phases: screening, treatment, and follow-up (Figure 1). The purpose of the screening phase was to assess the inclusion and exclusion criteria and to perform all screening procedures. In the screening phase, patients were screened for eligibility, confirmed by the investigator within 28 days before randomization. The treatment phase consisted of 28-day treatment cycles for up to 60 months plus 30 days of safety follow-up.

Figure 1: NATALEE Study Design

AJCC = American Joint Committee on Cancer; d = day, NSAI = nonsteroidal aromatase inhibitor; vs. = versus.

Source: NATALEE trial statistical analysis plan.⁴⁵

Three interim analyses were planned after approximately 200, 350, and 425 iDFS events of the approximately 500 targeted iDFS events (i.e., at approximately 40%, 70% and 85% information fractions, respectively) had been documented. The final iDFS analysis was performed when approximately 500 iDFS events had been documented. The end of ribociclib analysis was performed at 603 iDFS events when all patients in the ribociclib plus AI group discontinued ribociclib. Although this CDA-AMC report primarily focuses on the results from the end of ribociclib analysis with a data cut-off date of April 29, 2024, it also reports the results for the primary outcome, iDFS, at IA3 (data cut-off date: January 11, 2023), at which time the NATALEE trial met its primary end point.

Populations

Inclusion and Exclusion Criteria

Eligible patients included men and premenopausal or postmenopausal women who were 18 years of age or older and had histologically confirmed HR-positive, HER2-negative EBC, according to local assessment. Patients were required to have stage II or III disease based on anatomical stage according to the AJCC Cancer Staging Manual, 8th Edition.²⁹ Patients with stage IIA disease were eligible if they had at least 1 lymph node involved. Patients who had no nodal involvement and a grade 2 tumour with a Ki-67 proliferation index of at least 20% or who were classified in a high genomic risk group were also eligible. Patients with stage IIA disease with no nodal involvement and grade 3 tumours were also eligible. All patients with stage IIB or III disease were allowed to participate in the trial regardless of the nodal status. Patients who had received a previous CDK4/6 inhibitor or who had clinically significant uncontrolled heart disease, cardiac repolarization abnormalities, or both, were ineligible.

Interventions

Patients were randomized 1:1 to receive ribociclib (400 mg orally once daily on days 1 to 21 of a 28-day cycle for 36 months from the randomization date plus AI continuously) or AI alone continuously. The AI dosage could either be: letrozole (2.5 mg orally once daily) or anastrozole (1 mg orally once daily) for postmenopausal women or, alternatively, letrozole (2.5 mg orally once daily) or anastrozole (1 mg orally once daily) plus goserelin (3.6 mg subcutaneously once every 4 weeks) for men and premenopausal women. The duration of AI was 60 months starting from the randomization date. Ribociclib and AI were administered daily at the same time with or without food. AI crossovers were not allowed in the study unless there was intolerable toxicity, any important medical event that necessitated a change, or per patient’s request. Patients were discontinued from the ribociclib or ET treatment arms for any of the following reasons:

• completion of 36 months of ribociclib treatment (approximately 39 cycles) or 60 months of ET treatment from the randomization date

• first recurrence (any of the following or a combination of local, regional, or distant recurrences or contralateral invasive breast cancer, or second primary nonbreast invasive cancer)

• adjustments to study treatment due to toxicity that results in treatment discontinuation

• interruption of ribociclib dosing for greater than 28 days due to ribociclib-related toxicity

• withdrawal of consent by the patient

• lost to follow-up or death.

Patients in both groups had safety evaluations performed 30 days after the last dose of treatment.

Dose reduction or interruptions of ribociclib were authorized to allow patients to continue treatment. Patients were permitted to have 1 dose reduction (200 mg) if the recommended dosing schedule was not well tolerated, to allow patients to continue ribociclib. Ribociclib could also be temporarily interrupted until conditions were satisfied, as described in the study protocol. Discontinuation of ribociclib was mandatory when dosing was interrupted for more than 28 days due to ribociclib-related toxicity. For hepatic toxicities, if toxicity recurred after a dose reduction, or if recovery up to a grade 1 AE (or to baseline grade, depending on AE type) took more than 28 days, discontinuation of ribociclib was also required. In the case of a second dose reduction to manage AEs related to ribociclib, the treatment was discontinued.

Medications required to treat AEs or manage cancer symptoms or concurrent diseases, and supportive-care drugs such as pain medications, antiemetics, and antidiarrheals, were allowed during the trial. Prohibited medications during ribociclib included strong inhibitors or inducers of cytochrome P450 3A4/3A5, substrates of cytochrome P450 3A4/3A5 with a narrow therapeutic index, medications with a known risk for QT prolongation and/or torsades de pointes, and concomitant tamoxifen or toremifene use.

Outcomes

A list of efficacy end points assessed in this review is provided in Table 6, followed by descriptions of the outcome measures. The summarized end points are based on outcomes included in the sponsor’s Summary of Clinical Evidence as well as any outcomes identified as important to this review by the clinical experts consulted for this review, and input from patient and clinician groups and public drug plans. Using the same considerations, end points that were considered to be the most relevant to inform expert committee deliberations were selected and finalized in consultation with members of the expert committee. All summarized efficacy end points were assessed using GRADE. Select notable harms outcomes considered important for informing expert committee deliberations were also assessed using GRADE.

Table 6: Outcomes Summarized From the NATALEE Trial

EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; GHS = global health status; ILD = interstitial lung disease; NR = not reported; QoL = quality of life.

^aStatistical testing for invasive disease–free survival was adjusted for multiple comparisons across multiple interim analyses.

Sources: NATALEE Clinical Study Reports for the end of ribociclib analysis (2024).¹⁷ Details included in the table are from the sponsor’s Summary of Clinical Evidence.²¹

Efficacy Outcomes

This report primarily focused on the results from the end of ribociclib analysis with a data cut-off date of April 29, 2024 (median duration of follow-up, 44.2 months; range, 0 to 63 months). Results for the primary outcome, iDFS, and for HRQoL were reported at IA3 (data cut-off date: January 11, 2023; median duration of follow-up, 27.7 months; range, 0 to 45 months).

Invasive Disease–Free Survival

The primary efficacy end point of the NATALEE trial was iDFS, which was defined as the time from randomization to the first event of local invasive disease recurrence in the breast, regional invasive recurrence, distant recurrence, death (any cause), contralateral invasive breast cancer, or second primary nonbreast invasive cancer (excluding basal and squamous cell carcinomas of the skin), as defined by the Standardized Definitions for Efficacy End Points criteria:⁴⁶

• Local invasive breast cancer recurrence or ipsilateral invasive breast tumour recurrence. Invasive breast cancer involving the same breast as the original primary tumour. Ductal and lobular carcinoma in situ and tumours in the contralateral breast and/or contralateral lymph nodes are not considered a local invasive recurrence.

• Local recurrence has to be confirmed histologically. Histological type of local invasive breast cancer recurrence should be recorded in the case report form.

• Regional breast cancer recurrence. Invasive breast cancer in the ipsilateral axilla, regional lymph nodes (all levels), chest wall, or skin of the ipsilateral breast. A tumour in the contralateral breast is not considered a regional recurrence.

• Regional recurrence has to be confirmed histologically (preferred) or cytologically. The specific site of regional recurrence should be recorded in the case report form.

• Distant recurrence. Distant metastasis of breast cancer (bones, distant lymph nodes, internal organs, central nervous system, bone marrow, and so forth) or any areas of invasive breast cancer recurrence that are not local or regional.

• Distant recurrence has to be confirmed histologically (preferred) or cytologically unless there is an unacceptable risk to the patient due to the procedure.

  • If bone metastases were identified by a bone scan, this must be confirmed histologically (preferred) or radiographically (CT, MRI or fluorodeoxyglucose [FDG]-PET-CT) if biopsy confirmation is not possible.

  • Metastases in the central nervous system must be confirmed histologically (preferred), cytologically or radiographically (CT or MRI, both with IV contrast material) if biopsy confirmation is not possible.

  • All other sites of metastases must be confirmed histologically (preferred) or cytologically unless there is an unacceptable risk to the patient due to the procedure.

  • Location of the first 3 most dominant distant metastases should be reported in the case report form, with preference given to visceral (including brain) metastases, then to bone and then to distant lymph node or skin metastases.

• Contralateral invasive breast cancer. Any invasive breast cancer in the contralateral breast with or without contralateral lymph node involvement. Contralateral invasive breast cancer has to be confirmed histologically. In situ or noninvasive contralateral breast cancers are not included in contralateral invasive breast cancers. Histological type and the specific site of contralateral invasive breast cancer should be recorded in the case report form.

• Second primary nonbreast invasive cancer. Second primary nonbreast invasive cancer has to be confirmed histologically. In situ or noninvasive cancers and basal or squamous cell carcinomas of the skin are not considered second primary nonbreast invasive cancers. Histological type and the location of the second primary nonbreast invasive cancer should be recorded in the case report form.

Recurrences were detected by scheduled or unscheduled clinical evaluations. Suspected recurrence had to be evaluated by medical imaging and confirmed histologically (or cytologically, when applicable) unless there was an unacceptable risk to the patient or was otherwise specified, according to the study protocol.

Patients who did not have an iDFS event were censored at the last assessment before the data cut-off date (January 11, 2023, for IA3; April 29, 2024, for the end of ribociclib analysis). Any recurrence documented after the initiation of new antineoplastic therapy was considered for the primary analysis, provided that recurrence assessments continued after initiation of new cancer therapy. Discontinuation of treatment due to clinical suspicion of recurrence without histological, cytological, or imaging confirmation was not considered an iDFS event nor a censoring event, which indicated that patients who discontinued treatment were followed up, and treatment discontinuation did not lead to censoring. Detailed measurement properties of iDFS are summarized in Table 7.

Recurrence-Free Survival

RFS was a secondary end point of the NATALEE trial and was defined as the time from randomization to the first event of local invasive disease recurrence in the breast, regional invasive recurrence, distant recurrence, or death (any cause) as described in the previous section. Patients who did not have an RFS event were censored at the last assessment before the data cut-off date for the end of ribociclib analysis.

Distant Disease–Free Survival

Distant disease–free survival was a secondary end point of the NATALEE trial and was defined as the time from randomization to the first event of distant recurrence, death (any cause), or second primary nonbreast invasive cancer (excluding basal and squamous cell carcinomas of the skin), as described in the iDFS section. Patients who did not have a DDFS event were censored at the last assessment before the data cut-off date for the end of ribociclib analysis.

Overall Survival

OS was a secondary end point of the NATALEE trial and was defined as the time from randomization to death due to any cause. If a patient was not known to have died, then OS was censored at the latest date the patient was known to be alive (on or before the data cut-off date for the end of ribociclib analysis).

Health-Related Quality of Life

HRQoL was measured using the EORTC QLQ-C30 and was a secondary end point in the NATALEE trial. The EORTC QLQ-C30 contains 30 items and is composed of both multi-item scales and single-item measures. These include 5 functional scales (physical, role, emotional, cognitive, and social functioning), 3 symptom scales (fatigue, nausea and/or vomiting, and pain), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial impact) and a global health status and quality of life subscale score.⁴⁷ All of the scales and single-item measures range in score from 0 to 100. A high functional scale score represents a higher score for a healthy level of functioning; a high score for the global health status and quality of life subscale represents a high quality of life, but a high score for a symptom scale and item represents a high level of symptomatology and problems. All scoring followed the scoring procedures defined by the EORTC QLQ-30 scoring manual. Currently, there is no established minimal important difference in patients with EBC. A change of at least 10 points for improvement and −10 points for deterioration in the global health status and quality of life subscale score was considered meaningful in patients with advanced breast cancer.⁴⁸ Detailed measurement properties of the EORTC QLQ-C30 are summarized in Table 7.

Safety Outcomes

In the NATALEE trial, AEs were coded using the Medical Dictionary for Regulatory Activities and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (Version 4.03). An AE was defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s). Notable harms from the NATALEE trial included hepatobiliary toxicity, myelosuppression, infections, QT interval prolongation, renal toxicity, pulmonary toxicity (interstitial lung disease or pneumonitis), reproductive toxicity, and second malignancy. Among them, hepatobiliary toxicity, QT interval prolongation, and pulmonary toxicity (interstitial lung disease or pneumonitis) were selected for GRADE assessment because they were considered important by the clinical experts consulted for this review.

Table 7: Summary of Outcome Measures and Their Measurement Properties

DFS = disease-free survival; EBC = early breast cancer; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; GHS = global health status; HR = hormone receptor; HRQoL = health-related quality of life; iDFS = invasive disease–free survival; MID = minimal important difference; OS = overall survival; QoL = quality of life; STEEP = Standardized Definitions for Efficacy End Points.

Statistical Analysis

A summary of the statistical analysis of the efficacy end points from the NATALEE trial is provided in Table 8.

Sample Size and Power Calculation

The enrolment of patients in the NATALEE trial was based on an expected distribution of 40% of patients having stage II disease and 60% of patients having stage III disease. The 5-year iDFS probability for patients with stage II (excluding low-risk patients) and stage III disease was assumed to be approximately 79% and 72%, respectively, based on data from a retrospective study assessing the prognostic effect of Ki-67 and other disease characteristics in patients with HR-positive, HER2-negative EBC, and data for patients with 4 or more positive lymph nodes treated with AIs in the Early Breast Cancer Trialists’ Collaborative Group meta-analysis.^52,53 As a result, the expected overall 5-year iDFS of the control group would be approximately 74.8%. A total of 500 iDFS events would provide approximately 93% and 85% power to reject the null hypothesis of no difference under alternative hypotheses in which the overall hazard ratio is 0.73 and 0.76, respectively. The calculation is based on a 1-sided log-rank test at the overall 2.5% level of significance, patients randomized to the 2 treatment arms in a 1:1 ratio, and a 4-look group sequential design with a Lan-DeMets alpha-spending function and a Lan-DeMets beta-spending function. The final iDFS analysis was planned after approximately 500 documented iDFS events, regardless of the results of the interim analyses. Assuming that enrolment would continue at a rate of approximately 170 patients per month and assuming a 15% dropout rate by the time of the final iDFS analysis, a total of 5,000 patients would need to be randomized to observe the targeted 500 iDFS events at about 44 months after the randomization date of the first patient.

Primary Outcome Analysis

Statistical Test or Model

The primary analysis of iDFS was based on the full analysis set (FAS) and included all data observed up to the cut-off date (January 11, 2023, for IA3; April 29, 2024, for the end of ribociclib analysis). The Kaplan-Meier estimator was used to estimate the distribution of iDFS within each treatment group. A difference in iDFS events across groups was compared using a stratified log-rank test at a 1-sided 2.5% level of significance using the same stratification factors used for randomization. Estimates of hazard ratios were calculated, along with their 95% CIs, using a Cox model stratified by the same stratification factors used for randomization.

Interim and Final Analyses

Three interim analyses were planned after approximately 200, 350, and 425 iDFS events of the approximately 500 targeted iDFS events (i.e., at approximately 40%, 70% and 85% information fractions, respectively) had been documented. These interim analyses were expected to occur around 27, 35, and 39 months from the date the first patient was randomized in the study. An alpha-spending function according to a 3-look group sequential design with a stopping boundary (O’Brien-Fleming type) was used to construct the efficacy stopping boundaries.⁵⁴ A Lan-DeMets stopping boundary (O’Brien-Fleming type) was used as a beta-spending function to determine the nonbinding futility boundary. The choice of nonbinding nature of the futility-stopping boundary ensures that the efficacy stopping boundaries are not affected. Based on the choice of alpha-spending function described previously, the futility boundary expressed on the P value at the first interim analysis was calculated as P = 0.6752. At the time of the second interim analysis, the efficacy boundary was calculated as P = 0.0074. Similarly, if the third interim analysis was performed exactly at 425 iDFS events, the efficacy boundary was calculated as P = 0.0129. The final iDFS analysis was performed when approximately 500 iDFS events had been documented. If exactly 200, 350, and 425 events were observed at the interim analyses, the trial continued, and if exactly 500 events were obtained at the final analysis, the observed P value had to be less than 0.0202 to conclude statistical significance. The boundary for the final analysis was derived accordingly from the prespecified alpha-spending function such that the overall significance level across all analyses was maintained at 0.025. The end of ribociclib analysis was performed at 603 iDFS events when all patients in the ribociclib plus AI group discontinued ribociclib. Of note, all analyses performed after the final iDFS analysis (i.e., the end of ribociclib analysis) were exploratory.

Multiple-Testing Procedure

The primary end point of iDFS was tested multiple times and stopping boundaries from the group sequential design were calculated to maintain an overall type I error rate of alpha, as described in the previous section. No adjustment for multiple comparisons was planned for secondary and exploratory end points.

The NATALEE trial met its primary end point at IA3 (data cut-off date: January 11, 2023). This report describes the results of the primary end point of iDFS in IA3 because it was inferentially tested, and all other results use the data from the end of ribociclib analysis (data cut-off date: April 29, 2024); because it included more patients and had a longer follow-up time compared to IA3, HRQoL results were available only at IA3. Of note, the 95% CIs and P values were not adjusted for multiplicity for outcomes in the end of ribociclib analysis.

Data Imputation Methods

There were no data imputation methods reported for missing data in the primary analysis of iDFS in the NATALEE trial.

Subgroup Analyses

Subgroup analyses were performed on the primary efficacy end point of iDFS in the FAS population. The subgroups analyses were not controlled for multiplicity. The following subgroup analyses were conducted:

• nodal status (N0 versus N1-N3)

• menopausal status (postmenopausal versus premenopausal, with men grouped in the premenopausal category)

• anatomical stage (II versus III)

• prior neoadjuvant or adjuvant chemotherapy (yes versus no)

• region (North America, Western Europe, and Oceania versus rest of world).

Among them, the subgroups based on nodal status, menopausal status, anatomical stage, and prior neo- or adjuvant chemotherapy were considered important based on input from the clinical experts consulted by CDA-AMC.

Sensitivity Analyses

In the NATALEE trial, the following 9 sensitivity analyses were performed to evaluate the robustness of the primary end point of iDFS:

• Based on per-protocol analysis set.

• Stratification per case report form.

• Unstratified log-rank test and Cox model.

• Stratified Cox model adjusting for baseline covariates.

• Using the FAS and excluding an event if it occurred more than 28 weeks after the last assessment (i.e., after at least 2 missing assessments during the first 24 months or after at least 1 missing assessment after the first 24 months).

• Using the FAS and backdating events that occurred after 1 or more missing assessments. The date of such an event was changed to the date of the earliest missed scheduled assessment date preceding its detection. This means that, when 1 or more assessments were missed leading up to the event, the event date was backdated to the last assessment date that was missed before the event was captured.

• Using the FAS and censoring an iDFS event at the date of the last assessment before the start of new anticancer therapy if no iDFS event was observed before the start of new antineoplastic therapy.

• Using the FAS and considering treatment discontinuation due to disease recurrence without a confirmed recurrence event.

• Using the FAS and excluding the death due to COVID-19. The iDFS was censored at the last adequate assessment before the COVID-19 death.

Secondary Outcome Analysis

The efficacy analysis of the secondary outcomes was conducted among patients in the FAS population. The following statistics were used to summarize RFS, DDFS, and OS. The hazard ratios were calculated, along with their 95% CIs, using a Cox model stratified by the same stratification factors used for randomization. The survival curve distribution of RFS, DDFS, and OS were compared between the 2 treatment groups using a stratified log-rank test at a 1-sided 2.5% level of significance using the same stratification factors used for randomization.

HRQoL was measured using change from baseline for the global health status and quality of life subscale score of the EORTC QLQ-C30 and presented based on results from IA3 (data cut-off date: January 11, 2023). A repeated-measures model for longitudinal data was used to estimate differences in the global health status and quality of life subscale between treatment groups. The modelling was done on the actual score. This repeated-measure model included terms for treatment, the stratification factors assigned at randomization, time, baseline value as main effects, and an interaction term for treatment by time. This analysis was restricted to patients with an evaluable baseline score and at least 1 evaluable postbaseline score. All data collected until confirmation of first recurrence (including the assessment at confirmation of first recurrence) were included in the analysis. Time was considered a continuous variable expressed in months. This analysis only included assessments up to the time point where there were at least 50 patients on each of the treatments.

Safety Outcome Analysis

All safety analyses were based on the safety analysis set, unless otherwise specified. Descriptive statistics were calculated for continuous safety variables and frequency counts and percentages were tabulated for categorical safety variables.

Table 8: Statistical Analysis of Efficacy End Points

CRF = case report form; DDFS = distant disease–free survival; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; iDFS = invasive disease–free survival; NR = not reported; OS = overall survival; RFS = recurrence-free survival; vs. = versus.

Source: NATALEE trial statistical analysis plan.⁴⁵ Details included in the table are from the sponsor’s Summary of Clinical Evidence.²¹

Analysis Populations

A summary of analysis populations used in the NATALEE trial that are relevant to this review is provided in Table 9.

Table 9: Analysis Populations of the NATALEE Trial

AI = aromatase inhibitor; FAS = full analysis set.

Source: NATALEE statistical analysis plan.⁴⁵ Details included in the table are from the sponsor’s Summary of Clinical Evidence.²¹

Major Protocol Deviations

A summary of major protocol deviations in the NATALEE trial at IA3 is provided in Table 10. There were 29 patients (1.1%) in the ribociclib plus AI group and 18 patients (0.7%) in the AI alone group who reported major protocol deviations leading to exclusion from analysis sets. The most commonly reported major protocol deviation included inclusion and/or exclusion criteria not being met (1.1% versus 0.7% for ribociclib plus AI versus AI alone), for which 26 patients were excluded because they did not meet the anatomical stage requirement for the study; 18 patients were excluded because their HER2 status was unavailable; and 2 patients were excluded for having metastatic disease at study entry.

Table 10: Summary of Major Protocol Deviation From the NATALEE Trial (FAS; Data Cut-Off Date — January 11, 2023)

AI = aromatase inhibitor; FAS = full analysis set.

Source: NATALEE Clinical Study Report for interim analysis 3 (2023).

Results

Although this report primarily focuses on the results from the end of ribociclib analysis, which had a data cut-off date of April 29, 2024, it also reports the results for the primary outcome, iDFS, at IA3 (data cut-off date: January 11, 2023), at which time the NATALEE trial met its primary end point. This report also includes results from the 5-year follow-up analysis with a data cut-off date of May 28, 2025.

Patient Disposition

Patient disposition in the NATALEE trial is summarized in Table 11. At the time of the end of ribociclib analysis, a total of 6,068 patients were screened and 638 patients (10.5%) were excluded, with withdrawal by patient being the most reported reason (203 of 638 patients; 31.8%). A total of 5,101 patients were randomized: 2,549 patients to the ribociclib plus AI group and 2,552 patients to the AI alone group. Generally, a lower proportion of patients in the ribociclib plus AI group were randomized but not treated (0.9% versus 4.3% for ribociclib plus AI versus AI alone) or discontinued from the study (17.1% versus 22.1%) compared with the AI alone group. Fewer patients in the ribociclib plus AI group discontinued from the study compared to the AI alone group: 450 patients (17.7%) versus 565 patients (22.1%); the primary reason for study discontinuation was withdrawal by patient (11.0% versus 15.2%). Completion of the treatment (62.8%) was the most reported reason for ribociclib discontinuation followed by AEs (20.0%). A lower proportion of patients in the ribociclib plus AI group discontinued the AI portion of treatment (28.7% versus 31.9%), with the most reported reason for AI discontinuation being disease relapse (7.7% versus 10.5%). Two patients in the AI alone group received ribociclib but subsequently discontinued its use. Similar patient disposition was observed in the 5-year follow-up analysis (data cut-off date: May 28, 2025), but all patients were no longer receiving treatment with ribociclib. More patients discontinued the AI component of the regimens (72.0% and 71.9%), but 25.4% (1,295 out of 5,101) were still receiving AI treatment.

Based on the final iDFS analysis safety analysis set (data cut-off date: July 21, 2023), 1,091 patients (43.2%) completed the 3-year treatment duration of ribociclib and 1,752 patients (69.4%) completed at least 2 years of ribociclib treatment. At the time of the end of ribociclib analysis, 1,601 patients (62.8%) completed treatment with ribociclib.

Baseline Characteristics

The baseline characteristics outlined in Table 12 are limited to those that are most relevant to this review or were felt by the review team to affect the outcomes or interpretation of the study results. Baseline characteristics in the NATALEE trial were reported in the sponsor’s Clinical Study Report for IA3. Demographic and baseline characteristics were well balanced between treatment groups. The median age of all study patients was 52.0 years, with a range of 24 to 90 years. The NATALEE trial enrolled mostly women (99.6%) who were postmenopausal (55.8%) and had an ECOG Performance Status score of 0 (83.1%). More than half (59.6%) of patients had disease that was AJCC stage III, nearly half of patients (41.2%) had 1 to 3 positive ALNs (i.e., N1 classification), and most patients (88.1%) received prior adjuvant or neoadjuvant chemotherapy. Genomic risk was used to determine the eligibility for patients with stage IIA disease with grade 2 tumours. There were 676 patients (13.3%) who had genomic tests; Oncotype DX was the most reported test (249 [4.9%] of all patients).

Table 11: Summary of Patient Disposition From the NATALEE Trial (FAS)

AI = aromatase inhibitor; FAS = full analysis set; NA = not applicable; NR = not reported; PP = per protocol.

^aPercentage calculated based on the number of patients who were screened but not included in the trial (i.e., 638 patients).

Source: NATALEE Clinical Study Report for the end of ribociclib analysis (2024)¹⁷ and sponsor-provided additional information (March 13).⁵⁵ Details included in the table are from the sponsor’s Summary of Clinical Evidence.²¹

Table 12: Summary of Baseline Characteristics From NATALEE (FAS; Data Cut-Off Date — January 11, 2023)

AI = aromatase inhibitor; AJCC = American Joint Committee on Cancer; ECOG = Eastern Cooperative Oncology Group; ER = estrogen receptor; FAS = full analysis set; G1 = low-grade tumour; G2 = intermediate-grade tumour; G3 = high-grade tumour; GX = tumour grade cannot be assessed; iDFS = invasive disease–free survival; N0 = no nodal involvement; N1 = 1 to 3 positive axillary lymph nodes; N2 = 4 to 9 positive axillary lymph nodes; N3 = ≥ 10 positive axillary lymph nodes; NX = no nodal information available; PR = progesterone receptor; SD = standard deviation; T0 = main tumour cannot be found; T1 = tumour ≤ 2 cm in size across; T2 = tumour > 2 cm but ≤ 5 cm in size across; T3 = tumour > 5 cm in size across; T4 = tumour growing into chest wall or skin; Tis = carcinoma in situ; TX = main tumour cannot be measured.

Note: Baseline characteristics were reported in the NATALEE Clinical Study Report for interim analysis 3 (data cut-off date: January 11, 2024), considering they were not reported in either the final iDFS analysis report or the end of ribociclib analysis report. The FAS remained the same.

^aRacial categories used in the table are as reported in the source and may not align with Canada's Drug Agency inclusive language guidelines.

Sources: NATALEE Clinical Study Report for interim analysis 3 (2023). Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Exposure to Study Treatments

At the end of ribociclib analysis, patients in the ribociclib plus AI group had a median duration of exposure of 35.7 months to ribociclib and 45.01 months to AI. In the AI alone group, patients had a median duration of exposure to the AI of 44.7 months (Table 13). Overall, the relative dose intensity for the AI and goserelin was balanced between treatment groups. The mean relative dose intensity for ribociclib was 83.4%, the mean relative dose intensity for the AI was approximately 99% in both treatment groups, and the mean relative dose intensity for goserelin in men and premenopausal women was 101.37% in the ribociclib plus AI group and 100.19% in the AI alone group. A higher proportion of patients in the ribociclib plus AI group (46.7%) experienced AI dose interruption than in the AI alone group (36.8%), primarily due to included AEs (11.6% versus 5.7%). At the 5-year follow-up analysis (data cut-off date: May 28, 2025), the mean duration of exposure was 46.5 months (SD = 19.46) in the ribociclib plus AI group and 44.6 months (SD = 20.64) in the AI alone group.

Table 13: Summary of Patient Exposure From the NATALEE Study (Safety Analysis Set; Data Cut-Off Date — April 29, 2024)

AI = aromatase inhibitor; NA = not applicable; SD = standard deviation.

Sources: NATALEE Clinical Study Report for the end of ribociclib analysis (2024). Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Prior Therapies

Prior therapies for patients in the NATALEE trial at IA3 are summarized in (Table 14). Prior therapies were balanced between the treatment groups. There were 2,423 patients (95.1%) in the ribociclib plus AI group and 2,439 patients (95.6%) in the AI alone group who received 1 or more prior antineoplastic medications, the most common being prior antineoplastic radiotherapy (89.9% versus 90.2%).

Table 14: Summary of Prior Therapies From the NATALEE Study (FAS; Data Cut-Off Date — January 11, 2023)

AI = aromatase inhibitor; FAS = full analysis set.

Sources: NATALEE Clinical Study Report for interim analysis 3 (2023). Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Concomitant Medications

A summary of the concomitant medications used in the safety analysis set at the end of ribociclib analysis and the 5-year follow-up analysis is provided in Table 15. Medications required to treat AEs or manage cancer symptoms or concurrent diseases, and supportive-care drugs such as pain medications, antiemetics, and antidiarrheals, were allowed during the NATALEE trial. Overall, concomitant medications were balanced between the treatment groups. In total, 2,370 patients (93.8%) in the ribociclib plus AI group and 2,220 patients (90.9%) in the AI alone group received 1 or more concomitant medications at the end of ribociclib analysis; similar results were observed at the 5-year follow-up analysis. The most commonly used concomitant medications in both groups were bisphosphonates (end of ribociclib analysis: 17.6% versus 18.3%; 5-year follow-up analysis: 17.7% versus 18.4%).

Table 15: Summary of Concomitant Medications From the NATALEE Study (Safety Analysis Set)

AI = aromatase inhibitor; NR = not reported.

Sources: NATALEE Clinical Study Report for the end of ribociclib analysis (2024). Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Subsequent Treatment

██ ███ ██████ ████████ ███ ██ ███ ███ ██ ██████████ █████████ ██████████ ███████████████ ██████████ ███ ████████ ██ ███ ███████ ████████ ██ ███ ██████████ ████ ██ █████ ███ ███ ███████ ████████ ██ ███ ██ ██████ ████ ██████ █████████ ██ █████ ███████ ████████ ██ ███ ██████████ ████ ██ █████ ███ █████ ███████ ████████ ██ ███ ██ █████ ██ ███ ██████ █████████ ████████ █████ ███████ █████ ███ ███ █████ ██████ ████ ███ ████ ████████ ██████████ ███████████████ ███████████ █████████ ██ ██ █████ ██ ██ ████████ ██ ██████ ██████ ████████ ██ ████ ██ ██████████ █████████ ████ ████████ ██████ █████████ █████ ███ ███████ ██████████████ ████ ██ ██████████ █████████ ████ █████████ ██████ █████████ █████ ███ ████ ██ ██████████ █████████ ████ ███ █████ ██████ █████████ █████████ ████ ███ █████ ████ ████████ █████████ ███████ █████████ ███████.

Table 16: Summary of Subsequent Treatment From the NATALEE Study (Safety Analysis Set)

AI = aromatase inhibitor.

Source: Sponsor-provided additional data.¹⁹

Efficacy

Findings for key efficacy outcomes among the FAS population in the NATALEE trial are summarized in Table 17 and Table 18. The NATALEE trial met its primary end point at IA3 (data cut-off date: January 11, 2023). At IA3, the median duration of follow-up was 27.7 months (range, 0 to 45 months). At the time of end of ribociclib analysis (data cut-off date: April 29, 2024), the median duration of follow-up was 44.2 months (range, 0 to 63 months). At the time of the 5-year follow-up analysis (data cut-off date: May 28, 2025), the median duration of follow-up was 55.4 months. Results for iDFS were reported at IA3, the end of ribociclib analysis, and the 5-year follow-up analysis. No formal statistical analysis of secondary outcomes was planned at any time point; only the results for the end of ribociclib analysis and the 5-year follow-up analysis are summarized in detail for RFS, DDFS, and OS. Because no results were available at other time points, only the results for HRQoL at IA3 are presented for this outcome.

Invasive Disease–Free Survival

At IA3, 189 patients (7.4%) in the ribociclib plus AI group and 237 patients (9.3%) in the AI alone group experienced an iDFS event. Distant recurrence (4.7% versus 6.7%) was the most commonly reported iDFS event for both groups (Table 17). A total of 2,360 patients (92.6%) in the ribociclib plus AI group and 2,315 patients (90.7%) in the AI alone group were censored, primarily due to not experiencing the iDFS event (83.7% versus 77.3%). There was a statistically significant improvement in iDFS in the ribociclib plus AI group compared with the AI alone group (hazard ratio = 0.75; 95% CI, 0.62 to 0.91; P = 0.0014), though the median iDFS was not estimable for either treatment group. The Kaplan-Meier probability estimate of iDFS at 36 months was 90.4% (95% CI, 88.6% to 91.9%) for the ribociclib plus AI group, and 87.1% (95% CI, 85.3% to 88.8%) for the AI alone group (Figure 2a). The between-group difference was 3.3% (95% CI, 0.9% to 5.7%).

Results from the planned sensitivity and supplementary analyses were consistent with the primary analysis at IA3. Subgroup analyses of iDFS were also consistent with the primary analysis, except for the subgroup of patients with lobular breast cancer (hazard ratio = 1.05; 95% CI, 0.70 to 1.59). Refer to Appendix 1 for the detailed subgroup analyses data.

At the end of ribociclib analysis, a total of 263 patients (10.3%) in the ribociclib plus AI group and 340 patients (13.3%) in the AI group experienced an iDFS event, with distant recurrence (6.9% for ribociclib plus AI versus 9.6% for AI alone) being the most reported event for both groups. A total of 2,286 patients (89.7%) in the ribociclib plus AI group and 2,212 patients (86.7%) in the AI alone group were censored. The median iDFS was not estimable at the end of ribociclib analysis for either treatment group. The hazard ratio for the ribociclib plus AI group versus the AI alone group was 0.72 (95% CI, 0.61 to 0.84; nominal P < 0.0001), in favour of ribociclib plus AI. The Kaplan-Meier probability estimate of iDFS at 36 months for both groups was consistent with IA3. At 48 months, the Kaplan-Meier probability estimate of iDFS was 88.5% (95% CI, 87.1% to 89.8%) for the ribociclib plus AI group, and 83.6% (95% CI, 81.8% to 85.2%) for the AI alone group. The between-group difference was 4.9% (95% CI, 2.7% to 7.1%) (Figure 2b).

At the 5-year follow-up analysis, the hazard ratio for the ribociclib plus AI group versus the AI alone group was 0.72 (95% CI, 0.62 to 0.83) (Figure 3). At 60 months, the Kaplan-Meier probability estimate of iDFS was 85.5% (95% CI, 83.9% to 87.0%) for the ribociclib plus AI group, and 81.0% (95% CI, 79.2% to 82.7%) for the AI alone group, resulting in a between-group difference of 4.5% (95% CI, 2.1% to 6.9%).

Results for sensitivity analyses were available only at IA3. Subgroup analyses of iDFS at the end of ribociclib analysis were generally consistent with the primary analysis across all prespecified subgroups. Detailed subgroup analyses are reported in Appendix 1.

At the request of CDA-AMC, the sponsor provided additional data on a subset of patients in the NATALEE trial who would not meet the eligibility criteria for cohort 1 of the monarchE trial (Table 28). The results of a subgroup analysis that was based on patient eligibility for cohort 1 in the monarchE trial were used to inform the pharmacoeconomic model submitted to CDA-AMC to represent patients in the NATALEE trial who would or would not be eligible to receive abemaciclib. Of note, this subgroup was not a predefined subgroup in the NATALEE trial. ███ ████ ███████ ██ ████ ██████ ██ ████████ ████ ██████████ ████ ███ ████ ███████ ███ ███ ███ ███ ██████████ ████ ██ ███ ██ ███████ █████ █ ██████ ███ ███ █████ ██ ████████.

Table 17: Summary of Results for iDFS (Primary Outcome) From the NATALEE Trial (FAS)

AI = aromatase inhibitor; CI = confidence interval; DCO = data cut-off; FAS = full analysis set; iDFS = invasive disease–free survival; NE = not estimable; NR = not reported; vs. = versus.

Note: Only the P value in interim analysis 3 (data cut-off date: January 11, 2023) for iDFS was adjusted for multiple comparison. P values for all other outcomes were not adjusted for multiplicity.

^aOne-sided P value for log-rank test stratified by postmenopausal women vs. men and premenopausal women, anatomical stage group II vs. anatomical stage group III, prior neoadjuvant or adjuvant chemotherapy (yes vs. no) and North America, Western Europe, and Oceania vs. rest of world.

^bEstimated by Kaplan-Meier probabilities.

Sources: NATALEE Clinical Study Reports for the end of ribociclib analysis (2024),¹⁷ interim analysis 3 (2023),¹⁸ and sponsor-provided additional data.^19,20 Details included in the table are from the sponsor’s Summary of Clinical Evidence.²¹

Recurrence-Free Survival

At the end of ribociclib analysis, a total of 224 patients (8.8%) in the ribociclib plus AI group and 298 patients (11.7%) in the AI alone group experienced an RFS event (i.e., local invasive disease recurrence in the breast, regional invasive recurrence, distant recurrence, or death due to any cause). The median RFS was not estimable at the end of ribociclib analysis for either treatment group, though the risk of an RFS event favoured ribociclib plus AI compared with AI alone (hazard ratio = 0.70; 95% CI, 0.58 to 0.83; nominal P < 0.0001); however, no formal comparison was performed at the time of the end of ribociclib analysis (Table 18). Similar results were observed in IA3 (hazard ratio = 0.72; 95% CI, 0.58 to 0.88; nominal P = 0.0008).

███ ████████████ ███████████ ████████ ██ ███ ██ ██ ██████ ███ █████ ████ ███ █████ ██ ██████ ███ ███ ██████████ ████ ██ ██████ ███ █████ ████ ███ █████ ██ ██████ ███ ███ ██ ██████ ███ █████████████ ██████████ ███ ████ ████ ███ ████ ██ ██████ The results were also consistent with IA3. The Kaplan-Meier curve estimate of RFS distribution among the end of ribociclib analysis population is depicted in Figure 4. Similar results were observed at the 5-year follow-up analysis (Table 18 and Figure 4).

Distant Disease–Free Survival

At the end of ribociclib analysis, a total of 240 patients (9.4%) in the ribociclib plus AI group and 311 patients (12.2%) in the AI alone group experienced a DDFS event (i.e., distant recurrence, death due to any cause, or second primary nonbreast invasive cancer). The median DDFS was not estimable at the time of the end of ribociclib analysis for either treatment group, though the risk of a DDFS event favoured ribociclib plus AI compared with AI alone (hazard ratio = 0.72; 95% CI, 0.60 to 0.85; nominal P < 0.0001); however, no formal comparison was performed at the time of the end of ribociclib analysis. Similar results were observed in IA3 (hazard ratio = 0.74; 95% CI, 0.60 to 0.91; nominal P = 0.0017). ███ ████████████ ███████████ ████████ ██ ████ ██ ██ ██████ ███ █████ ████ ███ █████ ██ ██████ ███ ███ ██████████ ████ ██ ██████ ███ █████ ████ ███ █████ ██ ██████ ███ ███ ██ ██████ the between-group difference was 4.5% ████ ███ ████ ██ █████ (Table 18). The Kaplan-Meier curve estimate of the DDFS event-time distribution is depicted in Figure 5. Similar results were observed at the 5-year follow-up analysis (Table 18 and Figure 5).

Overall Survival

At the end of ribociclib analysis, a total of 105 patients (4.1%) in the ribociclib plus AI group and 121 patients (4.7%) in the AI alone group had died. The median OS was not estimable for either treatment group, and there was no difference in the risk of death between ribociclib plus AI compared with AI alone (hazard ratio = 0.83; 95% CI, 0.64 to 1.07; nominal P = 0.0766). However, no formal comparison was performed at the time of the end of ribociclib analysis. Similar results were observed in IA3 (hazard ratio = 0.76; 95% CI, 0.54 to 1.07; nominal P = 0.0563). ███ ████████████ ███████████ ████████ ██ ██ ██ ██ ██████ ███ █████ ████ ███ █████ ██ ██████ ███ ███ ██████████ ████ ██ ██████ ███ █████ ████ ███ █████ ██ ██████ ███ ███ ██ ██████ ███ █████████████ ██████████ ███ ████ ████ ███ ████ █ ██ ██████. The Kaplan-Meier curve estimate of the OS event-time distribution is depicted in Figure 6. Similar results were observed at the 5-year follow-up analysis (Table 18 and Figure 6).

Health-Related Quality of Life

Change From Baseline in Global Health Status and Quality of Life Subscale Score of the EORTC QLQ-C30

Results for HRQoL were not available at the end of ribociclib analysis. At IA3, the mean global health status and quality of life subscale score of the EORTC QLQ-C30 at baseline was 73.7 points (SD = 17.7 points) in the ribociclib plus AI group and 73.8 points (SD = 17.8 points) in the AI alone group. At the end of treatment as of IA3, patients in the ribociclib plus AI group reported an estimated mean decrease (deterioration) from baseline in the global health status and quality of life subscale score of the EORTC QLQ-C30 of –10.40 points (SE = 1.36 points) compared to –10.04 points (SE = 1.29 points) in patients in the AI alone group, the between-group difference was –0.36 points (95% CI, –3.12 to 2.39 points; nominal P = 0.7957). A plot of change from baseline to end of treatment in the global health status and quality of life subscale score of the EORTC QLQ-C30 is provided in Figure 7.

Table 18: Summary of Key Secondary Efficacy and Health-Related Quality of Life (FAS)

AI = aromatase inhibitor; CI = confidence interval; DCO = data cut-off; DDFS = distant disease–free survival; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; FAS = full analysis set; GHS = global health status; LS = least squares; NE = not estimable; NR = not reported; OS = overall survival; QoL = quality of life; RFS = recurrence-free survival; SD = standard deviation; SE = standard error; vs. = versus.

^aThe P value was not adjusted for multiple testing, 1-sided P value for log-rank test stratified by postmenopausal women vs. men and premenopausal women, anatomical stage group II vs. anatomical stage group III, prior neoadjuvant or adjuvant chemotherapy (yes vs. no), and North America, Western Europe, and Oceania vs. rest of world.

^bResults for health-related quality of life are from interim analysis 3, with a DCO of January 11, 2023.

Sources: NATALEE Clinical Study Reports for the end of ribociclib analysis (2024),¹⁷ interim analysis 3 (2023),¹⁸ and sponsor-provided additional data.^19,20 Details included in the table are from the sponsor’s Summary of Clinical Evidence.²¹

Harms

Refer to Table 19 for harms data in the NATALEE trial at the end of ribociclib analysis for the safety analysis set (data cut-off date: April 29, 2024).

Adverse Events

At the end of ribociclib analysis, 2,478 patients (98.1%) in the ribociclib plus AI group and 2,155 patients (88.3%) in the AI alone group experienced at least 1 TEAE. The most common TEAEs (reported by at least 20% of patients in either group) were neutropenia (41.7% versus 2.9%), which was reported more frequently in the ribociclib plus AI group than in the AI alone group, and arthralgia (38.8% versus 44.4%), which was reported less frequently in the ribociclib plus AI group than in the AI alone group. AEs with differences of 10% or more between groups included decreased neutrophil count (24.2% versus 1.7%), nausea (23.5% versus 7.9%), increased ALT (19.7% versus 5.7%), and increased AST (17.2% versus 5.9%).

Similar to any-grade AEs, grade 3 or higher AEs were reported more frequently in the ribociclib plus AI group than in the AI alone group (64.2% versus 19.7%). Grade 3 or higher neutropenia (27.0% versus 0.5%) and decreased neutrophil count (17.7% versus 0.3%) were the most reported grade 3 AEs and were more frequent in the ribociclib plus AI group than in the AI alone group.

Serious Adverse Events

At the end of ribociclib analysis, 375 patients (14.8%) in the ribociclib plus AI group and 237 patients (10.9%) in the AI alone group reported at least 1 SAE. The most common SAEs were COVID-19 (0.8% versus 0.5%) and pulmonary embolism (0.6% versus 0.2%). All other SAEs were reported at a frequency of less than 0.5%.

Withdrawals Due to Adverse Events

At the end of ribociclib analysis, TEAEs leading to discontinuation of study treatment were reported in 534 patients (21.1%) in the ribociclib plus AI group and 130 patients (5.3%) in the AI alone group. The most common TEAEs leading to treatment discontinuation were increased ALT (7.2% versus 0.1%), increased AST (2.9% versus 0), and arthralgia (1.3% versus 2.1%). All other AEs leading to discontinuation were reported at a frequency of less than 1.0%.

Mortality

There were 104 patients (4.1%) in the ribociclib plus AI group and 122 patients (5.0%) in the AI alone group who had died before the end of follow-up in the end of ribociclib analysis. Overall, the leading cause of death was disease recurrence or progression (3.0% versus 4.1%). AEs were reported as the primary cause of death for 16 patients (0.6%) in the ribociclib plus AI group and 6 patients (0.2%) in the AI alone group. Infections and infestations (0.3% versus 0.1%) and cardiac disorders (0.2% versus 0.1%) were the most reported AEs leading to death. All other AEs that led to death were reported at a frequency of less than 0.1%.

At the 5-year follow-up analysis, 137 patients (5.4%) in the ribociclib plus AI group and 163 patients (6.7%) in the AI alone group had died, primarily due to disease recurrence (101 patients; 4.0%) or progression (133 patients; 5.4%). There were 19 patients (0.8%) and 8 patients (0.3%) in the NATALEE trial who had fatal AEs in the ribociclib plus AI group and AI group, respectively, and the primary reasons were consistent with the end of ribociclib analysis.

Notable Harms

The clinical experts consulted by CDA-AMC identified hepatobiliary toxicity, QT interval prolongation, and pulmonary toxicity (interstitial lung disease or pneumonitis) as notable harms of interest to ribociclib. Hepatobiliary toxicity was observed in 675 patients (26.7%) in the ribociclib plus AI group and 279 patients (11.4%) in the AI alone group. QT interval prolongation was reported in 136 patients (5.4%) in the ribociclib plus AI group and 38 patients (1.6%) in the AI alone group. Interstitial lung disease or pneumonitis was reported in 41 patients (1.6%) in the ribociclib plus AI group and 21 patients (0.9%) in the AI alone group.

Table 19: Summary of Harms Results From the NATALEE Trial (Safety Analysis Set; Data Cut-Off Date — April 29, 2024)

AI = aromatase inhibitor; ILD = interstitial lung disease; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.

Sources: NATALEE Clinical Study Reports for the end of ribociclib analysis (2024)¹⁷ and sponsor-provided additional data.¹⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.²¹

Critical Appraisal

Internal Validity

The Health Canada–approved indication for ribociclib is for patients with HR-positive, HER2-negative EBC at high risk of recurrence. However, the eligibility criteria for the NATALEE trial population were based on disease stage and included a heterogenous population of patients with varying degrees of risk. There was no definition of high risk provided in the trial, nor were there any prespecified subgroup analyses specifically for high-risk patients in the NATALEE trial. As such, it was unclear what proportion of patients in the NATALEE trial were at high risk of recurrence.

The NATALEE trial was a phase III, multicentre, open-label, active-controlled RCT to evaluate the efficacy and safety of ribociclib plus AI compared to AI alone as an adjuvant treatment in patients with HR-positive, HER2-negative EBC. According to the clinical experts consulted by CDA-AMC, the choice of AI as the comparator was clinically relevant because it is commonly used in clinical practice in Canada for the treatment of patients with HR-positive, HER2-negative EBC.

The NATALEE trial was open label — meaning both the patients and the investigators knew who was receiving ribociclib and who was receiving AI alone — which could introduce performance bias (e.g., differences in how patients are managed or monitored based on their treatment) and detection bias in subjective, self-reported outcomes (e.g., a greater likelihood of reporting AEs or outcomes in the ribociclib plus AI group). Additionally, fewer patients discontinued the study in the ribociclib plus AI group compared to the AI alone group at both the end of ribociclib analysis (17.7% versus 22.1%) and 5-year follow-up (21.5% versus 26.0%). If treatment discontinuations were informed by patients knowing treatment assignment, the observed results may have been influenced by knowledge of and adherence to a treatment regimen rather than solely by the treatment effect.

The clinical experts noted that the median follow-up time at the end of ribociclib analysis (44.2 months) was shorter than ideal, but reasonable considering the NATALEE trial included patients with a high risk of recurrence. However, patients with HR-positive, HER2-negative breast cancer can experience recurrence even after 10 to 15 years. The analysis of iDFS was predominately influenced by the initial treatment response, which represents 10.3% and 13.3% of the probability of an event within each treatment group. In the NATALEE trial, at the end of ribociclib analysis, the survival curves showed a sudden drop beyond 36 months (around 42 months for iDFS, 56 months for RFS and DDFS, and 60 months for OS); this drop is likely artificial and driven by the large amount of censoring observed in the trial. Though more events had occurred at the 5-year follow-up analysis and the proportion of patients who were censored was generally balanced between treatment groups at previous data cut-off dates, there was still a substantial amount of censoring, with rapid drops in the number of patients at risk. The rapid depletion of the risk set may have introduced uncertainties in the estimates of the treatment effects of ribociclib plus an AI on iDFS, RFS, DDFS, and OS at 36, 48, and 60 months. Additionally, the treatment effect observed over 5 years does not permit definitive conclusions about the long-term effectiveness of ribociclib plus an AI.

According to the input provided, patients with EBC and clinicians considered RFS, DDFS, OS, and HRQoL to be relevant outcomes. However, these outcomes were not part of the statistical testing strategy in the NATALEE trial and thus were not controlled for type I error; therefore, the ability to draw causal conclusions from these results may be limited. Additionally, there was a notable attrition rate observed in the analysis of HRQoL measured using the change from baseline in global health status and quality of life subscale score of the EORTC QLQ-C30 at the end of treatment, with only 462 patients (18.8%) contributing to the analysis; considering the median duration of follow-up at the time of the interim analysis was 27.7 months, the attrition was likely due to the insufficient number of patients who had reached the end of treatment, which was defined as completing 5 years of AI in both groups. Given the NATALEE trial was open label and withdrawal by patient was the most common reason for study discontinuation, this would introduce bias because the characteristics of patients who remained in the study may differ from those who did not. Moreover, no sensitivity analyses were conducted for the analysis of HRQoL.

Upon a request from CDA-AMC, the sponsor provided a post hoc subgroup analysis of iDFS for patients who meet the definition of high risk per the monarchE trial (abemaciclib) (Table 28), which was generally consistent with the primary intention-to-treat population; however, this was a post hoc analysis with no statistical testing and was not controlled for overall type I error. As such, the results were purely descriptive and should be considered as supportive data only.

External Validity

The clinical experts highlighted that the NATALEE trial eligibility criteria were standard, but stricter than in clinical practice. For example, patients with significant comorbidities or poorer ECOG Performance Status (e.g., score of 2) were not eligible for the NATALEE trial; however, the clinical experts noted that they would consider patients with an ECOG Performance Status of 2 to be potential candidates for ribociclib based on the extensive experience with ribociclib in the metastatic setting. Additionally, the clinical experts noted there would be a higher proportion of postmenopausal female patients aged 60 to 70 years who are candidates for ribociclib in their clinical practice than the proportion enrolled in the NATALEE trial. Most patients in the NATALEE trial were white (73.4%). The clinical expert indicated there is a more diversified patient population in their clinical practice compared to the patient population in the NATALEE trial. Overall, the patient population in the NATALEE trial may not be fully representative of the patient profile seen in clinical practice.

In the NATALEE trial, genomic test results or Ki-67 levels were used to determine eligibility for patients whose disease was anatomical stage IIA, with no nodal involvement and with an intermediate-grade (grade 2) tumour, but were not used for patients whose disease was stage IIB or III. According to the clinical experts, genomic risk testing (e.g., Oncotype DX) is used to determine eligibility for chemotherapy rather than for ribociclib, and it is unclear whether genomic risk is predictive for treatment with ribociclib. Additionally, the use of genomic testing in the NATALEE trial may not be reflective of current clinical practice because genomic risk testing may be required (i.e., Oncotype DX) for all patients with stage II (A or B) and grade 2 or grade 3 tumour before initiating chemotherapy. Moreover, 88.1% of patients in the NATALEE trial had prior chemotherapy; however, the clinical experts indicated that in clinical practice, most patients with no nodal involvement would have been tested for genomic risk; thus, fewer patients (approximately 70%) in clinical practice would receive chemotherapy than in the NATALEE trial. Therefore, the study results may not be generalizable because patients in the NATALEE trial were more heavily pretreated than patients in clinical practice, which could introduce bias, but the direction of bias is uncertain.

More than half of the patients in the NATALEE trial (62.8%) completed the 3-year treatment duration of ribociclib at the time of the end of ribociclib analysis, and no patients were receiving ribociclib treatment at the end of the 5-year follow-up. The clinical experts commented that adherence to treatment is a challenge in the adjuvant setting due to the longer disease-free intervals. The percentage of patients who completed the 3-year treatment might reflect the clinical effectiveness of treatment in clinical practice, considering patients in the NATALEE trial were predominantly younger women who have more aggressive disease, who may be less willing to endure the side effects (e.g., nausea and fatigue) of ribociclib for the full 3 years.

Corticosteroids and antiemetic medications were allowed to be used concomitantly in the NATALEE trial. According to the clinical experts, these are not commonly used in the adjuvant setting, but patients may receive corticosteroids or antiemetic medications as supportive therapies for prior chemotherapy or to control the side effects of ribociclib, such as nausea and interstitial lung disease. Given the small proportion of patients who used these medications, the impact of the concomitant use of these medications on the study results would likely be minimal.

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for outcomes considered most relevant to inform expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group:^15,16

• High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate certainty: We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. We use the word “likely” for evidence of moderate certainty (e.g., “X intervention likely results in Y outcome”).

• Low certainty: Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect. We use the word “may” for evidence of low certainty (e.g., “X intervention may result in Y outcome”).

• Very low certainty: We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect. We describe evidence of very low certainty as “very uncertain.”

Following the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null. The reference points for the certainty of evidence assessment for iDFS, RFS, DDFS, OS, HRQoL, and harms were set according to the presence of an important effect based on thresholds agreed upon by clinical experts consulted for this review.

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for ribociclib plus AI versus AI alone.

Long-Term Extension Studies

No long-term extension studies were submitted for this review.

Indirect Evidence

Contents within this section have been informed by materials submitted by the sponsor. The following was summarized and validated by the review team.

Objectives for the Summary of Indirect Evidence

In the absence of head-to-head trial data for ribociclib plus AI compared with abemaciclib plus ET for the adjuvant treatment of patients with HR-positive, HER2-negative EBC, the sponsor submitted an MAIC. The objective of this section is to summarize and critically appraise the sponsor-submitted MAIC comparing ribociclib plus AI versus abemaciclib plus ET in the adjuvant treatment of patients with HR-positive, HER2-negative EBC at high risk of disease recurrence based on clinicopathological features.

Description of Indirect Treatment Comparison

Objectives

The objective of the ITC was to estimate the comparative efficacy and safety of ribociclib plus AI and abemaciclib plus ET to inform the economic model of adjuvant treatments for patients with HR-positive, HER2-negative EBC at high risk of disease recurrence based on clinicopathological features.

Indirect Treatment Comparison Design

Study Selection Methods

A systematic literature review (SLR) was conducted to identify trials for the adjuvant treatment of HR-positive, HER2-negative EBC. The SLR was conducted on March 30, 2023, and updated in October 2023 to identify any supplementary evidence published subsequent to the initial SLR searches. The following electronic databases were searched: MEDLINE All (1946‒), Embase (1974‒), MEDLINE In-Process, and the Cochrane Central Register of Controlled Trials. In addition, conference abstracts from the past 3 years were hand searched to retrieve the latest studies that had not yet been published in journals as full-text articles. Bibliographies of all relevant SLRs and meta-analyses identified during the review were also hand searched to identify any additional relevant studies for inclusion. Searches of the ClinicalTrials.gov registry, health technology assessment websites, and the FDA database were also performed.

The SLR followed the Cochrane Handbook and National Institute for Health and Care Excellence guidelines. Citations were screened by 2 independent reviewers, with discrepancies resolved by a third. Data extraction was performed using a predefined grid and checked by a second reviewer. Subgroup analyses based on the latest NATALEE trial were also extracted, focusing on menopausal status, disease stage, nodal status, and prior chemotherapy. The quality of RCTs was assessed using the York Centre for Reviews and Dissemination checklist.

Table 20: Study Selection Criteria and Methods for Indirect Comparisons

AI = aromatase inhibitor; CENTRAL = Cochrane Central Register of Controlled Trials; CRD = York University Centre for Reviews and Dissemination; DRFS = distant recurrence–free survival; EBC = early breast cancer; ESMO = European Society for Medical Oncology; ET = endocrine therapy; HR = hormone receptor; iDFS = invasive disease–free survival; NICE = National Institute for Health and Care Excellence; OS = overall survival; SLR = systematic literature review; TEAE = treatment-emergent adverse event; TNBC = triple-negative breast cancer.

Source: Ribociclib indirect treatment comparison technical report.⁵⁶

ITC Analysis Methods

Statistical Model

Based on the feasibility assessment, an unanchored MAIC was used to compare ribociclib plus AI versus abemaciclib plus ET. However, an anchored analysis (Bucher ITC) was conducted for iDFS via a common comparator in a subgroup of patients (i.e., iDFS in ribociclib plus AI in the NATALEE trial and the subgroup of the abemaciclib plus ET group in the monarchE trial that received AIs only).

The unanchored MAICs were conducted using procedures described in the National Institute for Health and Care Excellence Decision Support Unit Technical Support Document 18.^57-59 Standardized MAIC weights were generated using the method of moments, with active treatment and control arms matched separately to ensure any residual imbalances between active and control arms in the monarchE trial were replicated in the matched NATALEE sample.⁵⁹ Although the method of moments used in the MAIC typically ensures covariate balance for the reported characteristics for the 2 trials, standardized mean differences were also calculated for all baseline characteristics to validate the matching and to assess differences between treatments in characteristics not included in the matching algorithm (if any). Distributions of MAIC weights were plotted as histograms to identify outlier observations. The effective sample size for selected patients in the NATALEE trial after weighting was also calculated. A Cox regression model (semiparametric) was chosen to compare ribociclib plus AI with abemaciclib plus ET for time-to-event analyses. The validity of the Cox proportional hazards assumption between ribociclib plus AI and abemaciclib plus ET, before and after weighting, was tested by a visual inspection of the log-cumulative hazard plots and by the Schoenfeld global test of proportionality.

Data Sources

The ITCs used individual patient data (IPD) from the NATALEE trial’s ribociclib plus AI treatment group from the end of ribociclib analysis (April 29, 2024, data cut-off), and aggregate data from the monarchE trial’s abemaciclib plus ET treatment group. The aggregate data from the monarchE trial used in the MAICs come from the prespecified 5-year monarchE trial efficacy analysis.⁶⁰ However, the AE rates for cohort 1 of the monarchE trial had not been published at the time of these analyses. As such, safety outcomes were based on data reported for the safety set of the monarchE trial.⁶¹ The control arms in the NATALEE and monarchE trials consisted of different therapies, preventing a shared comparator necessary to form a connected network.

The NATALEE trial enrolled a broader patient population than the monarchE trial for treatment of EBC. Patients in the monarchE trial were enrolled in 2 cohorts, each with different criteria used to define high-risk characteristics. Cohort 1 of the monarchE trial included patients with 4 or more positive ALNs, or 1 to 3 positive ALNs with grade 3 disease and/or a tumour of 5 cm or greater. Cohort 2 included patients with 1 to 3 positive nodes and a Ki-67 of 20% or greater who did not meet the criteria for cohort 1. Cohort 2 was excluded from the ITC analyses. For the ITC, patients in the NATALEE trial were selected if they met the eligibility criteria for enrolment in cohort 1 of the monarchE trial. Per the NATALEE trial protocol, nodal involvement and tumour size were determined based on the worst of the measurements taken at the time of diagnosis and on a surgical specimen following resection (i.e., anatomical assessment). Information on histologic grade and nodal status were captured at baseline assessment for patients enrolled in the NATALEE study. However, information on explicit tumour size was not captured in the NATALEE study. As such, patients who met the criteria for 1 to 3 positive lymph nodes and a tumour size of 5 cm or greater were identified using information on the tumour, node, and metastasis (TNM) staging as a proxy. Key characteristics of the studies selected for the MAIC are summarized in Table 21.

Table 21: Assessment of Homogeneity

AI = aromatase inhibitor; EBC = early breast cancer; ET = endocrine therapy; iDFS = invasive disease–free survival; ITC = indirect treatment comparison; MAIC = matching-adjusted indirect comparison; OS = overall survival; SMD = standardized mean difference; STEEP = Standardized Definitions for Efficacy End Points.

Source: Ribociclib ITC technical report.⁵⁶

Adjustment Factors Included in the MAIC Analyses

The baseline characteristics reported for cohort 1 of the monarchE trial that were included for adjustment in the MAIC based on a literature review and clinician input are listed in Table 22. The relevance of baseline characteristics as effect modifiers and/or prognostic factors for efficacy was determined through interviews with key opinion leaders and assessed using statistical tests. External clinicians were interviewed to determine which characteristics were known to be prognostic factors for efficacy in EBC, by varying degrees of influence.

Statistical tests were conducted to identify treatment-effect modifiers and prognostic factors, which are summarized in the ITC report.⁵⁶ Table 22 also reports the results of the statistical tests identifying effect modifiers and prognostic factors. Sensitivity analyses were conducted to assess the range of plausible estimates for treatment effects when adjusting for fewer variables. Two alternative sets of MAIC weights were estimated for characteristics that were of high importance based on consensus among the clinicians, and for characteristics indicated by clinicians as important prognostic factors (high or low), as well as all characteristics with evidence of prognostic influence based on quantitative tests (Table 22). The weights estimated in these sensitivity analyses were then used in the comparison of outcomes, following the same procedures as the primary analysis.

Missing values in the IPD from the NATALEE trial that did not have a corresponding missing category in the summary-level data from the monarchE trial were imputed by randomly assigning values from the nonmissing values. The primary analysis for the unanchored MAIC included all of the available characteristics shown in Table 22. The weighting scheme chosen was adjusted for all available characteristics, provided the effective sample size remained reasonable.

Table 22: Adjustment Factors Included in the MAIC Analyses

BMI = body mass index; Dx = diagnosis; EBC = early breast cancer; ECOG PS = Eastern Cooperative Oncology Group Performance Status; HR = hormone receptor; NA = not adjusted; SA = sensitivity analysis; TNM = tumour, node, and metastasis.

Note: “—” indicates not important (per clinician interview) or not statistically significant at alpha = 0.05 (if statistical test).

^aBased on P value for interaction test.

^bAdjusted for all of the available effect or prognostic modifiers.

^cAdjusted for high importance of effect or prognostic modifiers based on clinician interviews.

^dAdjusted for any importance effect or prognostic modifiers based on clinician interviews and/or statistically significant based on statistical test.

Source: Ribociclib indirect treatment comparison technical report.⁵⁶

Outcomes

The outcomes assessed in the ITC were iDFS, DRFS, OS, and grade 3 or higher TEAEs with an incidence of at least 5% in either trial. Time-to-event data for iDFS, DRFS, and OS for patients in the monarchE trial were obtained by digitizing published Kaplan-Meier curves.^61,62 Reconstructed individual patient time-to-event data for iDFS, DRFS, and OS for the monarchE treatment arms was generated using an adaptation of a published algorithm from Guyot et al. (2012).⁶³ Hazard ratios and 95% CI were calculated with a Cox proportional hazards regression model.⁵⁹ Safety was assessed based on rates of AEs; ORs and 95% CI were calculated. ORs for TEAEs were calculated using logistic regression. For TEAEs for which there were no events in 1 or more treatment arms, ORs were calculated using a continuity correction by adding 1 patient with the event and 1 without the event to each arm. Results were estimated separately for each of the MAIC analyses: selected unweighted, selected with primary analysis weights applied, and selected with weights applied from the 2 sensitivity analyses.

Secondary Analysis

An anchored analysis of iDFS, via common comparator, was conducted as a second analysis using data reported for a subgroup of patients who received an AI as the ET component of each treatment arm in cohort 1 of the monarchE trial and excluding patients who received tamoxifen as the endocrine partner. This subgroup analysis employed a Bucher ITC.⁶⁴ It was noted that baseline characteristics for this subgroup of the monarchE trial were not available, which prohibited the calculation of MAIC weights specific to the AI-only subgroup of the monarchE trial. As such, hazard ratios for iDFS in the NATALEE study were based on those estimated for the selected, unweighted sample.

Matching-Adjusted Indirect Comparison Methods

MAIC methods are summarized in Table 23.

Table 23: Matching-Adjusted Indirect Comparison Methods

AI = aromatase inhibitor; CI = confidence interval; DRFS = distant recurrence–free survival; EBC = early breast cancer; ESS = effective sample size; ET = endocrine therapy; HR = hormone receptor; iDFS = invasive disease–free survival; IPD = individual patient data; MAIC = matching-adjusted indirect comparison; OR = odds ratio; OS = overall survival; TEAE = treatment-emergent adverse event.

Source: Ribociclib indirect treatment comparison technical report.⁵⁶

Results of the ITC

Summary of Included Studies

Search Results

A total of 399 records were initially screened for the SLR. A total of 44 studies reported in 136 publications were included in this SLR. Of the 44 included studies, only 2 studies met the eligibility criteria for the ITC: 1 trial (NATALEE) evaluating ribociclib plus AI and 1 trial (monarchE) evaluating abemaciclib plus ET.

Evidence Networks

Selection of Patients

Patients were selected from the NATALEE trial who would meet high-risk eligibility criteria for cohort 1 of the monarchE trial.

MAIC Weights

The patient baseline characteristics before adjustment are presented in Table 29 in Appendix 1. The patients selected from the NATALEE trial and patients in cohort 1 of the monarchE trial were balanced for many of the reported characteristics at baseline, and standardized mean differences did not exceed 50% for almost all characteristics, except region and missing Ki-67 status. After weighting, the effective sample size for the ribociclib plus AI and AI-only arms was 448 and 453, respectively, constituting a reduction of 73.0% to 72.5% from the selected sample size in each arm, respectively. After weighting, the standardized mean differences between the patient characteristics of the weighted NATALEE trial population and the monarchE study cohort 1 population are relatively small or zero.

The KM curves for iDFS, DRFS, and OS are presented in Figure 7, Figure 8, and Figure 9 in Appendix 1. Kaplan-Meier curves for abemaciclib plus ET treatment and the weighted ribociclib plus AI treatment largely overlapped for all outcomes.

Efficacy

The overall MAIC results are presented in Table 24.

Invasive Disease–Free Survival

Primary Analysis

After applying the MAIC weights, the estimated iDFS hazard ratio was 0.901 for ribociclib plus AI versus abemaciclib plus ET (95% CI, 0.677 to 1.197; P = 0.4701).

Sensitivity Analyses

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Table 24: Summary of MAIC Results Comparing Ribociclib Plus AI With Abemaciclib Plus ET

AI = aromatase inhibitor; CI = confidence interval; DRFS = distant recurrence–free survival; ESS = effective sample size; ET = endocrine therapy; iDFS = invasive disease–free survival; MAIC = matching-adjusted indirect comparison; OS = overall survival.

Note: ET in the NATALEE study consisted of letrozole and anastrozole only, while ET in the monarchE trial consisted of letrozole, anastrozole, exemestane, and tamoxifen.

^aIn the primary analysis, MAIC weights were adjusted for all available baseline characteristics published for the monarchE trial.

^bSensitivity analysis 1 was adjusted for characteristics for which there was a consensus of high prognostic importance among clinicians.

^cSensitivity analysis 2 was adjusted when there was evidence of some prognostic importance among clinicians and statistically significant based on statistical test.

Source: Ribociclib indirect treatment comparison technical report.⁵⁶

Subgroup Analysis (i.e., Secondary Analysis)

The estimated hazard ratio for ribociclib plus AI versus abemaciclib plus AI based on the Bucher ITC was 0.957 (95% CI, 0.726 to 1.261) (Table 25).

Table 25: Anchored Bucher Model ITC of iDFS in the NATALEE Study vs. iDFS in the monarchE Trial AI Subgroup (Unweighted)

AI = aromatase inhibitor; CI = confidence interval; iDFS = invasive disease–free survival; ITC = indirect treatment comparison; vs. = versus.

Source: Ribociclib ITC technical report.⁵⁶

Distant Relapse–Free Survival

Primary Analysis

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Sensitivity Analyses

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Overall Survival

Primary Analysis

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Sensitivity Analyses

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Harms

Grade 3 or higher TEAEs with an incidence of at least 5% in either trial were compared in the unanchored MAIC. Results of the weighted comparisons are presented in Table 26. In the weighted comparison, ribociclib plus AI also had significantly increased odds of neutropenia (OR = 1.56; 95% CI, 1.23 to 1.97) compared with abemaciclib plus ET, and increased ALT (OR = 3.94; 95% CI, 2.56 to 6.05). Odds ratios for diarrhea, leukopenia, and lymphopenia were reduced with ribociclib plus AI versus abemaciclib plus ET, with estimated ORs of 0.11 (95% CI, 0.03 to 0.40), 0.27 (95% CI, 0.16 to 0.46), and 0.14 (95% CI, 0.04 to 0.53), respectively, based on the weighted analysis. Results from 2 sensitivity analyses were consistent with the primary analyses for TEAEs (Table 26).

Table 26: MAIC Results of Grade 3 or Higher TEAEs

AI = aromatase inhibitor; CI = confidence interval; ET = endocrine therapy; OR = odds ratio; TEAE = treatment-emergent adverse event; vs. = versus.

Note: OR < 1 means results were in favour of ribociclib plus ET; OR > 1 means results were in favour of abemaciclib plus ET. Event rates equal to zero were adjusted with continuity correction to allow for the estimation of odds ratios via logistic regression. AI in the NATALEE study consisted of letrozole and anastrozole only, while ET in the monarchE trial consisted of letrozole, anastrozole, exemestane, and tamoxifen.

Source: Ribociclib indirect treatment comparison technical report.⁵⁶

Critical Appraisal of ITC

The search for potentially eligible studies was reasonably comprehensive, and the methods used to select relevant studies, extract data, and assess the risk of bias of the included studies were adequate. The MAIC estimation procedure was mostly conducted according to best practice. One limitation is the use of matching weights for each treatment arm separately. This approach has been criticized in the past because it may break randomization in the IPD, distorting the balance between treatment arms on covariates that are not accounted for in the weighting, and potentially compromising the internal validity of the within-study estimate.^65,66 The unanchored approach makes the interpretation of the efficacy results difficult to translate as an estimate of effectiveness in the Canadian clinical setting. The absence of a comparator that aligns with Canadian clinical practice increases the uncertainty about the magnitude and direction of effect for ribociclib plus AI versus abemaciclib plus ET.

A key limitation of the MAIC was heterogeneity across the included studies. The sponsor identified potential prognostic modifiers and effect modifiers — including pathological diagnosis, HR status, lymph nodes, histopathology at diagnosis, TNM stage, tumour size, and Ki-67 Index — through literature searches and clinical expert opinion. In the primary analysis, the MAIC was adjusted for all of the baseline characteristics identified in published reports of cohort 1 from the monarchE study but excluded patients from both studies outside of this subcohort. The omission of these patients, who are within the Health Canada indication for ribociclib, leads to uncertainty in the generalizability of the efficacy results to the clinical context. It should be noted that CDA-AMC recommended that public drug plans reimburse abemaciclib in combination with ET for the adjuvant treatment of adults with HR-positive, HER2-negative, node-positive, EBC at high risk of recurrence based on the clinicopathological features of the patients included in cohort 1 and cohort 2 of the monarchE trial (4 or more positive ALNs, or 1 to 3 positive ALNs plus histologic grade 3 disease, or 1 to 3 positive ALNs plus a tumour size of 5 cm or more, or 1 to 3 positive ALNs plus a Ki-67 score of 20% or more if tumour size is less than 5 cm and disease is not grade 3). Excluding data from cohort 2 of the monarchE trial leads to uncertainty in the generalizability of the ITC efficacy results to the clinical context.

A Bucher analysis of iDFS, via common comparator (i.e., AI), was conducted as a second analysis (subgroup analysis) using data reported for a subgroup of patients receiving AI as the ET component of each treatment arm in cohort 1 of the monarchE trial and excluding patients who received tamoxifen as the endocrine partner. However, this subgroup analysis was not weighted and adjusted for the prognostic and treatment-effect modifiers; thus, this comparison may not be capturing the real-life treatment regimen used in clinical practice.

Overall, the results for iDFS, DRFS, and OS generally suggested no difference between ribociclib plus AI and abemaciclib plus ET in cohort 1 of the monarchE trial, but the generalizability of the results to the Canadian clinical setting is uncertain. A reduced effective sample size (approximately 70% across various analyses), and wide 95% CIs for the comparative effect estimates (hazard ratios) contributed to imprecision and suggested either benefit or harm in efficacy outcomes. Grade 3 or higher TEAEs (that occurred in ≥ 5% patients) were assessed in the MAIC, but no other safety outcomes such as SAEs and discontinuation due to AEs were assessed. HRQoL was identified by patient groups as an important outcome; however, no indirect comparison was conducted for HRQoL.

Studies Addressing Gaps in the Systematic Review Evidence

No studies addressing gaps in the evidence from the systematic review were submitted for this review.

Discussion

Summary of Available Evidence

The evidence included in this review consisted of 1 pivotal study (NATALEE) and an MAIC. No long-term extension studies or studies addressing gaps in the evidence were included.

The NATALEE trial was a phase III, open-label, active-controlled RCT to evaluate the efficacy and safety of ribociclib plus AI (n = 2,549) compared to AI alone (n = 2,552) in adult patients with HR-positive, HER2-negative, stage II or III EBC, irrespective of nodal status. Randomization was conducted using an interactive response technology system and stratified by menopausal status (postmenopausal versus premenopausal, with men included in the premenopausal category), anatomical stage (II versus III), prior adjuvant or neoadjuvant chemotherapy (yes versus no), and geographical region (North America, Western Europe, and Oceania versus rest of the world). The primary objective of the NATALEE trial was to evaluate the efficacy of ribociclib plus AI compared to AI alone as an adjuvant treatment in premenopausal and postmenopausal women, and men, with HR-positive and HER2-negative EBC in prolonging iDFS, and secondary outcomes included RFS, DDFS, OS, HRQoL, and safety. The baseline demographic and disease characteristics were balanced between the treatment groups. The median age of all patients was 52.0 years, with ages ranging from 24 to 90 years. Most patients were postmenopausal (55.8%) women (99.6%) and most were white (73.4%), but the trial also included patients who self-reported as American Indian or Alaska Native, Asian, Black or African American, and Native Hawaiian or other Pacific Islander. The majority of patients had an ECOG Performance Status score of 0 (83.1%). More than half (59.6%) of patients had disease that was AJCC stage III, nearly half of patients (41.2%) had 1 to 3 positive ALNs, and most patients (88.1%) had received prior adjuvant or neoadjuvant chemotherapy.

In the absence of direct comparative evidence versus relevant comparators, the sponsor conducted an ITC using MAIC methods to estimate the relative efficacy of ribociclib plus AI compared with abemaciclib plus ET in the adjuvant treatment of patients with HR-positive, HER2-negative EBC at high risk of disease recurrence based on clinicopathological features of the monarchE trial. The outcomes of interest in the MAICs included iDFS, DRFS, OS, and safety.

Interpretation of Results

Efficacy

The indication for ribociclib plus AI is for the adjuvant treatment of patients with HR-positive, HER2-negative stage II and III EBC at high risk of recurrence. According to the clinical experts consulted for this review, current systemic therapies for the indicated patient population included chemotherapy, ET (e.g., an AI), and abemaciclib (for patients with a high risk of recurrence). In clinical practice, treatment decisions are often based on tumour pathological features and genomic testing results such as Oncotype DX. In the NATALEE trial, genomic testing results (e.g., Oncotype DX) were used to determine the eligibility for patients with stage IIA disease and a grade 2 tumour. However, the clinical experts commented that genomic risk testing (e.g., Oncotype DX) is used to determine eligibility for chemotherapy rather than for ribociclib because it is unclear whether genomic risk is predictive for treatment with ribociclib. Additionally, genomic risk is not currently used to determine eligibility for abemaciclib. This is a challenge when comparing the drug with other treatments, such as chemotherapy and abemaciclib. Furthermore, patients with an ECOG Performance Status score greater than 1 were excluded from the NATALEE trial; however, the clinical experts consider patients with a poorer ECOG Performance Status (e.g., score of 2) to be potential candidates for ribociclib in clinical practice. Moreover, the NATALEE trial predominantly included patients with a median age of 52 years, which the clinical experts noted is younger than the patients they see in clinical practice. Overall, these limitations may compromise the generalizability of the study results to clinical practice in Canada.

The patient and clinician input highlighted the need for effective treatments for EBC that reduce the risk of recurrence with manageable side effects and that maintain quality of life. Based on the results of the NATALEE trial at IA3 (data cut-off date: January 11, 2023) — when the NATALEE trial met its primary end point — treatment with ribociclib plus AI resulted in an improvement in iDFS compared with AI alone (hazard ratio = 0.75; 95% CI, 0.62 to 0.91; P = 0.0014). The between-group difference in iDFS probability was 3.3% (95% CI, 0.9% to 5.7%) at 36 months. Results from the end of ribociclib analysis with a longer follow-up time (data cut-off date: April 29, 2024) were consistent with the primary analysis in IA3 (hazard ratio = 0.72; 95% CI, 0.61 to 0.84; nominal P < 0.0001).The between-group difference in iDFS probability at 36 months was nearly identical to IA3 and, at 48 months, was 4.9% (95% CI, 2.7% to 7.1%). At the 5-year follow-up analysis, the between-group difference in iDFS probability at 60 months was 4.5% (95% CI, 2.1% to 6.9%). The between-group differences in iDFS event-free probability at 36, 48, and 60 months were considered beneficial but potentially not clinically meaningful, based on the threshold of 5% suggested by the clinical experts. In the review of abemaciclib for a similar population, a threshold range of clinical meaningfulness of 3% to 5% was used. Supposing these results were considered in the context of a 3% threshold, the results for iDFS at 36 months would not be considered clinically meaningful, though there would be moderate certainty that the results for iDFS at 48 and 60 months were clinically meaningful, given that most of the observed effect lies higher than the threshold; however, the 95% CIs also include the possibility of no benefit, though the imprecision may not be considered serious.

Results of the GRADE assessments for RFS, DDFS, and OS also suggested there is moderate certainty that when compared with AI alone, ribociclib plus AI likely results in a little to a small clinically important difference in the probabilities of RFS and DDFS, and little to no clinically important difference in the probability of being alive at 48 and 60 months. The differences between groups were not deemed clinically meaningful at a 3% (for OS) or 5% (for RFS and DDFS) threshold, particularly for OS at 60 months when the majority of the effect lies less than the threshold of 3% suggested by the experts.

The median iDFS, RFS, DDFS, and OS were not reached in either treatment group at IA3, the end of ribociclib analysis, or the 5-year follow-up. The analysis of iDFS is predominately influenced by the initial treatment response, which is represented by the event rate of 10.3% in the ribociclib plus AI group and 13.3% in the AI alone group at the end of ribociclib analysis, and 12.4% and 16.0%, respectively, at the 5-year follow-up analysis. However, the treatment effect observed over 5 years does not permit definitive conclusions about the long-term effectiveness of ribociclib plus AI. There were observed improvements in the iDFS, RFS, and DDFS, though the degree to which the observed benefits in the trial in terms of these outcomes could be translated to an improvement in OS remains uncertain. Additionally, despite the high probabilities of remaining event-free at 48 and 60 months, it remains uncertain how long the treatment response could be sustained. Considering fewer patients in the ribociclib plus AI group received subsequent antineoplastic medications than patients in the AI alone group, there is the potential for bias in the OS results favouring the AI alone group because they received more treatment, which might have led to the dilution of any OS benefit in the ribociclib plus AI group. Moreover, compared to the AI alone group, the ribociclib plus AI group had fewer discontinuations and more patients remaining on treatment. Additionally, patient withdrawal was less frequent in the ribociclib plus AI group. These factors may introduce attrition bias that could lead to better observed efficacy outcomes, not solely due to the treatment effect, but because more patients adhered to ribociclib plus AI. Overall, there were treatment and attrition biases both potentially against and in favour of ribociclib plus AI, which increase the uncertainty in the magnitude of the treatment effect.

As previously noted, results for HRQoL were available only as of IA3 and not at longer follow-ups (i.e., the end of ribociclib analysis or 5-year follow-up). Though the results for HRQoL suggested a decline in quality of life, they were similar between the ribociclib plus AI and AI alone groups. There was a high proportion of missing data, with only 462 of 2,549 patients in the ribociclib plus AI group and 497 of 2,552 patients in the AI alone group contributing to the analysis, which may be due to the limited number of patients who had reached the end-of-treatment stage. This high rate of attrition introduces uncertainty and difficulty in interpreting the effect of ribociclib plus AI on HRQoL.

The indication of ribociclib plus AI is for patients with HR-positive, HER2-negative EBC at high risk of recurrence. However, the eligibility criteria of the NATALEE trial enrolled patients based on disease stage, not exclusively patients at high risk, for which there was no definition. The primary comparator for the high-risk population, abemaciclib, defined high-risk patients as those with either 4 or more positive ALNs, or between 1 and 3 positive ALNs and either grade 3 disease or tumour size of 5 cm or larger.⁶¹ Therefore, CDA-AMC asked the sponsor to provide additional data on a subset of patients in the NATALEE trial who would or would not meet the eligibility criteria for cohort 1 of the monarchE trial. Although the subgroup analysis results were consistent with the primary iDFS analysis, this subgroup was not predefined in the NATALEE trial and was not subject to multiplicity controls. As such, these results were considered supportive, and no definitive conclusions were able to be drawn from the subgroup analysis on patients with EBC at high risk of recurrence.

To address the previously mentioned concern about the high-risk population, and given the lack of direct comparative evidence between ribociclib plus AI and relevant comparators, the sponsor conducted an MAIC to estimate the relative efficacy of ribociclib plus AI compared with abemaciclib plus ET in the adjuvant treatment of patients with HR-positive, HER2-negative EBC at high risk of disease recurrence according to the eligibility criteria of cohort 1 of the monarchE trial. Overall, in terms of iDFS, DRFS, and OS, the results of the MAIC suggested there was no difference in efficacy between treatments, but the reduced sample size and wide 95% CIs reduced the precision of the effect. In addition, the MAIC analysis was further limited by the omission of potential effect modifiers from the model, which can result in a biased estimate of comparative efficacy. Importantly, the MAIC was conducted only for patients matching the high-risk characteristics of the monarchE trial, which does not reflect the reimbursement request, and should not be generalized to all patients with HR-positive, HER2-negative EBC. Therefore, the MAIC results should be interpreted with caution, taking into consideration the limitations of the methods to adjust for potential confounding and the key differences in the trial population.

Harms

Ribociclib has been available in Canada for patients with metastatic breast cancer since 2018, providing extensive clinical experience with the drug. Overall, no new safety signals for ribociclib plus AI were identified in the NATALEE trial. Generally, increased incidences of AEs were observed and more patients stopped treatment due to AEs in the ribociclib plus AI group compared to the AI alone group. In addition, grade 3 or higher AEs were reported more frequently in the ribociclib plus AI group than in the AI alone group. These AEs typically require medical intervention and can significantly impact a patient’s daily life. The clinical experts indicated that increased incidences of neutropenia and infections due to the addition of ribociclib would be expected in clinical practice based on their experience with the drug in the metastatic setting. Although more patients died in the AI alone group overall, there was a numerically higher incidence of AEs (e.g., infections and cardiac disorders) leading to death observed in the ribociclib plus AI group. The combination of ribociclib and an AI may offer improved treatment effect; however, the increased risk of death must be weighed against these benefits. In the NATALEE trial, there were increased incidences of hepatobiliary toxicity, QT interval prolongation, and interstitial lung disease or pneumonitis. According to the clinical experts, these AEs are particularly concerning in the adjuvant setting, and there would be added management burden because patients receiving both ribociclib and an AI require more frequent blood work, cardiac monitoring, and clinic visits compared to patients on ET alone. In terms of comparative safety, the MAIC results report increased odds of neutropenia among the ribociclib plus AI group, and decreased odds of TEAEs, such as diarrhea, leukopenia, and lymphopenia, compared to abemaciclib plus ET.

The inputs from patient and clinician groups highlighted that the treatment duration for ribociclib is 3 years and 2 years for abemaciclib, which will increase the need for clinical monitoring for an extra year. Although the median duration of treatment with ribociclib was approximately 3 years (35.7 months) in the NATALEE trial, the mean duration was slightly more than 2 years (26.5 months). The longer median duration may provide more robust data on long-term efficacy and safety effects, but the shorter mean duration suggests that not all patients may benefit from extended treatment with ribociclib. Additionally, the clinical experts and the clinician groups consulted by CDA-AMC noted that adherence is an issue in the adjuvant setting due to longer disease-free intervals, and speculated that the longer treatment duration of ribociclib may cause more adherence issues, based on their experience in the real-world setting.

Conclusion

The input from patients and clinicians highlighted the need for new effective treatments for EBC that reduce the risk of recurrence with manageable side effects and that maintain quality of life. Evidence from 1 phase III, open-label, active-controlled RCT (NATALEE) comparing the efficacy and safety of ribociclib plus AI with AI alone as adjuvant treatment in patients with HR-positive, HER2-negative, stage II or III EBC demonstrated that, when compared to AI alone, the addition of ribociclib to AI results in a statistically significantly prolonged iDFS; however, the magnitude of the benefit was not clinically meaningful based on the 5% threshold suggested by the clinical experts. Using a threshold of 3%, as has been done previously, the results for iDFS at 48 and 60 months may be considered clinically meaningful because most of the observed effect lies higher than the threshold, although this remained uncertain. Results for RFS, DDFS, and OS were consistent with the primary outcome; however, they were secondary and were not controlled for multiplicity. Therefore, they were only considered supportive of the overall effect of ribociclib plus AI. Additionally, the differences between treatment groups for RFS, DDFS, and OS are likely not clinically meaningful based on the thresholds suggested by the clinical experts. The results were uncertain for all time-to-event efficacy outcomes because the medians of these end points were not reached in either study group at the time of the end of ribociclib analysis, indicating the data were immature. There was a decrease in overall quality of life for both ribociclib plus AI and AI alone, although there was little to no difference in HRQoL between treatments and the results were difficult to interpret due to the large amount of missing data, precluding definitive conclusions.

There is extensive experience with ribociclib because it has been available to patients in Canada since 2018. In the NATALEE trial, no new safety signals were identified, and the safety profile was considered manageable based on the clinical experts’ experience with the drug in the metastatic setting.

Indirect evidence via 1 sponsor-submitted MAIC comparing ribociclib plus AI to abemaciclib plus ET suggested no difference between the 2 treatment regimens. However, there were limitations in the indirect evidence, specifically, that the population of patients from the NATALEE study was matched to cohort 1 of the monarchE trial and was not representative of the entire population within the scope of this Reimbursement Review. Additionally, considerable reductions in effective sample size resulting in wide 95% CIs undermined the validity and precision of the results, precluding conclusions on the comparative efficacy of ribociclib plus AI.

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Appendix 1: Detailed Outcome Data

Please note that this appendix has not been copy-edited.

Figure 2: Kaplan-Meier Plot for Invasive Disease–Free Survival at IA3 (FAS; Data Cut-Off Date — January 11, 2023) and the End of Ribociclib Analysis (FAS; Data Cut-Off Date — April 29, 2024)

CI = confidence interval; ET = endocrine therapy; NE = not evaluated.

Sources: NATALEE Clinical Study Report for interim analysis 3 (2023)¹⁸ and NATALEE Clinical Study Report for the end of ribociclib analysis (2024).¹⁷

Table 27: iDFS Results by Subgroups

AI = aromatase inhibitor; BMI = body mass index; CI = confidence interval; ER = estrogen receptor; PR = progesterone receptor; NSAI = nonsteroidal aromatase inhibitor.

Sources: NATALEE Clinical Study Report for interim analysis 3 (2023)¹⁸ and NATALEE Clinical Study Report for the end of ribociclib analysis (2024).¹⁷

Table 28: Post Hoc Subgroup Results for the monarchE Trial Cohort 1–Eligible vs. Cohort 1–Ineligible From the NATALEE Study (FAS; Data Cut-Off Date — April 29, 2024)