Reimbursement Recommendation

Ribociclib (Kisqali)

Indication: In combination with an aromatase inhibitor for the adjuvant treatment of adult patients with HR-positive, HER2‑negative stage II-III early breast cancer at high risk of recurrence. In pre- or perimenopausal women, or men, the aromatase inhibitor should be combined with a luteinizing hormone-releasing hormone agonist.

Sponsor: Novartis Pharmaceuticals Canada Inc.

Final recommendation: Reimburse with conditions

What Is the Reimbursement Recommendation for Kisqali?

Canada’s Drug Agency (CDA-AMC) recommends that Kisqali in combination with an aromatase inhibitor (AI) should be reimbursed by public drug plans for the adjuvant treatment of adult patients with hormone receptor (HR)–positive, HER2‑negative stage II or III early breast cancer (eBC) at high risk for recurrence, if certain conditions are met.

Which Patients Are Eligible for Coverage?

Kisqali, in combination with an AI, should only be covered to treat adults with breast cancer that has receptors for estrogen and progesterone hormones, tests negative for the HER2 protein, has been surgically removed, and has not spread to other parts of the body. It should only be used in patients with stage IIA, IIB, or III disease. For stage IIA node-negative disease, the cancer must also be either grade 3 or grade 2 with high-risk features (e.g., a Ki-67 proliferation index score ≥ 20%), or the patient must have a high-risk result with a genomic test. Eligible patients should also have good performance status.

What Are the Conditions for Reimbursement?

Kisqali, in combination with an AI, should only be reimbursed if prescribed by clinicians with expertise in managing eBC and if the cost of Kisqali is reduced.

Why Did CDA-AMC Make This Recommendation?

• Evidence from a clinical trial showed that treatment with Kisqali plus an AI resulted in added clinical benefit in delaying the return of breast cancer compared with an AI alone in patients with eBC at high risk for recurrence. The sponsor also submitted an indirect comparison suggesting no difference between Kisqali and abemaciclib among patients at high risk for recurrence, but important limitations made the results unreliable and prevented clear conclusions about how the 2 treatments compare.

• Based on the CDA-AMC assessment of the health economic evidence, Kisqali plus an AI does not represent good value to the health care system at the public list price. A price reduction is therefore required. The committee determined that there is not enough evidence to justify a greater cost for Kisqali plus an AI compared with abemaciclib plus endocrine therapy (ET) over the duration of treatment in the subgroup of patients at high risk for recurrence.

• Patients expressed a need for effective treatments that lower the chance of their breast cancer coming back, improve survival, maintain quality of life (QoL), and have manageable side effects. Kisqali plus an AI meets some of these needs because it offers an additional treatment option that helps reduce the risk of recurrence and has manageable side effects. However, it is unclear whether Kisqali helps patients live longer or maintain QoL.

• Based on public list prices, Kisqali plus an AI is estimated to cost public drug plans approximately $212 million over the next 3 years.

Additional Information

What Is eBC?

Breast cancer is the most common cancer diagnosed in female patients, and it can become life-threatening if it spreads beyond the breast. eBC refers to disease that has not spread to other parts of the body. Although it mainly affects female patients, male patients can also develop breast cancer. In Canada, more than 138,000 people are living with breast cancer, and in 2024 about 30,500 new cases in female patients and 290 in male patients were expected to be diagnosed.

Unmet Needs in eBC

Patients with stage II or III HR-positive, HER2-negative eBC still face a high risk of the disease coming back despite current treatments, creating a major need for more effective therapies. There is also a need for treatments that limit side effects, maintain QoL, and reduce burdens on patients, caregivers, and the health care system.

How Much Does Kisqali Cost?

Treatment with Kisqali is expected to cost $3,953 (Kisqali plus an AI: $3,980 to $3,992) per patient per 28-day cycle.

Recommendation

The CDA-AMC pan-Canadian Oncology Drug Review Expert Review Committee (pERC) recommends that ribociclib in combination with an AI be reimbursed for the adjuvant treatment of adult patients with HR-positive, HER2-negative stage II or III eBC at high risk for recurrence, only if the conditions listed in Table 1 are met.

Rationale for the Recommendation

Evidence from 1 phase III, open-label, active-controlled randomized controlled trial (RCT) (NATALEE, N = 5,101) demonstrated that adjuvant treatment with ribociclib plus an AI resulted in added clinical benefit when compared with adjuvant AI alone in female patients in premenopausal and postmenopausal stages and male patients with HR-positive, HER2-negative stage II or III eBC at high risk for disease recurrence. Results from the NATALEE trial showed that treatment with ribociclib plus an AI resulted in a statistically significant, albeit modest, improvement in invasive disease–free survival (iDFS) compared with an AI alone, with hazard ratios of 0.75 (95% confidence interval [CI], 0.62 to 0.91) and 0.72 (95% CI, 0.61 to 0.84) at 36 months and 48 months, respectively. Results were generally consistent at 60 months, but the clinical importance of the results remained unclear. No new safety signals were identified in the NATALEE trial, and pERC and the clinical experts consulted by CDA-AMC considered the safety profile of ribociclib manageable.

The sponsor submitted indirect evidence in the form of a matching-adjusted indirect comparison (MAIC) comparing ribociclib plus an AI and abemaciclib plus ET among patients at high risk for recurrence, which suggested no difference between the 2 treatment regimens; however, important limitations affected the validity and certainty of the results, which precluded pERC from drawing conclusions on the comparative efficacy and safety of ribociclib versus abemaciclib.

Patients identified a need for new, effective treatments for eBC that reduce the risk of recurrence, improve survival, have manageable side effects, and maintain QoL. pERC concluded that ribociclib met some patient needs because it is an additional treatment option that reduces the risk of recurrence and has manageable side effects. However, the magnitude of the benefit was modest, and pERC could not conclude whether there was any improvement in overall survival (OS). Although patients also expressed a need for treatments that maintain QoL, no definitive conclusions could be reached regarding the effects of ribociclib on health-related QoL (HRQoL).

Using the sponsor-submitted price for ribociclib and publicly listed prices for all other drug costs, the incremental cost-effectiveness ratio (ICER) for ribociclib plus an AI in the indicated population was $100,626 to $127,959 per quality-adjusted life-year (QALY) gained compared with an AI alone. At this ICER, ribociclib plus an AI is not cost-effective versus an AI alone at a $50,000 per QALY willingness-to-pay threshold. A price reduction is required for ribociclib plus an AI to be considered cost-effective at a $50,000 per QALY gained threshold. In patients who are at high risk for recurrence, abemaciclib is a relevant comparator to consider; however, the cost-effectiveness of ribociclib plus an AI versus abemaciclib plus ET in this subgroup of patients is highly uncertain because of limitations in the submitted indirect evidence.

Table 1: Reimbursement Conditions and Reasons

AI = aromatase inhibitor; AJCC = American Joint Committee on Cancer; CDA-AMC = Canada’s Drug Agency; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; ET = endocrine therapy; HR = hormone receptor; ICER = incremental cost-effectiveness ratio; pERC = pan-Canadian Oncology Drug Review Expert Review Committee; QALY = quality-adjusted life-year; vs. = versus.

Discussion Points

• Unmet needs: pERC emphasized the high rates of disease recurrence in patients with HR-positive, HER2-negative stage II or III eBC despite aggressive treatment. Clinical experts estimated recurrence rates of 10% to 30% for stage II eBC and 30% to 50% for stage III eBC over 10 years, with even higher rates over 20 years, underscoring the need for improved long-term management strategies. pERC and the clinical experts consulted by CDA-AMC highlighted the need for improved treatments that reduce the risk of recurrence. pERC agreed with the clinical experts that current therapies, although delivered with curative intent, do not eliminate the risk of relapse and highlighted the importance of approaches that further reduce the risk of recurrence while maintaining QoL. Additionally, pERC highlighted that patients who have node-negative disease and are at high risk for recurrence but are not eligible for abemaciclib require additional advanced treatment options. Patients and clinicians emphasized the importance of treatment efficacy, manageable side effects, and preservation of independence, with many patients willing to tolerate additional toxicity for better outcomes. Younger patients stressed the need for durable remission to allow them to sustain personal and professional roles, while patient groups raised concerns about long-term medication effects and the impact of side effects on daily functioning. As noted, pERC concluded that ribociclib provides an additional treatment option to reduce the risk of recurrence.

• Place in therapy: pERC discussed the differences between populations at high-risk in the NATALEE trial of ribociclib and in cohort 1 of the monarchE trial of abemaciclib. Patients in the NATALEE trial were considered to be at high risk for disease recurrence based on anatomic stage (i.e., stage IIB or III eBC regardless of nodal status; patients with stage IIA disease were eligible if they had had at least 1 lymph node involved, and for those with grade 2 tumours with no nodal involvement, a Ki-67 proliferation index ≥ 20% or high genomic risk classification). In the monarchE trial, patients with 4 or more positive axillary lymph nodes, or with 1 to 3 positive axillary lymph nodes with grade 3 disease and/or tumour size greater than or equal to 5 cm, were considered to be at high risk for recurrence. As such, patients with node-negative disease who are otherwise at high risk for recurrence (per the NATALEE trial) are not considered eligible for treatment with abemaciclib, but they would be eligible for ribociclib. pERC noted that patients with node-negative disease therefore have fewer treatment options available, representing an additional unmet need for effective therapies that can reduce disease recurrence in this population. pERC highlighted that ribociclib represents an alternative treatment option to abemaciclib; however, based on discussions with the clinical experts consulted by CDA-AMC, pERC also noted that there may be a preference to prescribe abemaciclib instead of ribociclib due to the shorter treatment duration.

• Certainty of evidence: pERC discussed the pivotal evidence submitted for this review, which consisted of 1 phase III open-label RCT (NATALEE). pERC noted with moderate certainty, based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, that treatment with ribociclib plus an AI resulted in statistically significant improvements in iDFS compared with an AI alone. The committee agreed with the clinical experts that iDFS is a clinically meaningful, well-recognized, and accepted end point for clinical trials of adjuvant breast cancer treatments because disease recurrence is associated with breast cancer mortality. While improvements in iDFS with ribociclib were observed and consistent across analysis time points compared to treatment with an AI alone, the magnitude of benefit relative to an AI alone at 36 months did not reach the clinical meaningfulness threshold of 3%. Although results at 48 months and 60 months exceeded this threshold, pERC noted these estimates were associated with imprecision, as the 95% CIs included the possibility of no benefit. pERC also stated that at the threshold of 5% suggested by the clinical experts (and considered in the review for abemaciclib), the results for ribociclib were considered beneficial but potentially not clinically meaningful. For secondary outcomes (recurrence-free survival [RFS], distant disease–free survival [DDFS], and OS), pERC noted that the differences between groups were not clinically meaningful, with little to no improvement in OS at 60 months. pERC commented that in addition to reducing disease recurrence, extending survival is an important treatment outcome in eBC. While OS follow-up was immature in the NATALEE trial, pERC emphasized that the long median survival duration among patients with eBC and lengthy disease-free intervals make it challenging to demonstrate improvements in OS in a clinical trial setting. pERC also noted that median survival outcomes were not reached, and the long-term durability of benefit remains uncertain. Potential biases related to treatment discontinuation (e.g., only 62.8% of patients completed 3 years of treatment with ribociclib), subsequent therapies, and attrition further increase uncertainty regarding the true magnitude of effect. Overall, pERC agreed that treatment with ribociclib plus an AI likely provides some benefit in reducing the risk of disease recurrence, but the clinical importance and sustainability of this benefit remain unclear.

• Subgroup analysis: pERC noted that patients with negative nodal status are not eligible for abemaciclib using the current criteria. In contrast, patients with stage IIA node-negative breast cancer who are considered at high risk for disease recurrence (i.e., grade 3 disease, or grade 2 with a high-risk Ki-67 index score [≥ 20%], or a genomic test result indicating high risk) are eligible for ribociclib. Predefined subgroup analyses from the NATALEE trial demonstrated that, among patients with negative nodal status, ribociclib plus an AI reduced the risk of iDFS events compared with an AI alone (hazard ratio = 0.666; 95%CI, 0.397 to 1.118), though there was uncertainty in the results as the subgroup analysis was not powered to detect a difference and the number of events was small. pERC noted that these findings suggest that ribociclib may provide clinical benefit in patients whose disease is node negative, who are at high risk for disease recurrence, and who are not eligible for abemaciclib, potentially addressing an unmet need in this population.

• Indirect evidence: In the absence of direct comparative evidence between ribociclib plus an AI and relevant comparators, the sponsor conducted a MAIC to estimate the relative efficacy of ribociclib plus an AI versus abemaciclib plus ET in patients at high risk of disease recurrence (consistent with the definition of high risk used to describe cohort 1 of the monarchE trial). The MAIC suggested no differences in iDFS, DRFS, or OS between treatment groups; however, the small sample size and wide CIs limited the precision of the estimates. pERC agreed that the analysis was further constrained by the omission of potential effect modifiers (which introduced risk of bias) and by its focus on a subgroup of patients at high risk who do not reflect the broader reimbursement population (matched to cohort 1 of the monarchE trial). Given these methodological limitations and population differences, pERC concluded that the MAIC results should be interpreted with caution and cannot be generalized to all patients with high-risk HR-positive, HER2-negative eBC. pERC also discussed the post hoc subgroup analysis of patients from the NATALEE trial who were considered eligible for cohort 1 of the monarchE trial and those who were ineligible for cohort 1 but would still be eligible for ribociclib. ███ ████ ███████ ██ ████ ████████ ████ ██████████ ████ ███ ███████ ████████ ███████████ ██ ████████ ████ ████ ██████ ███ ███ ███ ███ ██████████ ████ ██ ███ ██ ███████ █████ █ ██████ ███ ███ █████ ██ ████████ ███ ███████████ ██ ████ ████████ █████████ ███ ██████████ ████████████ ██████ ███ ███████ ████ ██████████ ██████ ████████ ███ ████ ████████ ██ ██████████ ███ ██████ █ ██ █████████.

• Safety: pERC noted that ribociclib has been used in Canada since 2018 for metastatic breast cancer, providing extensive clinical experience, and highlighted that no new safety signals were identified in the NATALEE trial. pERC noted that no new safety signals were identified for ribociclib plus an AI; however, the combination was associated with higher rates of adverse events (AEs), including grade 3 or higher events, and it was associated with more treatment discontinuations compared to AI alone. Clinical experts highlighted that these toxicities, such as neutropenia, infections, and other serious AEs (SAEs), are expected and raise concerns in the adjuvant setting, in which patients require more frequent monitoring and clinic visits. The longer treatment duration with ribociclib adds to the management burden and may affect treatment adherence. Overall, pERC agreed that the safety profile and monitoring requirements must be weighed against the potential benefits of ribociclib plus an AI.

• Economic considerations: pERC discussed that the results of the CDA-AMC base case suggest that ribociclib plus an AI is similarly effective and less costly than abemaciclib plus ET in the subgroup of patients who meet the eligibility criteria for cohort 1 of the monarchE trial, but that it is highly uncertain whether these benefits would be realized in practice because of the identified limitations with the sponsor’s MAIC. In the subgroups of patients who were eligible or ineligible for abemaciclib, pERC noted that ribociclib plus an AI would be considered cost-effective at the submitted price compared to an AI alone if the public health care system were willing to pay $100,626 to $127,959 for each additional QALY gained. pERC discussed that the estimated cost-effectiveness of ribociclib plus an AI compared to either abemaciclib plus ET or an AI alone is highly uncertain due to uncertainty in the comparative clinical data, including the lack of long-term data and that higher price reductions than those noted in Table 1 may be required.

• Budget impact: pERC discussed that, considering only drug costs, the expected budget impact of reimbursing ribociclib for use in combination with an AI for the indicated population would be approximately $99 million over the first 3 years of reimbursement compared to the amount currently spent on comparators. The expenditure on ribociclib plus an AI over this period is expected to be $212 million. The actual budget impact of reimbursing ribociclib will depend on the total size of the eligible population, the proportion of patients eligible for abemaciclib plus ET, and the uptake of ribociclib plus an AI in the subgroups of patients who are eligible and ineligible for abemaciclib. The incremental budget impact of reimbursing ribociclib plus an AI for this indication is expected to be greater than $40 million in year 3 of reimbursement, and the economic feasibility of adoption must be addressed.

• Organizational feasibility: pERC discussed that additional health care resources will be required for the provision of ribociclib plus an AI versus abemaciclib plus ET because of a longer treatment duration (3 years versus 2 years) and additional recommended testing, including but not limited to oncologist visits and pharmacist time, as well as electrocardiogram, complete blood count, and liver function testing. pERC noted that these considerations may not have been adequately captured in the pharmacoeconomic analysis and that the estimated budget impact noted in the previous discussion point ($99 million over the first 3 years) does not include costs beyond drug acquisition costs. Higher price reductions than those noted in Table 1 may be required to ensure that the total treatment cost of ribociclib plus an AI does not exceed the total treatment cost of abemaciclib plus ET. Additionally, pERC noted that the group of patients who are ineligible for abemaciclib but would be eligible for ribociclib represent a considerable number of patients, which could add constraints to health care systems and budgets.

Background

Breast cancer is the most commonly diagnosed cancer in female patients in Canada. In 2022, the 5-year prevalence of breast cancer in the overall population was 138,072 in Canada. Although breast cancer primarily affects female patients, it can also occur in male patients. In 2024, an estimated 30,500 new cases were projected to be diagnosed in female patients and 290 in male patients in Canada. The age-standardized mortality rate for breast cancer is 11.8 per 100,000 people for the overall population, rising to 21.8 per 100,000 among female patients, making it the second leading cause of cancer-related deaths among female patients. The most common subtype of breast cancer is HR-positive, HER2-negative disease, which accounts for 73% of all breast cancer cases. eBC refers to cancer that has not spread beyond the breast to other parts of the body.

Most 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. Generally, breast cancer does not induce symptoms in the early stage. Among symptomatic cases, a painless mass in the breast is the most common sign. 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. In contrast to advanced or metastatic breast cancer, eBC is considered curable. However, breast cancer can recur after the initial treatment, even when diagnosed at an early stage.

Curative therapy in eBC aims to prevent recurrence and improve long-term survival. According to the clinical experts consulted for this review, curative 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 pathologic features and genomic test 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 who are at high risk for recurrence based on clinicopathologic features). For patients with stage II eBC, systemic therapy may or may not include chemotherapy depending on other pathologic features and genomic test results (e.g., Oncotype DX). However, ET is routinely offered to patients with stage II eBC. Additionally, the adjuvant use of olaparib is reserved for patients with (suspected) deleterious germline breast cancer gene mutations.

Ribociclib is currently under review by Health Canada. The proposed indication is in combination with an AI for the adjuvant treatment of adult patients with HR-positive, HER2-negative stage II or III eBC at high risk for disease recurrence. In female patients in premenopausal or perimenopausal stages, or in male patients, the AI should be combined with a luteinizing hormone-releasing hormone agonist. Ribociclib is a CDK4/6 inhibitor. It is available as tablets and the dosage recommended in the product monograph 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.

Sources of Information Used by the Committee

To make its recommendation, the committee considered the following information:

• a review of 1 phase III, multicentre, open-label, active-controlled RCT in female patients in premenopausal and postmenopausal stages and male patients with HR-positive, HER2-negative eBC (NATALEE); 1 indirect treatment comparison (ITC) using a MAIC

• patients’ perspectives gathered by 4 patient groups — the Canadian Breast Cancer Network (CBCN), Rethink Breast Cancer (Rethink), Quebec Breast Cancer Foundation (QBCF), and a joint submission from Breast Cancer Canada (BCC) and the McPeak-Sirois Group for Clinical Research in Breast Cancer (McPeak-Sirois Group)

• input from public drug plans that participate in the reimbursement review process

• 2 clinical specialists with expertise diagnosing and treating patients with eBC

• input from 2 clinician groups: the Research Excellence, Active Leadership Canadian Breast Cancer Alliance (REAL Alliance) and the Ontario Health (Cancer Care Ontario) (OH [CCO]) Breast Cancer Drug Advisory Committee

• a review of the pharmacoeconomic model and report submitted by the sponsor.

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 clinical experts consulted by 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 web page.

Patient Input

CDA-AMC received 4 patient group submissions from the CBCN, Rethink, the QBCF, and a joint submission from BCC and the McPeak-Sirois Group. The 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. The QBCF 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 survivor Susan McPeak and entrepreneur Charles Sirois.

The 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. CBCN also conducted 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 who had experience with ribociclib for high-risk HR-positive, HER2-negative eBC. The QBCF 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; the group also conducted literature research and social media reviews. Between November 14 and 18, 2024, BCC and the 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 had a substantial impact on their lives, causing emotional, physical, and financial strain. Rethink highlighted that younger patients face additional challenges such as fertility issues, childcare needs, and career disruptions. Despite these difficulties, patients across all groups are motivated to undergo therapy to reduce disease recurrence, and they strive to maintain normal activities and manage disease-related symptoms.

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

Overall, patients prioritize maximizing treatment efficacy, reducing the risk of recurrence, managing side effects, and maintaining a good QoL, with many willing to endure additional side effects for better outcomes. According to Rethink, younger patients tend to emphasize the importance of long-term remission so they can continue their personal and professional lives. The QBCF highlighted concerns about long-term medication effects and the considerable impact of side effects on daily life.

In input from BCC and the McPeak-Sirois Group and from Rethink, there were 8 and 4 patients, respectively, with eBC who had experience with ribociclib. In the input from the CBCN and from the 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 and emphasized 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 Clinical Experts Consulted for This Review

The clinical experts consulted by CDA-AMC emphasized the substantial unmet needs that exist in treating stage II or III HR-positive, HER2-negative breast cancer, noting the high rates of recurrence despite aggressive treatments. They indicated the goals of treatment are to cure the disease, minimize side effects, minimize the impact on QoL, 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 at high risk for recurrence (based on genomic testing [e.g., Oncotype DX, 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 have a disease response to and benefit from ribociclib when it is added to ET. However, ribociclib is not suitable for patients with severe liver dysfunction, patients who are pregnant or breastfeeding, those with a history of QT prolongation, or patients with severe neutropenia.

Both clinical experts indicated that for patients with stage II or III HR-positive, HER2-negative eBC, preventing recurrence (measured by RFS) is considered a clinically meaningful outcome to use to measure response to treatment. Other meaningful outcomes to use to measure disease responses include improved OS, QoL, 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 posttreatment, depending on the initial extent of disease, with clinical examinations and/or imaging conducted regularly to check for disease recurrence, especially for those at high risk for recurrence (e.g., those with node-positive disease or large tumours). The clinical experts noted that with ribociclib treatment, frequent toxicity assessments are also required beyond routine surveillance with frequent blood work and electrocardiograms (i.e., every 2 weeks), and more frequent 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: substantial impact on QoL, 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 Canadian Breast Cancer Alliance (REAL Alliance) and the OH (CCO) Breast Cancer Drug Advisory Committee. A total of 19 clinicians (11 from the REAL Alliance [along with 3 other clinicians who agreed with the REAL Alliance Clinical Input and supported the submission]; and 5 clinicians from the OH [CCO] Breast Cancer Drug Advisory Committee) provided input for this submission.

Input from the clinician groups aligned with that of the clinical experts consulted for this review regarding treatment goals, the unmet needs of this patient population, assessment of treatment response, the drug’s place in therapy, decisions on 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 clinical experts consulted for the review provided advice on the potential implementation issues raised by the drug programs.

Table 2: Responses to Questions From the Drug Programs

AI = aromatase inhibitor; AJCC = American Joint Committee on Cancer; ALN = axillary lymph node; eBC = early breast cancer; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; ET = endocrine therapy; HR = hormone receptor; OWG = Oncology Working Group; pERC = pan-Canadian Oncology Drug Review Expert Review Committee.

Clinical Evidence

Systematic Review

Description of Studies

One phase III, open-label, active-controlled RCT (NATALEE, N = 5,101) evaluated the efficacy and safety of ribociclib plus an AI compared to an AI alone as an adjuvant treatment in female patients in premenopausal or postmenopausal stages and in male patients with HR-positive, HER2-negative stage II or III eBC. The primary end point was iDFS assessed by the investigator using the Standardized Definitions for Efficacy End Points (STEEP) criteria. Secondary end points included RFS, DDFS, OS, HRQoL, and safety. Patients were randomized 1:1 to receive either ribociclib plus an AI (n = 2,549) or an AI alone (n = 2,552). Randomization was stratified by menopausal status (female patients in the premenopausal stage, and female patients in the postmenopausal stage versus male patients), anatomic stage (II versus III), prior adjuvant or neoadjuvant chemotherapy (yes versus no), and geographical region (North America, Western Europe, and Oceania versus the 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 of participants were well balanced between treatment groups. The median age of all patients was 52.0 years (range, 24 years to 90 years). Most patients were female (99.6%) and most were in the postmenopausal stage (55.8%), and while most patients were white (73.4%) the trial also included patients self-reporting as Asian (13.2%), Black or African American (1.7%), Native Hawaiian or Other Pacific Islander (0.1%), and American Indian or Alaska Native (0.1%) [wording of original source]. Most patients (83.1%) had an Eastern Cooperative Oncology Group Performance Status score of 0. More than half of patients (59.6%) had disease that was classified as American Joint Committee on Cancer (AJCC) stage III, nearly half (41.2%) had 1 to 3 positive axillary lymph nodes, and most patients (88.1%) had received prior adjuvant or neoadjuvant chemotherapy. A total of 676 patients (13.3%) had had genomic testing, and Oncotype DX was the most commonly reported test used (249 patients [4.9%]).

Efficacy Results

Three analysis time points are described in this report. The NATALEE trial met its primary end point (iDFS) at the interim analysis 3 (IA3) time point (data cut-off date: January 11, 2023). At the IA3 time point, the median duration of follow-up was 27.7 months (range, 0 months to 45 months). At the end of ribociclib analysis (data cut-off date: April 29, 2024) time point, the median duration of follow-up was 44.2 months (range, 0 months 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 the IA3 time point, 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. As no results were available at the end of ribociclib analysis, only the results for HRQoL at the IA3 time point are presented for this outcome.

Invasive Disease–Free Survival

At the IA3 time point, a total of 189 patients (7.4%) in the ribociclib plus an AI group and 237 patients (9.3%) in the AI group had experienced an iDFS event. Distant disease recurrence (4.7% versus 6.7%, respectively) was the most commonly reported iDFS event for each group. Though the median iDFS was not estimable for each treatment group, there was a statistically significant improvement in iDFS in the ribociclib plus an AI group compared with the AI group (hazard ratio = 0.75; 95% CI, 0.62 to 0.91; P = 0.0014). The Kaplan-Meier probability estimates of iDFS at 36 months were 90.4% (95% CI, 88.6% to 91.9%) for the ribociclib plus an AI group and 87.1% (95% CI, 85.3% to 88.8%) for the AI 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 an AI group and 340 patients (13.3%) in the AI group had experienced an iDFS event. Distant disease recurrence (6.9% versus 9.6%, respectively) was the most reported iDFS event for each group. The median iDFS was not estimable at the end of ribociclib analysis for either treatment group. The hazard ratio for iDFS for the ribociclib plus an AI group versus the AI group was 0.72 (95% CI, 0.61 to 0.84, nominal P < 0.0001), in favour of ribociclib plus an AI. The Kaplan-Meier probability estimates of iDFS at 36 months for each group were consistent with those of the IA3. At 48 months, the Kaplan-Meier probability estimates of iDFS were 88.5% (95% CI, 87.1% to 89.8%) for the ribociclib plus an AI group and 83.6% (95% CI, 81.8% to 85.2%) for the AI 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 an AI group versus the AI group was 0.72 (95% CI, 0.62 to 0.83). At 60 months, the Kaplan-Meier probability estimates of iDFS were 85.5% (95% CI, 83.9% to 87.0%) for the ribociclib plus an AI group and 81.0% (95% CI, 79.2% to 82.7%) for the AI group, resulting in a between-group difference of 4.5% (95% CI, 2.1% to 6.9%)

Subgroup and sensitivity analyses of iDFS at the IA3 and 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 an AI group and 298 patients (11.7%) in the AI group had experienced an RFS event. The median RFS was not estimable for each treatment group, though the treatment benefit in RFS favoured ribociclib plus an AI (hazard ratio = 0.70; 95% CI, 0.58 to 0.83; nominal P < 0.0001). The Kaplan-Meier probability estimates of RFS at 48 months were █████ ████ ███ █████ ██ ██████ for the ribociclib plus an AI group and ████ █ ████ ███ █████ ██ ██████ for the AI group. The between-group difference was 4.8% (95% CI, 2.7% to 6.9%). These results were consistent with those observed at the IA3 time point, and similar results were observed in the 5-year follow-up analysis.

Distant Disease–Free Survival

At the end of ribociclib analysis, a total of 240 patients (9.4%) in the ribociclib plus an AI group and 311 patients (12.2%) in the AI group had experienced a DDFS event. The median DDFS was not estimable for each treatment group, though the treatment benefit in DDFS favoured ribociclib plus an AI compared with an AI alone (hazard ratio = 0.72; 95% CI, 0.60 to 0.85; nominal P < 0.0001). The Kaplan-Meier probability estimates of DDFS at 48 months were █████ ████ ███ █████ ██ ██████ for the ribociclib plus an AI group and █████ ████ ███ █████ ██ ██████ for the AI group. The between-group difference was 4.5% ████ ███ ████ ██ █████. These results were consistent with those observed at the IA3 time point, and similar results were observed in 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 an AI group and 121 patients in the AI group (4.7%) had died. The median OS was not estimable for either treatment group. There was no difference in the risk of death between ribociclib plus an AI compared with an AI alone (hazard ratio = 0.83; 95% CI, 0.64 to 1.07; nominal P = 0.0766). The Kaplan-Meier probability estimates of OS at 48 months were █████ ████ ███ █████ ██ ██████ for the ribociclib plus an AI group and █████ ████ ███ █████ ██ ██████ for the AI group. The between-group difference was ████ ████ ███ ████ █ ██ ██████. These results were consistent with those observed at the IA3 time point and similar results were observed in the 5-year follow-up analysis.

Health-Related Quality of Life

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

Harms Results

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

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

A total of 21.1% of patients in the ribociclib plus an AI group and 5.3% of patients in the AI group had TEAEs leading to discontinuation of study treatment. The most common TEAEs that caused treatment discontinuation were elevated alanine aminotransferase levels (7.2% versus 0.1%, respectively) and elevated aspartate aminotransferase levels (2.9% versus 0%, respectively).

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

The clinical experts consulted by CDA-AMC identified 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%) as notable harms, which were reported more frequently in the ribociclib plus an AI group than in the AI group.

Critical Appraisal

The Health Canada–approved indication for ribociclib is for patients with HR-positive, HER2-negative eBC who are 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 patients at high risk for disease recurrence in the NATALEE trial. As such, it was unclear what proportion of patients in the NATALEE trial were at high risk for recurrence.

The choice of AIs as the comparator in the NATALEE trial was clinically relevant, as this 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 an AI group compared to the AI group at both the end of ribociclib analysis (17.7% versus 22.1%, respectively) and 5-year follow-up (21.5% versus 26.0%, respectively).

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 accurate assessment of treatment effect, as recurrence can occur beyond 10 years of follow-up. The analysis of iDFS was predominately influenced by the initial treatment response, which is represented by event rates of 10.3% in the ribociclib plus an AI group and 13.3% in the AI group 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 time point and the proportions of patients who were censored were generally balanced between treatment groups at previous data cut-off dates, there was still a substantial amount of censoring, with rapid drops in the numbers of patients at risk for recurrence, which may introduce uncertainties in the estimates of 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 █████ of patients contributing to the analysis, potentially introducing bias due to differing characteristics between those who continued in 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 substantial comorbidities or poorer performance status. However, the clinical experts noted they would consider patients with an Eastern Cooperative Oncology Group 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 55.8% were in the postmenopausal stage. The clinical expert indicated that there is a more diverse patient population in their clinical practice compared to the patient population in the NATALEE trial, and there would be a higher proportion of female patients in the postmenopausal stage aged 60 to 70 years who are candidates for ribociclib in their clinical practice 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 for ribociclib, and the use of genomic testing in the NATALEE trial may not reflect current clinical practice. More than 88% of patients in the NATALEE trial had 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 those in 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 pivotal NATALEE trial findings identified in the sponsor’s systematic review, the GRADE approach 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. Following the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refers 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.

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 3: Summary of Findings for Ribociclib Plus an AI vs. an AI Alone for Patients With eBC

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.

Notes: 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 change from baseline in GHS and QoL subscale score of the EORTC QLQ-C30 at 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 are no established between-group MIDs for iDFS, RFS, or 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 an AI vs. an AI 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, as the 95% CI would continue to suggest the possibility of no benefit and the possibility of benefit, and would be rated down 1 level for serious imprecision, and the certainty of evidence would remain moderate. However, at 3%, most of the effect lies higher than the threshold, which would result in greater confidence that the result exceeds 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 small number of patients at risk. There were substantial uncertainties at 48 and 60 months due to the small numbers of patients at risk and the rapid depletion of the risk set. Imprecision was not rated down. There are no established between-group MIDs 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 an AI vs. an AI based on a 3% threshold.

^dRated down 2 levels for very serious risk of bias due to the large amount of missing data and the 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 an AI vs. an AI 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 participants lost to follow-up or those who withdrew from the study. 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 are no established between-group MIDs for the incidence of hepatobiliary toxicity or 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 thresholds 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 an AI vs. an AI 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 End of Ribociclib Analysis (2024), Interim Analysis 3 (2023), and sponsor-provided additional data. Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Long-Term Extension Studies

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

Indirect Comparison

Description of Studies

The sponsor conducted an ITC using a MAIC to estimate the relative efficacy of ribociclib plus an AI compared with abemaciclib plus ET in the adjuvant treatments of patients with HR-positive, HER2-negative eBC at high risk for disease recurrence based on clinicopathologic features.

Efficacy Results

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

Harms Results

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

Critical Appraisal

Overall, the MAIC was conducted according to accepted methodological guidance. A key limitation of the MAIC 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 it excluded patients from both studies outside this subcohort (i.e., the patients excluded from cohort 2 of the monarchE study were those with 1 to 3 positive axillary lymph nodes plus Ki-67 index scores ≥ 20% [if tumour size is < 5 cm and disease is not grade 3]). The omission of these patients, whose disease falls 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 study and excluding patients who received tamoxifen as the endocrine partner. However, this subgroup analysis was not weighted and was not adjusted for the prognostic and treatment effect modifiers. Overall, the results for iDFS | █████ ███ ██ generally suggested no difference between ribociclib plus an AI and abemaciclib plus ET in cohort 1 of the monarchE trial, but the generalizability of the results to clinical settings in Canada is uncertain | | ███████ ███ ██████████████ ███ ██████ ███████ ██████████ ███ ████ ███ ███ ███ ███ ███████████ ██████ █████████ ███████ ███████ 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.

Economic Evidence

• Ribociclib is available as 200 mg tablets. At the submitted price of $94.13 per tablet, the 28-day cycle cost of ribociclib is expected to be $3,953 per patient (ribociclib plus an AI: $3,980 to $3,992 per patient) based on the Health Canada–recommended dosage. Ribociclib should be administered for a maximum of 3 years.

• Clinical efficacy in the economic analysis for ribociclib plus an AI was derived from the NATALEE trial, which suggests that ribociclib plus an AI results in prolonged iDFS compared to an AI alone in the full NATALEE trial population; however, the difference in iDFS between groups may not be clinically meaningful and there may be no difference in OS. For the subgroup of patients eligible for abemaciclib, the sponsor-submitted ITC (MAIC) comparing ribociclib plus an AI to abemaciclib plus ET) suggested no differences in iDFS or OS between treatments but indicated greater odds of grade 3 or higher neutropenia and elevated alanine aminotransferase levels compared with abemaciclib plus ET among patients who met the eligibility criteria for cohort 1 in the monarchE study.

• Results of the CDA-AMC base case suggest that:

  • In the subgroup of patients eligible for abemaciclib, ribociclib plus an AI may be associated with lower costs to the health care system compared to abemaciclib plus ET (incremental savings = $9,884), primarily driven by lower predicted drug acquisition costs. There was no difference in incremental QALYs gained between ribociclib plus an AI and abemaciclib plus ET. When compared to an AI alone, ribociclib plus an AI is predicted to be associated with higher total costs and more QALYs gained compared to an AI alone (incremental costs = $86,179; incremental life-years gained = 0.84; incremental QALYs gained = 0.67), with an ICER of $127,917 per QALY gained.

  • In the subgroup of patients ineligible for abemaciclib, ribociclib plus an AI is predicted to be associated with higher total costs than an AI alone (incremental costs = $97,641), driven by higher drug acquisition costs. Ribociclib plus an AI is predicted to be associated with a gain of 1.23 life-years and 0.97 QALYs compared to AI alone, resulting in an ICER of $100,626 per QALY gained.

  • The estimated ICER for ribociclib plus an AI versus an AI alone in each subgroup was highly sensitive to assumptions about treatment effectiveness waning. In each subgroup, approximately 99% to 100% of the incremental benefit versus AI alone was gained in the extrapolated period. In the absence of long-term comparative evidence, the predicted QALYs gained for patients receiving ribociclib plus an AI in each subgroup are highly uncertain and may be overestimated. Additional price reductions may therefore be required.

• CDA-AMC estimates that the budget impact of reimbursing ribociclib for use in combination with an AI for the adjuvant treatment of HR-positive, HER2-negative eBC will be approximately $99 million over the first 3 years of reimbursement compared to the amount currently spent on comparators. The expenditure on ribociclib plus an AI over this period is expected to be $212 million. The actual budget impact of reimbursing ribociclib will depend on the total size of the eligible population, the proportion of patients eligible for abemaciclib plus ET, and the uptake of ribociclib plus an AI in the subgroups of patients who are eligible or ineligible for abemaciclib. The incremental budget impact of reimbursing ribociclib plus an AI for this indication is expected to be greater than $40 million in year 3 of reimbursement, and the economic feasibility of adoption must be addressed.

pERC Information

Members of the Committee

Dr. Catherine Moltzan (Chair), Dr. Kelvin Chan (Vice chair), Dr. Philip Blanchette, Dr. Matthew Cheung, Dr. Michael Crump, Annette Cyr, Dr. Jennifer Fishman, Dr. Jason Hart, Terry Hawrysh, Dr. Yoo-Joung Ko, Dr. Aly-Khan Lalani, Amy Peasgood, Dr. Anca Prica, Dr. Adam Raymakers, Dr. Patricia Tang, Dr. Pierre Villneuve, and Danica Wasney.

Meeting date: December 3, 2025

Regrets: Three expert committee members did not attend.

Conflicts of interest: None