Treatment of Patients With Node-Positive, HR-Positive/HER2-Negative Early Breast Cancer at High Risk of Recurrence: monarchE 7-Year Outcomes

With commentaries by

Seth Wander, MD, PhD
Director, Precision Medicine, Termeer Center for Targeted Therapies
Director, Translational Research, Breast Oncology Program
Assistant Professor of Medicine, Harvard Medical School
Massachusetts General Hospital
Boston, MA

ET: The Backbone of CDK4/6 Inhibitor Therapy

CDK4/6 inhibitors are used in combination with ET, as ET is supported by decades of clinical trials demonstrating efficacy in patients with HR-positive breast cancers. ET is generally recommended for patients for a minimum of 5 years to reduce recurrence.⁵ Options for ET selection include selective estrogen receptor modulators (SERMs), such as tamoxifen, or aromatase inhibitors (AIs), such as anastrozole, letrozole, and exemestane, and may be combined with therapies, such as goserelin or leuprolide, to produce ovarian function suppression (OFS) or ablation in premenopausal women.⁶

The impact of adjuvant ET on reducing the risk of death varies from 10% to 30% according to multiple meta-analyses and clinical trials. The first meta-analysis found that for women with estrogen receptor (ER)-positive disease, 5 years of tamoxifen resulted in a 30% reduction in the risk of death due to breast cancer and a 9.2% absolute reduction in breast cancer mortality at 15 years compared with no tamoxifen treatment (P<.00001) using data from 20 trials and 10,645 patients.⁷ A second meta-analysis examined 2 trials and 9885 postmenopausal women with ER-positive early breast cancer and found that 5 years of AI therapy offered improvement over tamoxifen, reducing the risk of death due to breast cancer by 15% and an absolute reduction in breast cancer mortality by 2.1% at 10 years (P=.009).⁸ Several studies have investigated AI therapy for a duration longer than 5 years. Among postmenopausal patients who had already completed 5 years of AI therapy, an analysis of more than 22,000 individuals from 12 trials revealed that extending AI treatment for an additional 5 years resulted in a 10% reduction in risk of death due to breast cancer, but only a nonsignificant 0.6% absolute reduction in breast cancer mortality at 15 years, and a significantly increased risk of bone fracture.⁹ In the higher-risk setting of premenopausal female patients with HR-positive breast cancer, the SOFT trial examined the addition of OFS to a SERM or AI for 5 years.¹⁰ This trial compared tamoxifen alone, tamoxifen with OFS, and exemestane with OFS. The combination of exemestane and OFS emerged as the most effective, reducing the overall risk of death by 26% and absolute reduction in breast cancer mortality by 5.6% compared with tamoxifen alone at a median follow-up of 12 years.¹⁰

These same studies demonstrated improvement in disease recurrence, yet the long-term risk of recurrence remained high. Following 5 years of tamoxifen treatment, the 15-year recurrence rates were 33.0% compared with 46.2% for the arm receiving no tamoxifen treatment (rate ratio [RR], 0.61; 95% CI, 0.57-0.65).⁷ When comparing 5 years of an AI or tamoxifen, the 10-year recurrence rates were 19.1% for the AI group and 22.7% for the tamoxifen group (RR, 0.80; 95% CI, 0.73-0.88).⁸ After 5 years of extended AI treatment, the 15-year recurrence rates were 11.6% compared with 15.2% for the arm receiving no further treatment (RR, 0.71; 95% CI, 0.61-0.81).⁹ For premenopausal women receiving 5 years of ET, the 12-year distant recurrence-free interval was 75.1% with tamoxifen alone, 77.7% with tamoxifen plus OFS, and 79.6% with exemestane plus OFS.¹⁰

ET in Node-Positive, HR-Positive/HER2-Negative Breast Cancer

Whereas ET demonstrates a reduction in recurrence and mortality rates in the broader HR-positive population, real-world data highlight significant differences in outcomes between high-risk and non−high-risk patients with HR-positive/HER2-negative disease. A retrospective study utilized the Flatiron Health database of electronic health records from approximately 16,000 adult patients with early breast cancer, treated with adjuvant ET. This study showed that node-positive, high-risk disease (as defined by criteria in the monarchE trial) was associated with a greater 5-year recurrence (29.1% vs 8.8%) and 5-year mortality (18.4% vs 6.1%) compared with non−high-risk disease. In contrast, 5-year recurrence (29.1% vs 25.7%) and 5-year mortality (18.4% vs 20.8%) in these patients were similar to those observed in patients with early triple-negative breast cancer (TNBC).¹¹ TNBC is considered particularly aggressive due to its high recurrence rates, limited treatment options, and poor prognosis compared with other breast cancer subtypes.¹² Although N1 disease, defined as the presence of 1 to 3 positive lymph nodes, is not typically categorized as high risk, this study revealed that in the presence of additional high-risk features, patients with N1 disease that is grade 3 or a tumor size ≥5 cm face significantly worse outcomes, including a 6.3% higher 5-year mortality risk and a 14.3% higher recurrence risk when compared with N1 non−high-risk disease.¹¹ These findings underscore the importance of recognizing that even limited nodal involvement can represent a doubled risk of recurrence and death when additional clinical or pathological factors are present.

The IDFS benefit of the CDK4/6 inhibitor abemaciclib for treatment of HER2-negative advanced or metastatic breast cancer has long been established.⁴ In the early breast cancer setting, abemaciclib is indicated in combination with ET (tamoxifen or an AI) for the adjuvant treatment of adult patients with HR-positive/HER2-negative, node-positive early breast cancer at high risk of recurrence based on an IDFS benefit at 4 years, including in patients with high-risk N1 disease.⁴ The recent publication of the landmark 7-year analysis of abemaciclib’s pivotal trial, monarchE, marks the first report of a statistically significant increase in overall survival (OS), along with a continued IDFS benefit in patients with high-risk, node-positive, HR-positive/HER2-negative early breast cancer receiving a CDK4/6 inhibitor and ET compared with ET alone.¹³

Long-Term Outcomes of Abemaciclib: 7-Year Updated Analysis of monarchE

monarchE (NCT03155997) was a global, randomized, open-label, phase 3 study that included patients aged ≥18 years with node-positive, HR-positive/HER2-negative early breast cancer with a high risk of recurrence.¹³ A total of 5637 patients were randomized in a 1:1 ratio to receive at least 5 years of adjuvant ET with (n=2808) or without (n=2829) 2 years of adjuvant abemaciclib.¹³ Patients in either arm were assigned to 1 of 2 subgroup cohorts based on tumor pathology. Cohort criteria are outlined in Figure 1.

In addition to the criteria in Figure 1, cohort 1 also allowed micrometastatic, multifocal, or multicentric disease, and constituted 91% of the study’s total patients.

The primary endpoint was IDFS.¹³ IDFS was defined as the time from randomization until the first occurrence of 1 of the following events: ipsilateral invasive disease, ipsilateral locoregional invasive disease, contralateral invasive breast cancer, distant recurrence, second primary noninvasive cancer, or death from any cause.¹³ Key secondary endpoints included OS and distant recurrence-free survival (DRFS).¹³ OS was defined as the time from randomization until the date of death from any cause, and DRFS was defined as the time from randomization until the first occurrence of metastatic disease or death from breast cancer. Both primary and secondary endpoints were analyzed in the intention-to-treat (ITT) population, which included both cohort 1 and cohort 2.¹³ Landmark analyses were performed annually for up to 7 years using the Kaplan-Meier method. Safety was assessed, with serious adverse events (AEs) monitored for up to 5 years from randomization.¹³

At the 4-year primary efficacy analysis, a significant improvement in IDFS was observed in the ITT population, driven predominantly by patients in cohort 1. IDFS rates for cohort 1 were 85.5% for treatment with abemaciclib plus ET versus 78.6% for treatment with ET alone (hazard ratio, 0.65; 95% CI, 0.57-0.75).⁴

IDFS results were updated at the 7-year landmark analysis (Table 1). In the ITT population (cohorts 1 and 2), an IDFS benefit was maintained at 7 years for patients receiving abemaciclib plus ET, with an absolute improvement of 6.5% (median follow-up time was 6.3 years; hazard ratio, 0.73; 95% CI, 0.66-0.82; P<.0001; Figure 2). The IDFS rate was 77.4% for the abemaciclib plus ET group compared with 70.9% for the ET alone group, and there was a 26.6% reduction in the risk of IDFS events. This benefit was also consistent at 7 years in cohort 1.¹³

This was consistent across prespecified subgroups regardless of menopausal status, prior treatments, or choice of first ET.¹³ Most IDFS events involved distant metastatic disease.¹³ However, there were approximately 30% fewer patients in the abemaciclib arm living with metastatic disease compared with the ET arm (180 patients [6.4%] vs 266 patients [9.4%], respectively).^13,14

In the ITT population, treatment with abemaciclib plus ET resulted in a 25.4% reduction in the risk of developing a DRFS event compared with ET alone, with higher rates at 5.1% for abemaciclib plus ET (hazard ratio, 0.75; 95% CI, 0.66-0.84; P<.0001).¹³ For cohort 1, consistent outcomes for DRFS were also observed (Table 1).

Primary OS analysis was a much anticipated prespecified key secondary endpoint as part of the 7-year analysis. For the ITT population at 7 years, the risk of death was 15.8% lower in the abemaciclib arm compared with ET alone (hazard ratio, 0.84; 95% CI, 0.72-0.98; 2-sided P=.027; Figure 3), meeting the prespecified criteria for statistical significance.¹⁴ Increased OS was consistent across prespecified subgroups, including patients aged <65 years, premenopausal patients, and patients utilizing tamoxifen as their first ET.¹⁴ In cohort 1, consistent OS outcomes were also observed (Table 1).¹³

At 7 years, the majority of patients without documented distant recurrence continued to receive ET.¹³ Assessed in the ITT population, 97.0% of patients in the abemaciclib plus ET group remained on ET, with 85.4% receiving therapy for ≥5 years. Similarly, in the ET alone group, 96.7% of patients continued ET, with 82.4% receiving it for ≥5 years. In addition to ET, the most frequently reported first-line treatments following metastatic recurrence were CDK4/6 inhibitors (30.0% vs 47.3%) and chemotherapy (32.7% vs 23.7%) in the abemaciclib plus ET and ET alone groups, respectively.¹³ Metastatic first-line therapies were also evaluated by time to distant recurrences, with early recurrences defined as those occurring on metastatic first-line treatment or within 12 months of 2-year adjuvant treatment completion/discontinuation, and later recurrences as those occurring >12 months from adjuvant treatment completion/discontinuation.¹³ In the ITT population, patients with early recurrences in the ET alone arm had higher rates of CDK4/6 inhibitor utilization as their first post-discontinuation treatment compared with the abemaciclib arm (44.7% vs 15.2%), whereas the difference between groups was less pronounced in patients with later recurrences (50.6% vs 43.1%).¹³

Since the primary safety analysis, no new safety signals were detected, and the AE profiles of both arms were consistent with prior analyses.¹⁵ In the safety set, deaths after 30 days of study treatment discontinuation due to AEs in the abemaciclib (n=2791) and ET (n=2800) arms were 1.6% versus 1.1%, respectively.¹³ Among patients who had post-discontinuation AE data (n=2621 and n=2637, respectively), rates of serious AEs post-discontinuation were similar between the 2 arms (7.5% vs 8.1%).¹³

Considerations for Clinical Practice

Abemaciclib is associated with a distinct toxicity profile that requires proactive management, and if left unaddressed, can compromise patient adherence, reduce quality of life, and lead to early treatment discontinuation. Common grade 3/4 AEs in monarchE included leukopenia (19%), neutropenia (18.7%), lymphopenia (13.2%), diarrhea (8%), and fatigue (2.9%). Dose interruptions occurred in 62% of patients in monarchE. Grade 3 or 4 AEs included neutropenia, leukopenia, diarrhea, and lymphopenia, which led to permanent discontinuation in 19% of patients.⁴

Proactive management strategies to mitigate side effects include instructing patients to initiate antidiarrheal therapy, increase oral fluids, and notify their healthcare provider at the first sign of loose stools.⁴ Additionally, regular monitoring of blood counts is recommended, starting with the initiation of abemaciclib therapy and continuing at least every 2 weeks for the first 2 months, followed by monthly checks for the next 2 months.⁴

Dose reductions are another proactive management strategy to keep patients on treatment for the recommended duration. This strategy is supported by clinical trial experience demonstrating maintained efficacy at reduced doses and RWE demonstrating the feasibility of achieving treatment persistence in clinical practice. In the monarchE trial, dose reductions due to an AE were employed in 44% of patients, with 17%, 8%, and 5% of AEs attributed to diarrhea, neutropenia, and fatigue, respectively. Abemaciclib was administered orally twice daily (BID) at a full dose of 150 mg, and doses were reduced to 100 mg and then to 50 mg BID if AE issues persisted following the first reduction.¹⁶ Data from monarchE’s 4-year long-term analysis demonstrated relatively consistent IDFS across relative dose intensity (RDI) subgroups of abemaciclib plus ET. A time-dependent Cox analysis showed sustained IDFS benefit in full-dose recipients compared with those dose-reduced in both the ITT population (hazard ratio, 0.91; 95% CI, 0.73-1.13; P value not reported; Figure 4) and cohort 1.¹⁷ Therefore, certain AEs may be managed by dose reductions while maintaining a primary IDFS benefit.

Moving into the real-world setting, a study using 354 patients from the US Flatiron Health database demonstrated that half of patients initiating the full 150-mg dose of abemaciclib had at least 1 dose reduction with a median time to the first dose reduction of 59 days.¹⁸ Of note, 88% of patients initiating treatment continued abemaciclib beyond 3 months, whereas for 11% of patients who discontinued treatment due to an AE, 70% were not dose-reduced (Figure 5). Similarly, the majority of patients (75%) continued abemaciclib beyond 6 months.¹⁹ More patients (85%) with ≥1 dose reduction compared with patients with no dose reduction (64%) continued abemaciclib beyond 6 months. Among patients who discontinued by 6 months, 70% did not have a dose reduction. Abemaciclib treatment persistence in patients meeting monarchE high-risk criteria (cohort 1) was consistent with that in the overall study population. The proportion of patients who discontinued due to an AE within the first 90 days was 4 times lower for those with ≥1 dose reduction versus those remaining at full dose (5.6% vs 22.4%).¹⁹

Given the high rate of dose reductions, the potential impact of dose adjustments and step-up dosing with abemaciclib was investigated. The phase 2 TRADE study assessed the impact of step-wise abemaciclib escalation (50 mg BID for 2 weeks, 100 mg BID for 2 weeks, and 150 mg BID thereafter) on composite AE rates, including discontinuation or inability to maintain the target dose. This dosing strategy resulted in 70.8% of patients reaching the 150-mg dose and maintaining this dose for up to 12 weeks. This exceeds the number of patients in monarchE continuing at the full target dose of abemaciclib at 12 weeks.

Conclusions

These long-term results highlight the importance of staying on abemaciclib therapy. Dose-reducing as indicated by treatment experience or employing a dose-escalation strategy may aid in AE management and treatment persistence. At the 7-year mark, the IDFS benefit was maintained, and DRFS rates and OS were both higher for abemaciclib in combination with ET compared with ET alone. This reinforces a critical role for CDK4/6 inhibitors, such as abemaciclib, combined with ET in the adjuvant treatment of high-risk, node-positive, HR-positive/HER2-negative early breast cancer as demonstrated by the ability to reduce the risk of recurrence and the first statistically significant difference in OS reported for adjuvant CDK4/6 inhibitor treatment.

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For full prescribing information see:
www.accessdata.fda.gov/drugsatfda_docs/label/2025/208716s019lbl.pdf