CDK4/6 Inhibitors for Treatment of High-Risk, HR-Positive/HER2-Negative Early Breast Cancer: Addressing Tolerability to Maximize Treatment Persistence

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The first installment of this series highlighted the role of adjuvant cyclin-dependent kinase (CDK)4/6 inhibitors in reducing recurrence and mortality risks for patients with node-positive, high-risk, hormone receptor (HR)-positive/HER2-negative early breast cancer (eBC). In particular, 2 long-term analyses presented at ESMO 2025 demonstrated sustained improvements in invasive disease-free survival (IDFS) and overall survival (OS) for CDK4/6 inhibitors in the adjuvant setting. In the monarchE trial, abemaciclib combined with endocrine therapy (ET) showed sustained benefit over time, with outcomes reported up to 7 years.¹ The NATALEE trial also reported long-term efficacy with ribociclib plus a nonsteroidal aromatase inhibitor (NSAI), with results extending to 5 years.² Real-world evidence (RWE) further emphasized the importance of appropriate consideration of available options beyond adjuvant ET alone in this high-risk population, showing recurrence and mortality risks when treated with ET alone comparable with those seen in early triple-negative breast cancer. Despite demonstrated efficacy of CDK4/6 inhibitors, RWE also revealed significant underutilization of these therapies, particularly among older patients and those with N1 disease, highlighting important gaps in care. In some patients, CDK4/6 tolerability remains a key challenge in ensuring completion of recommended duration of therapy. This installment explores trial data and RWE, focusing on strategies to address tolerability challenges and support treatment persistence without compromising outcomes.

CDK4/6 Inhibitors Tolerability: Clinical Trial Experience in eBC

Abemaciclib is FDA approved for use with ET as an adjuvant treatment for adults with node-positive, HR-positive/HER2-negative, eBC at high risk of recurrence based on the monarchE trial (NCT03155997).³ Patients were divided into 2 cohorts. Cohort 1 included patients with either ≥4 positive auxiliary lymph nodes (ALNs) or 1 to 3 positive ALNs accompanied by additional high-risk features such as grade 3 tumors or tumor size ≥5 cm. Cohort 2 consisted of patients with 1 to 3 positive lymph nodes and a Ki-67 score ≥20% who did not meet the criteria for cohort 1. Patients in each cohort were randomized to receive abemaciclib plus ET (tamoxifen or an aromatase inhibitor [AI]), or ET alone, for 2 years. ET was continued for 5 years as appropriate.³

Ribociclib is indicated for use alongside an AI as adjuvant therapy for adults with HR-positive/HER2-negative stage II and III eBC at high risk of recurrence, based on findings from the NATALEE trial (CLEE011O12301C).⁴ This trial enrolled patients with HR-positive/HER2-negative eBC that was stage group IIB to III, or stage group IIA, that is either node-positive or node-negative with histologic grade 3 or histologic grade 2 with any of the following criteria: Ki67 ≥20% and/or high risk by gene signature testing. Patients were randomized to receive ribociclib plus an NSAI (letrozole or anastrozole), or an NSAI only, and goserelin.⁵ Ribociclib was administered for up to 3 years and an NSAI was administered for at least 5 years.⁵

In clinical practice, treatment objectives balance ensuring patients remain on therapy for the recommended duration to maximize potential benefit, while effectively managing tolerability challenges. Proactive side effect management, including early dose adjustments and the use of concomitant medications, is essential to improving tolerability and ensuring patients remain on therapy.

For abemaciclib, clinical trial experience in monarchE demonstrated adjuvant treatment was generally well tolerated. For a portion of patients, adverse events (AEs) included grade 3 or 4 neutropenia, leukopenia, diarrhea, and lymphopenia, leading to permanent discontinuation in 19% of patients. Dose interruptions occurred in 62% of patients. Dose reductions due to an AE occurred in 44% of patients, without compromising efficacy.^3,6 Data from the monarchE trial indicate that efficacy outcomes were maintained in patients who had a dose reduction. Patients were dose-reduced from 150 mg twice daily (BID) to either 100 mg BID or 50 mg BID.^3,6

Clinical trial experience in NATALEE demonstrated that treatment with ribociclib was well tolerated. The most common grade 3 or 4 AEs were infections, fatigue, diarrhea, and asthenia, leading to permanent discontinuation in 20% of patients. Dose interruptions occurred in 73% of patients, and dose reductions of ribociclib due to an AE occurred in 23% of patients.⁴ A subsequent post-hoc exploratory analysis of the latest data from the phase 3 NATALEE trial revealed that dose reductions occurred in 27.2% of patients, and that ribociclib maintained its clinical benefit in patients with HR-positive/HER2-negative eBC at reduced doses, according to findings presented at the San Antonio Breast Cancer Symposium (SABCS) 2024.⁴ Patients treated with ribociclib (3 weeks on/1 week off) who required dose reductions were initiated with 400 mg daily and reduced to 200 mg daily.

RWE Supports CDK4/6 Tolerability and the Use of Dose Reductions Strategies to Improve Adherence to Treatment

Findings presented at SABCS 2024 demonstrate that dose reductions and the low rate of adjuvant abemaciclib discontinuation in US clinical practice suggest that abemaciclib is well tolerated by most patients.⁷ This retrospective study, using the US Flatiron Health electronic health records–derived de-identified database, describes the clinical characteristics, dose-modification patterns, and 3-month treatment persistence in adult patients with node-positive, HR-positive/HER2-negative, stage I to III eBC who initiated abemaciclib at 150 mg BID in the first year following FDA approval.⁷

The majority of patients (88%) continued abemaciclib beyond 3 months.⁷ The low rate of adjuvant abemaciclib discontinuation in US clinical practice suggests that abemaciclib is well tolerated by most patients. Among patients who discontinued, 70% did not attempt dose modifications despite effective dose management being crucial for optimizing abemaciclib treatment. Nearly half of patients required dose reductions to improve tolerability while maintaining efficacy, particularly among older patients. Approximately 50% of patients remained on the initial abemaciclib dose, while the other 50% required dose reductions.⁷ The median time to the first dose reduction was approximately 2 months. Patients with dose reductions had improved persistency, with 93% continuing abemaciclib beyond 3 months. Among patients who discontinued treatment due to AEs, the most frequently reported AEs were diarrhea (n=24), fatigue (n=16), and nausea/vomiting (n=12).⁷ This RWE demonstrates that dose reductions may serve as a strategy to improve treatment persistence.

Conclusions

Abemaciclib and ribociclib, in combination with ET, have emerged as critical components of care for patients with node-positive, high-risk, HR-positive/HER2-negative eBC, offering significant benefits in reducing recurrence risk and improving long-term outcomes. However, ensuring patients remain on treatment for the recommended duration is essential. Clinical trial data from monarchE and NATALEE, along with supporting RWE, highlight that dose reductions and proactive side effect management strategies can improve treatment tolerability and persistence without compromising efficacy. Tailored side effect management and education for both patients and clinicians on the importance of adherence is vital to improving outcomes. With their durable efficacy and manageable safety profiles, abemaciclib and ribociclib continue to play an essential role in optimizing care and reducing recurrence risk for patients with node-positive, high-risk, HR-positive/HER2-negative eBC.

References

1. Johnston SR, Martin M, O’Shaughnessy J, et al. monarchE: primary overall survival (OS) results of adjuvant abemaciclib + endocrine therapy (ET) for HR+, HER2-, high-risk early breast cancer (EBC). Presented at: ESMO Congress 2025. October 17, 2025; Berlin, Germany. Abstract LBA13.
2. Crown JP, Stroyakovskiy D, Yardley D, et al. Adjuvant ribociclib (RIB) plus nonsteroidal aromatase inhibitor (NSAI) in patients (pts) with HR+/HER2− early breast cancer (EBC): NATALEE 5-year outcomes. Presented at: ESMO Congress 2025. October 17, 2025; Berlin, Germany. Abstract LBA14.
3. VERZENIO [prescribing information]. 2025. Lilly USA, LLC; Indianapolis, IN.
4. US Food & Drug Administration. FDA approves ribociclib with an aromatase inhibitor and ribociclib and letrozole co-pack for early high-risk breast cancer [press release]. October 24, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ribociclib-aromatase-inhibitor-and-ribociclib-and-letrozole-co-pack-early-high-risk
5. KISQALI [prescribing information]. 2025. Novartis Pharmaceuticals Corporation; East Hanover, NJ.
6. Goetz MP, Cicin I, Testa L, et al. Impact of dose reductions on adjuvant abemaciclib efficacy for patients with high-risk early breast cancer: analyses from the monarchE study. NPJ Breast Cancer. 2024;10:34.
7. Hudson K, et al. Presented at: San Antonio Breast Cancer Symposium. December 10-14, 2024; San Antonio, TX. Poster P1-11-29.