CDK 4/6 Inhibitors for the Treatment of HR-Positive, HER2-Negative High-Risk Early Breast Cancer
The majority of patients with HR-positive, HER2-negative early breast cancer receive standard endocrine therapy as part of the treatment plan for the management of their disease, which can significantly reduce the risk of mortality. However, a proportion of patients face a high risk of recurrence, which is related to disease stage, nodal status, and other factors.1

The majority of patients with hormone receptor (HR)-positive, HER2-negative early breast cancer receive standard endocrine therapy (ET) as part of the treatment plan for the management of their disease, which can significantly reduce the risk of mortality. Some patients, however, face a high risk of breast cancer recurrence.1 Both early and late relapse remain a significant clinical challenge, and more effective therapies are needed to prevent recurrences in this population.2,3 Additionally, in patients with HR-positive, HER2-negative early breast cancer, variation in stage, age, comorbidities, and other prognostic factors is linked to differing risks of recurrence among this patient population and requires an individualized approach to treatment decisions and choice of therapies. Among available targeted therapies, inhibitors of cyclin-dependent kinases 4 and 6 (CDK 4/6) have demonstrated clinical efficacy in the treatment of HR-positive, HER2-negative metastatic disease, and two CDK 4/6 inhibitors have shown improvements in their primary clinical trial endpoints (invasive disease–free survival [iDFS]) for HR-positive, HER2-negative early breast cancer when used in combination with ET.4

Risk of Recurrence in HR-Positive, HER2-Negative High-Risk Early Breast Cancer

Approximately 70% of all patients with breast cancer have HR-positive, HER2-negative breast cancer, more than 90% of whom are diagnosed with early-stage disease.1,5 For the majority of patients with HR-positive, HER2-negative early breast cancer, standard treatment consists of (neo)adjuvant ET (aromatase inhibitors [AIs] and/or antiestrogens, with or without ovarian suppression), chemotherapy, and local therapies such as surgery and radiotherapy. However, 20% to 30% of these patients will experience disease recurrence within the first 10 years.6-8 While recurrences peak at 1 to 2 years after primary diagnosis, some can occur even after 10 years.6,7 An unmet need therefore exists for additional effective adjuvant therapies to reduce the risk of recurrence for these patients.

Accurate determination of risk level is essential since it can inform the use of individualized adjuvant therapy, but identifying patients with high-risk disease can be challenging.9 In addition to the heterogeneity of such tumors, various methods are used to assess recurrence risk.10 Risk of recurrence is especially high for those with certain clinicopathologic features, based on tumor size and histologic grade, nodal involvement, breast cancer genomic risk score, Ki-67 expression level, and response to primary systemic treatment.11,12 In one analysis, patients judged to be at high risk based on clinicopathologic criteria had a threefold greater risk of recurrence compared with patients who were not at high risk.5 According to Hope Rugo, MD, of the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, the challenge is to identify which patients are at higher risk. “The standard clinical pathologic tools we use are not perfect, and there's no single test that alone determines prognosis and risk of recurrence, so you have to use a combination of different tools,” she said.

The standard clinical pathologic tools we use are not perfect, and there's no single test that alone determines prognosis and risk of recurrence, so you have to use a combination of different tools. Hope Rugo, MD

CDK 4/6 as Therapeutic Target

CDK 4/6 play key roles in cell cycle regulation, and the cyclin-D1–CDK4/6–Rb pathway is dysregulated in the majority of human tumors. In breast cancer, cyclin D overexpression/dysregulation leads to CDK activation and tumor cell proliferation. Inhibition of CDK 4/6 can block the growth of breast cancers, particularly when combined with ET, for the treatment of HR-positive, HER2-negative early breast cancer.13,14

Three CDK 4/6 inhibitors are currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of various lines of advanced or metastatic HR-positive, HER2-negative breast cancer in combination with ET: palbociclib, abemaciclib, and ribociclib; abemaciclib is also approved as monotherapy in later lines. These agents differ with respect to structure and binding affinity to the ATP binding pocket of these CDKs as well as in pharmacokinetics/pharmacodynamics, recommended dosing and scheduling, efficacy, and toxicity profiles.13,15-18 Currently, two CDK 4/6 inhibitors in combination with ET are also approved by the FDA as adjuvant therapy for patients with HR-positive, HER2-negative early breast cancer at high risk of recurrence. Abemaciclib in combination with ET is approved for patients with HR-positive, HER2-negative, node-positive early breast cancer at high risk of recurrence. Ribociclib in combination with an AI is approved for patients with HR-positive, HER2-negative stage II and III early breast cancer at high risk of recurrence. See the respective U.S. Prescribing Information for further details on each patient population.16,18

Clinical Trials of CDK 4/6 Inhibitors for HR-Positive, HER2-Negative Early Breast Cancer

In light of their efficacy in advanced breast cancer, clinical trials of adjuvant CDK 4/6 inhibitors for HR-positive, HER2-negative early breast cancer have been conducted, with most centered on patients at high risk of recurrence. These trials differed with respect to eligibility criteria, dosing, and duration of CDK 4/6 inhibitor therapy as well as definition of recurrence risk (Table 1).

Table 1. Key Adjuvant Trials of CDK 4/6 Inhibitors for HR-Positive, HER2-Negative High-Risk Early Breast Cancer

Patient characteristics

Stage II or III

N

5,796

Dosing

Palbociclib
125 mg daily
3 weeks on/1 week off

Duration of CDK4/6i therapy

2 years

Duration of follow-up (median)

31 months

Patients completing CDK4/6i + ET therapy

55.1%

Invasive disease–free survival rate

4 year: 84.2% vs 84.5%
HR = 0.96 (95% CI = 0.81–1.14);
P = NS

Distant relapse–free survival rate

4 year: 86.2% vs 87.8%
HR = 1.05 (95% CI = 0.87–1.28); P = NS

Patient characteristics

High risk with residual disease after taxane-containing neoadjuvant chemotherapy (CPS-EG score ≥ 3 or 2 and ypN+)

N

1,250

Dosing

Palbociclib
125 mg daily
3 weeks on/1 week off

Duration of CDK4/6i therapy

1 year

Duration of follow-up (median)

42.8 months

Patients completing CDK4/6i + ET therapy

80.5%

Invasive disease–free survival rate

4 year: 73.0% vs 72.4%
HR = 0.93 (95% repeated CI = 0.74–1.17); P = NS

Distant relapse–free survival rate

NR

Patient characteristics

Cohort 1: ≥ pN2 or ≥ pN1 and G3 or pT3b
Cohort 2: pN1, < G3, tumor size < 5 cm, and Ki-67 ≥ 20%

N

5,637

Dosing

Abemaciclib
150 mg daily
Continuous

Duration of CDK4/6i therapy

2 years

Duration of follow-up (median)

4 year: 42 months

5 year: 54 months

Patients completing CDK4/6i + ET therapy

4 year : 69.0%

Invasive disease–free survival rate

4 year: 85.8% vs 79.4%
HR = 0.664 (95% CI = 0.578–0.762); P < .0001c

5 year: 83.6% vs 76.0%
HR = 0.680 (95% CI = 0.599–0.772); P < .001c,d

Distant relapse–free survival rate

4 year: 88.4% vs 82.5%
HR = 0.659 (95% CI = 0.567–0.767); P < .0001c

5 year: 86.0% vs 79.2%
HR = 0.675 (95% CI = 0.588–0.774); P < .001c

Patient characteristics

Stage IIA: N1, or N0 G3, or N0 G2 if any of the following features:I

Oncotype Dx RS ≥ 26, EndoPredict High Risk, Prosigna/PAM50 High Risk, MammaPrint High Risk or Ki-67 ≥ 20%

Stage IIB (N0 or N1) or III (N0, N1, N2, N3)

N

5,101

Dosing

Palbociclib
125 mg daily
Ribociclib
400 mg daily
3 weeks on/1 week off

Duration of CDK4/6i therapy

3 years

Duration of follow-up (median)

2 year: 27.7 months

3 year: 33.3 months

Patients completing CDK4/6i + ET therapy

2 year: 56.8%

3 year: 42.8%

Invasive disease–free survival rate

3 year: 90.7% vs 87.6%
HR = 0.749 (95% CI = 0.628–0.892); P = .0006c

Distant relapse–free survival rate

3 year: 92.9% vs 90.2%
HR = 0.749 (95% CI = 0.623–0.900); P = .0010c
a Prior adjuvant and neoadjuvant chemotherapy were allowed in monarchE trial.
b Cohort 1 represents FDA-approved population in abemaciclib label.
c Nominal P value.
d 5-year monarchE data based on most recent disclosed analysis.
NOTE: No head-to-head trials exist between the three molecules discussed herein. This table presents a summary of efficacy data for representation purposes only and not for comparative analysis.
Abbreviations: CDK4/6i = CDK 4/6 inhibitor; CI = confidence interval; CPS-EG = relapse probability based on clinical and pathologic stage (CPS) plus ER status and histologic grade (EG); ER = estrogen receptor; FDA = U.S. Food and Drug Administration; HR = hazard ratio; NR = not reported; NS = not significant.

Palbociclib

The phase III PALLAS trial compared adjuvant palbociclib (2 years) plus ET (tamoxifen or AI) to ET alone (≥ 5 years) in patients with HR-positive, HER2-negative early breast cancer (not limited to those at high risk). The addition of palbociclib did not significantly improve iDFS (4-year iDFS rate: 84.2% vs 84.5%; hazard ratio [HR] = 0.96 [95% confidence interval (CI) = 0.81–1.14]; P = .65; Table 1).19,20 In the phase III PENELOPE-B trial, the combination of palbociclib (1 year) and ET (tamoxifen or AI) was compared to ET alone (≥ 5 years) in patients with HR-positive, HER2-negative early breast cancer and residual invasive disease (following resection and neoadjuvant chemotherapy) who were at high risk of relapse. Similar to PALLAS, the addition of palbociclib to endocrine therapy did not significantly improve iDFS compared with endocrine therapy alone (4-year iDFS rate: 73.0% vs 72.4%; HR = 0.93 [95% CI = 0.74–1.17]; P = .525). The most common adverse events on the palbociclib arm were neutropenia, leukopenia, thrombocytopenia, anemia, hypocalcemia, fatigue, stomatitis, constipation, cough, and infection. The risk of grade 3/4 neutropenia (70% vs 1%) and grade 3/4 leukopenia (56% vs 1%) was also higher with palbociclib plus endocrine therapy compared to endocrine therapy alone.21,22

Abemaciclib

The phase III monarchE trial compared treatment with abemaciclib (2 years) plus ET (tamoxifen or AI) to ET alone (≥ 5 years) in patients with HR-positive, HER2-negative, node-positive early breast cancer at high risk of recurrence (defined as four or more positive pathologic axillary lymph nodes or one to three positive axillary lymph nodes and at least one of the following: tumor size ≥ 5 cm, histologic grade 3, or centrally assessed Ki-67 ≥ 20%). At the time of interim analysis (median follow-up, 15.5 months), 12.5% of patients had completed the 2-year study period and 72.8% remained on study treatment. Compared with patients who received ET alone, those who received abemaciclib had a statistically significant improvement in iDFS (2-year iDFS rate: 92.2% vs 88.7%; HR = 0.75 [95% CI = 0.60–0.93]; P = .01) and superior distant relapse–free survival (2-year DRFS rate: 93.6% vs 90.3%; HR = 0.72 [95% CI = 0.56–0.92]; nominal P = .01), independent of the number of positive lymph nodes or menopausal status.23 Clinically relevant adverse events were more frequent on the abemaciclib arm (98.4% vs 88.8%), the most common of which were diarrhea, infections, neutropenia, fatigue, leukopenia, nausea, anemia, and headache. Grade 3/4 adverse events were also increased with abemaciclib (49.7% vs 16.3%). The discontinuation rate of abemaciclib during study treatment due to adverse events was 18.5%.24 These results, in addition to a follow-up at a median of 27 months confirming the efficacy of abemaciclib, led to the FDA approval of abemaciclib plus ET as adjuvant therapy for patients with HR-positive, HER2-negative, node-positive early breast cancer at high risk of recurrence and a Ki-67 score ≥ 20%.16,25 A later analysis found that long-term patient-reported health-related quality-of-life outcomes in monarchE were similar between treatment arms.26

A subsequent OS interim analysis after all patients were off abemaciclib treatment (median follow-up, 42.0 months) confirmed the initially observed benefit for iDFS (HR = 0.664 [95% CI = 0.578–0.762]; nominal P < .0001) and DRFS (HR = 0.659 [95% CI = 0.567–0.767]; nominal P < .0001).27 In this analysis, 30% of abemaciclib-treated patients had one dose reduction and 14% required two. However, these did not significantly compromise the iDFS rate. Dose reductions were more common in patients ≥ 65 years old and those with ≥ 4 preexisting comorbidities.28,29 Based on this interim analysis, the U.S. indication was broadened (in 2023) by removal of the Ki-67 testing requirement, thereby expanding the use of abemaciclib to a broader patient population.30 A 5-year interim analysis (median follow-up, 54 months) further supported the benefit for iDFS (HR = 0.680 [95% CI = 0.599–0.772]; nominal P < .001) and DRFS (HR = 0.675 [95% CI = 0.588–0.774]; nominal P < .001), reflecting a 32.5% relative reduction in the risk of developing a DRFS event and 32.0% relative reduction in the risk of developing an iDFS event (Table 1). At the time of this data cutoff, all patients on both arms had been off treatment for at least 1 year, and more than 80% of patients had been followed for at least 2 years since completing abemaciclib treatment. At this OS interim analysis, statistical significance was not reached for OS. Continued follow-up is ongoing until final assessment of OS.31,32 The iDFS and DRFS curves continue to separate over time, consistent with a carryover effect beyond completion of 2 years of abemaciclib and ET (ie, continued reduction in risk of recurrence even following cessation of abemaciclib).32

According to the American Society of Clinical Oncology (ASCO) and NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®), ET combined with abemaciclib is a treatment option for patients with HR-positive, HER2-negative, node-positive early breast cancer at high risk of recurrence.33,34 NCCN Guidelines® (category 1, preferred) indicate that 2 years of adjuvant abemaciclib in combination with ET can be considered in patients with HR-positive, HER2-negative high-risk breast cancer.33

Ribociclib

Ribociclib has also demonstrated efficacy for treatment of HR-positive, HER2-negative early breast cancer, although in a different patient population than the PENELOPE-B, PALLAS, and monarchE trials. The phase III NATALEE trial compared treatment with ribociclib (3 years) plus adjuvant nonsteroidal AI (≥ 5 years) to nonsteroidal AI alone in patients with HR-positive, HER2-negative early breast cancer (stage II and III) at increased risk of recurrence, including selected patients with no nodal involvement (N0). At the time of data cutoff for the prespecified interim analysis (median follow-up, 27.7 months), 77.8% of patients were continuing to receive study treatments. One-fifth (20.2%) of patients had completed the 3-year ribociclib plus ET study period.35,36 At this iDFS interim analysis, there was a significant benefit for ribociclib plus ET compared to ET alone (3-year iDFS rate: 90.4% vs 87.1%; HR = 0.75 [95% CI = 0.62–0.91]; nominal P = .003).36

The final iDFS analysis (median follow-up, 33.3 months) reported 3-year iDFS rates of 90.7% and 87.6%, respectively, reflecting a 25% relative reduction in the risk of developing an iDFS event with ribociclib (HR = 0.749 [95% CI = 0.628–0.892]; P = .0006). The iDFS benefit of ribociclib was consistent across all clinicopathologic subgroups, including patients with stage II, stage III, node-negative, and node-positive disease.37 (Note that stage IIA, node-negative patients were considered high risk according to eligibility criteria, and not all stage II node-negative patients were included.) DDFS, a secondary endpoint, also favored the ribociclib arm, with 3-year DDFS rates of 92.9% and 90.2%, respectively, reflecting a 25% relative reduction in the risk of developing a DDFS event (HR = 0.749 [95% CI = 0.623–0.900]; nominal P = .001).37 Because most patients were still on study treatment at the time of this analysis, the long-term carryover effect is unclear. The most common adverse events with ribociclib plus ET were neutropenia, liver-related adverse events, arthralgia, nausea, headache, and fatigue. Grade 3/4 neutropenia was significantly more common with ribociclib plus ET compared to ET alone (43.8% vs 0.8%).35,36 Discontinuation of ribociclib therapy due to adverse events occurred in 18.9% of patients at the interim analysis and 19.5% at the primary outcome, mainly due to liver-related toxicity and arthralgia.35-37 The results at the final iDFS analysis led to the FDA approval of ribociclib plus AI as adjuvant therapy for patients with HR-positive, HER2-negative stage II and III early breast cancer at high risk of recurrence.

Based on these results, the ASCO guidelines were updated in May 2024 to conditionally recommend the use of adjuvant ribociclib plus ET for patients who would have met NATALEE eligibility criteria and have a high risk of recurrence.34 For patients who meet the eligibility criteria for both the monarchE and NATALEE trials, the guidelines reserve the use of ribociclib for patients with a contraindication to or intolerance of abemaciclib, otherwise favoring the use of abemaciclib due to its longer follow-up, deepening benefit over time, shorter duration of therapy, and FDA approval in the adjuvant setting at the time the guidelines were published (May 2024).

Practical Considerations With CDK 4/6 Inhibitor Adjuvant Therapy

Because CDK 4/6 inhibitors are orally administered, maintaining adherence and persistence to therapy is key to maximizing their efficacy, particularly since patients may be on such therapy for many years. Factors that can affect adherence include patient-oncologist relationship and communication, patient age and cognitive issues (eg, forgetfulness, depression), high pill burden, insurance/out-of-pocket costs, and medical and social support (Figure 1).38-40 When selecting a CDK 4/6 inhibitor, clinicians should also consider its toxicity profile, dose and dosing schedule, recommended therapy duration, and relative risks and benefits for individual patients. They should reinforce to patients the importance of remaining adherent throughout the course of CDK 4/6 inhibitor therapy. In the monarchE trial, for example, dose modifications (when required) were shown to support adherence and improve abemaciclib tolerability.28 The use of smart phone and Internet-based apps, smart pill bottle reminders, and enhanced personal and social supports may help patients improve their adherence to breast cancer therapy.39-43

Figure 1. Improving Adherence to CDK 4/6 Inhibitor Therapy

Clear, proactive communication between health-care providers and patients is essential for improving breast cancer survivorship. In addition to maintaining adherence, this includes addressing risk of recurrence, selection of appropriate therapy, minimizing adverse events, reducing financial toxicity, and alleviating psychosocial distress. Yet despite the availability of breast cancer survivorship guidelines, key gaps in survivorship care remain.44,45 Oncologists should appreciate that comprehensive survivorship care includes shared decision-making and patient education regarding the potential benefits and risks of CDK 4/6 inhibitor–based therapy. This will help improve patient engagement and help reduce concerns relating to treatment decisions. Dr. Rugo emphasized that shared decision-making is a critical aspect of this therapy. “You talk about the potential benefits as well as the [risks], and the fact that you can dose reduce and discontinue at any time,” she said. “And that seems to work best with patients.”

[Health-care providers can] talk about the potential benefits as well as the [risks of CDK 4/6 inhibitors], and the fact that you can dose reduce and discontinue at any time. That seems to work best with patients. Hope Rugo, MD

Conclusion

Randomized clinical trials have demonstrated the survival benefit provided by selected CDK 4/6 inhibitors when used as adjuvant therapy in combination with ET for patients with HR-positive, HER2-negative early breast cancer at high risk of recurrence. Abemaciclib and ribociclib each have significantly improved iDFS in this setting (albeit in different patient populations) and have been approved by the FDA for the treatment of patients with HR-positive, HER2-negative early breast cancer at high risk of recurrence.

Treatment algorithms are continuing to evolve in an effort to standardize optimal CDK 4/6 inhibitor therapy for this patient population. For now, selection of CDK 4/6 inhibitors should be based on the eligibility criteria used in pivotal trials and as specified by the corresponding prescribing information. Continuing to improve patient communication and education regarding CDK 4/6 inhibitor therapy including risk of recurrence, selection of therapy, and adherence and persistence to treatment will contribute to informed decision-making, enhanced quality of life, and survivorship care for patients with HR-positive, HER2-negative early breast cancer. “We are excited about these data, about impacting patients using an oral therapy,” concluded Dr. Rugo. “We hope that ongoing follow-up and additional analyses will help us understand how we can identify the optimal treatment, patients, and duration of therapy.”

Published on October 1, 2024.

Disclosure

Dr. Rugo reported a consulting or advisory role with Napo Pharmaceuticals, Puma Biotechnology, Mylan, Eisai, and Daiichi Sankyo; and institutional research funding from OBI Pharma, Pfizer, Novartis, Lilly, Merck, Daiichi Sankyo, AstraZeneca, Gilead Sciences, Astellas Pharma, Taiho Oncology, Veru, GlaxoSmithKline, Hoffmann-La Roche AG/Genentech, Inc; and Stemline Therapeutics.

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