CE / CME
Physician Assistants/Physician Associates: 0.50 AAPA Category 1 CME credit
Nurses: 0.50 Nursing contact hour
Pharmacists: 0.50 contact hour (0.05 CEUs)
Physicians: maximum of 0.50 AMA PRA Category 1 Credit™
ABIM MOC: maximum of 0.50 Medical Knowledge MOC point
Released: January 24, 2025
Expiration: January 23, 2026
Risk Assessment Algorithm to Inform Systemic Adjuvant Therapy Selection in EBC
For patients who have a high risk of recurrence in terms of having a greater clinical anatomic risk, preoperative therapy and neoadjuvant chemotherapy can sometimes be considered.5,6 However, for the vast majority of patients, upfront surgery is performed, and then decisions about the use of chemotherapy post surgery are made based on results from genomic assays. If chemotherapy is needed, once treatment is complete, adjuvant endocrine-based therapy can be administered. A question that arises at this point is whether there is an additional need for the use of targeted agents with ET in the adjuvant setting, where patients may benefit from the use of adjuvant CDK4/6 or PARP inhibition.
monarchE and NATALEE Trial Populations
Two large, randomized phase III trials (monarchE and NATALEE) have investigated the use of adjuvant CDK4/6 inhibition in the HR-positive/HER2-negative EBC setting.7-10 In these 2 trials, the patient populations were different. The majority of pre/postmenopausal patients on monarchE had very high-risk disease with 4 or more positive ALNs. If they had 1 to 3 positive ALNs, the disease had to be categorized as grade 3 and/or the patient had a tumor size 5 cm or larger or had a Ki-67 score ≥20%. On the other hand, patients on the NATALEE trial were eligible if they had any degree of nodal positivity without the requirement for additional high-risk features except for those with node-negative disease. For these patients, if the disease is node-negative with a tumor between 2 cm and 5 cm in size, the tumor had to be high grade. If they had grade 2 disease, Ki-67 ≥20% or an Oncotype Dx RS 26 or higher is required. So basically, the NATALEE trial included a broader population of patients compared with monarchE, which focused on patients with very high-risk disease.
monarchE: Adjuvant Abemaciclib + ET in High-Risk, Node-Positive HR+/HER2- EBC
The phase III monarchE trial for pre- or postmenopausal patients with node-positive, HR-positive/HER2-negative EBC allowed for the inclusion of patients who had previously received neoadjuvant or adjuvant chemotherapy without distant metastasis.7,8 Patients were required to be within 16 months from surgery and be within 12 weeks of initiating ET to be eligible. A total of 5637 patients who were enrolled on the trial were divided into 2 cohorts before randomization. Cohort 1 included 91% of the total patient population. Cohort 1 was for patients with 4 or more positive ALNs or those with 1 to 3 positive ALNs who had histologic grade 3 disease with or without a tumor size 5 cm or larger. Cohort 2 included 9% of the total patient population. Patients in Cohort 2 had 1 to 3 ALNs, a tumor size less than 5 cm, Ki-67 ≥20% and grade 1/2 disease. All patients in Cohorts 1 and 2 were randomly assigned to receive either ET alone (n = 2829) or ET in combination with abemaciclib 150 mg twice daily (n = 2808) for up to 2 years. Patients continued to receive ET for 5 to 10 years. The primary endpoint was invasive disease-free survival (iDFS), and the secondary endpoints included distant relapse–free survival (DRFS), overall survival (OS), and safety.
monarchE: 5-Yr iDFS in ITT Population
The 5-year iDFS rate showed a statistically significant improvement with the addition of abemaciclib to ET (83.6%) vs ET alone (76%), with an absolute difference between arms of 7.6% (HR: 0.680; 95% CI: 0.599-0.772; P <.001).8 Of interest, even after the patients discontinued treatment with abemaciclib, which was given for a maximum of 2 years, the curves continued to separate. These results suggest that there is a carryover effect from having received abemaciclib on the trial which continues to improve with longer follow-up.
monarchE: 5-Yr DRFS in ITT
Of importance, majority of patients had DRFS at 5 years. With the addition of abemaciclib, the 5-year DRFS rate was 86% vs 79.2% with ET alone, with an absolute difference in 5-year DRFS rate of 6.7% (HR: 0.675; 95% CI: 0.588-0.774; P <.001).
monarchE: Overall Survival in ITT Population 5-Year Update
Although the OS data remain immature, there is a slight trend towards favoring abemaciclib (HR: 0.903; 95% CI: 0.749-1.088; P = .284). However, longer follow-up is still needed to understand whether abemaciclib will have an impact on OS.
monarchE: Metastatic Recurrences in the ITT Population at IA3
It is noteworthy that there are fewer patients in the abemaciclib arm that are living with metastatic disease, compared with the patients who received ET alone. Currently, metastatic disease is not curable in the majority of patients. Therefore, these data will likely have an impact on survival outcomes. Fortunately, patients with breast cancer are living for many years with metastatic disease. A longer follow-up duration is needed to definitively determine the effect of the addition of abemaciclib to adjuvant ET on OS in these patients.
monarchE: Safety With Adjuvant Abemaciclib + ET
Overall, the safety data from monarchE are consistent with what have previously been seen in the metastatic setting, with abemaciclib being associated with GI toxicity.11-13 In the abemaciclib arm, 83.5% of the patients experienced diarrhea of any grade. However, only 7.8% of the patients experienced grade 3 or higher diarrhea. Though rare, some of the patients experienced venous thromboembolic events (VTEs), which were more commonly observed on the abemaciclib arm (2.5%) compared with the ET only arm (0.7%). Of importance, the rate of VTE by first ET received was higher among patients who received tamoxifen (4.3%) vs those who received an AI (1.8%) on the abemaciclib arm. It is also important to note that interstitial lung disease (ILD) is a possible toxicity of abemaciclib, and this was observed in 3.3% of patients on the abemaciclib arm vs 1.3% of patients who received ET alone.
Given the higher rate of VTE seen with the combination of tamoxifen and abemaciclib, it is important to think about what the patient's risk factors could be for developing a thromboembolic event before prescribing abemaciclib in combination with tamoxifen. If a patient has significant risk factors for developing a blood clot, the combination of abemaciclib with tamoxifen should be used with caution.
monarchE: iDFS According to RDI in the Adjuvant Abemaciclib Arm
A question that keeps arising regarding the use of abemaciclib in the adjuvant setting is whether dose reduction impacts the efficacy of this agent. Many of my patients have asked me this question. monarchE showed that for patients who required dose modification, there was no impact on the 4-year iDFS rate.14,15 Looking at iDFS based on the relative dose intensity, data from monarchE demonstrated that irrespective of dose intensity, the benefits of abemaciclib were preserved and not compromised by dose reductions. Therefore, it is very important to reassure patients that dose modification does not impact the efficacy seen with abemaciclib.
TRADE: Phase II Dose-Escalation Trial of Abemaciclib + ET in HR+/HER2- EBC Planned for Adjuvant Abemaciclib
Approximately 40% of patients will require abemaciclib dose modification.12 Based on this, there is a lot of interest in trying to see if there are other strategies that would help patients to receive the full dose and potentially prevent early abemaciclib discontinuation. TRADE is a phase II trial that is investigating whether a dose-escalation approach for abemaciclib will reduce the associated drug discontinuations and dose modifications among patients with HR-positive/HER2-negative EBC who are about to start treatment with abemaciclib (NCT06001762). The phase II TRADE trial will investigate the impact of starting abemaciclib at 50 mg twice daily on Day 1 to Day 14 followed by a dose increase to 100 mg twice daily on Day 15 to Day 28, and thereafter, increasing to the full dose of abemaciclib at 150 mg twice daily. The primary endpoint is the composite adverse rate at 3 months of abemaciclib discontinuation for any reason, dose reduction, and/or inability to maintain the full dose. This trial will provide very important information that could help us better understand if dose escalation of abemaciclib may be better tolerated by patients.
NATALEE: Phase III of Adjuvant Ribociclib + ET vs ET in HR+/HER2- EBC
The phase III NATALEE trial for pre- or postmenopausal patients with HR-positive/HER2-negative EBC allowed for the inclusion of patients who had previously received neoadjuvant or adjuvant chemotherapy.9,10 Patients were required to be within 12 weeks of initiating ET to be eligible. As noted earlier, patients were eligible if they had any degree of ALN involvement, including those with stage IIA (N0 or N1), stage IIB (N0 or N1), and stage III (N0-N3) EBC.
Patients with node-negative, grade 2, stage IIA disease needed to have evidence of high-risk features including Ki-67 ≥20%, Oncotype Dx RS 26 or higher, or high-risk disease assessed via genomic risk profiling. Patients with node-negative, grade 3, stage IIA disease were also eligible to participate in the study. A total of 5101 patients enrolled on the trial were randomly assigned to receive either a nonsteroidal aromatase inhibitor (NSAI) alone (n = 2552) or in combination with ribociclib 400 mg/day (n = 2549) for up to 3 years. In addition, premenopausal women and men received goserelin. The primary endpoint was iDFS, and the secondary endpoints included distant disease–free survival (DDFS), overall survival, and safety.
It is important to note that the dose of ribociclib utilized in the NATALEE trial (400 mg/day on a 3-week on/1-week off schedule) is lower than the dose that was approved in the metastatic setting in which a dose of 600 mg/day on a 3-week on/1-week off schedule is used.
NATALEE: iDFS (Primary Endpoint at 4 Yr)
The 4-year iDFS rate showed a statistically significant improvement with the addition of ribociclib to NSAI (88.5%) vs NSAI alone (83.6%), with an absolute difference between arms of 4.9% (HR: 0.715; 95% CI: 0.609-0.840; P <.0001).
NATALEE: 4-Yr iDFS in Key Patient Subgroups
With regard to iDFS, benefit with the addition of ribociclib to NSAI was consistent across all prespecified subgroups including patients with stage II, stage III, node-negative, and node-positive disease. In the subgroup of patients with node-negative disease, the relative risk reduction in terms of the 4-year iDFS with the addition of ribociclib vs NSAI alone was 5.1% (HR: 0.666; 95% CI: 0.397-1.118), and this was very similar to that obtained in the population of patients with node-positive disease (5%) (HR: 0.731; 95% CI: 0.617-0.866).
However, it is important to note that only 613 (12%) of the patients on the NATALEE trial had node-negative EBC compared with 4480 (88%) who had node-positive disease. Therefore, the confidence interval regarding ribociclib benefit in the node-negative patient population is quite wide.
NATALEE: DDFS and OS at 4 Years
Of note, patients who received ribociclib plus NSAI predominantly achieved DDFS at 4 years (HR: 0.715; 95% CI: 0.604-0.847; P <.0001). Similar to the monarchE trial, after a median follow-up of 44.3 months, the OS data are still immature (HR: 0.827; 95% CI: 0.636-1.074; P = .0766).
NATALEE: Safety
In the metastatic setting, it is known that ribociclib is associated with a higher rate of neutropenia. However, given that the dose utilized in NATALEE was lower than that typically used in the metastatic setting, the rate of high-grade neutropenia is lower than that typically seen in patients with metastatic disease. In the NATALEE trial, all-grade neutropenia was reported in 62.8% of patients, 44% of whom experienced grade 3 or higher neutropenia. Liver-related adverse events (26.7%), predominantly increased liver function enzyme levels without a concomitant elevation in bilirubin level, were also associated with ribociclib. QT interval prolongation was reported in 5.4% of patients with 1% occurring at grade 3 or higher intensity. ILD is also a potential toxicity with ribociclib occurring in 1.6% of patients, all which were grade 1/2.
NATALEE: iDFS by Dose Reductions Due to AEs
As with the monarchE trial, a question that certainly arises with use of ribociclib is whether dose reductions impact iDFS benefit. In an analysis of data from the NATALEE trial, ribociclib dose reduction did not have any significant impact on iDFS benefit at the 25th, 50th or 75th percentile.16
FDA-Approved CDK 4/6 Inhibitors for HR+/HER2- EBC
We now have 2 different CDK4/6 inhibitors with FDA approval in the adjuvant EBC setting.17,18 Based on the results of monarchE, abemaciclib 150 mg twice daily for 2 years received FDA approval in combination with ET (tamoxifen or an AI) for the adjuvant treatment of adult patients with HR-positive, HER2-negative, node-positive, EBC at high risk of recurrence.8,17,19 More recently, based on the results of NATALEE, the FDA approved ribociclib in combination with an AI for the adjuvant treatment of adults with HR-positive, HER2-negative stage II and III EBC at high risk of recurrence.10,18,20
Key AEs With CDK4/6 Inhibitors: Monitoring and Prevention
When thinking about choosing between these 2 FDA-approved CDK4/6 inhibitors for patients with HR-positive/HER2-negative EBC, it is important to try to individualize treatment decisions and consider the differences in toxicity profiles. For instance, diarrhea is more commonly reported with abemaciclib compared with ribociclib. Measures to mitigate diarrhea include the use of antidiarrheal therapy, oral hydration, and dietary modification. Hepatobiliary toxicity is associated with both drugs but is certainly more common with ribociclib. The incidence of neutropenia is more common with ribociclib but is also associated with abemaciclib. So, when either of these CDK4/6 inhibitors is used, it is necessary to monitor the patient’s complete blood counts.
VTE is associated with abemaciclib, and certainly occurs more when used in combination with tamoxifen vs an AI. Of note, ribociclib cannot be given in combination with tamoxifen because both tamoxifen and ribociclib are associated with QT prolongation. So, when using ribociclib, it is very important to know that it can only be given in combination with an AI. If ribociclib will be prescribed to a premenopausal woman or a man with HR-positive, HER2-negative EBC, ovarian suppression is also needed. For patients receiving either abemaciclib or ribociclib, it is also important to monitor for pulmonary symptoms which are indicative of ILD or pneumonitis.
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