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Role of CDK4/6 Inhibitors in HR+/HER2- EBC

CE / CME

Risk Factors for Recurrence, Molecular Testing, and Treatment of Patients With HR-Positive/HER2-Negative EBC

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

Sara M. Tolaney
Sara M. Tolaney, MD, MPH
CME/CE Information

Activity

Progress
1 2
Course Completed

Ongoing Randomized Phase III Trials of Adjuvant Abemaciclib in HR+/HER2- EBC

We need more data to guide us so that treatment with CDK4/6 inhibitors can be optimally tailored for patients. Fortunately, there are several ongoing studies that may help with this. The randomized, phase III ADAPTlate trial is investigating the efficacy and tolerability of adjuvant abemaciclib plus ET vs ET alone for pre- and postmenopausal patients with intermediate to high clinical or genomic risk HR-positive, HER2-negative EBC if the primary diagnosis was 6 years or less before enrollment (NCT04565054). In essence, ADAPTlate is investigating the benefits of administering abemaciclib in the late adjuvant setting.

The randomized phase III POETIC study is investigating the efficacy and safety of adjuvant abemaciclib plus ET vs ET alone for postmenopausal patients with ER-positive, HER2-negative primary breast cancer with Ki-67 ≥8% after 2 weeks of preoperative therapy with an AI (NCT04584853). 

Ongoing Randomized Phase III Trials of Adjuvant Palbociclib or Ribociclib in HR+/HER2- EBC

The randomized phase III POLAR trial is investigating the efficacy and safety of adjuvant palbociclib plus ET vs ET alone for patients with HR-positive, HER2-negative resected isolated locoregional recurrence of breast cancer (NCT03820830). ADAPTcycle is a randomized phase III study that is investigating the efficacy and safety of ribociclib plus ET vs standard of care chemotherapy followed by adjuvant ET for pre- and postmenopausal patients with intermediate-risk, HR-positive, HER2-negative EBC (NCT04055493).

These trials will help to decipher whether there are patients for whom CDK4/6 inhibition could be used instead of chemotherapy, if late CDK4/6 inhibition can be beneficial, and how to specifically tailor CDK4/6 inhibitor-based therapies for our patients with HR-positive, HER2-negative EBC.

Conclusions

In general, when considering the use of a CDK4/6 inhibitor for patients with HR-positive, HER2-negative EBC, both abemaciclib and ribociclib have demonstrated very robust efficacy, suggesting that either of these CDK 4/6 inhibitors will result in an improvement in iDFS vs ET or an NSAI alone. For patients with 4 or more positive ALNs or those with 1 to 3 positive ALNs with an additional high-risk feature, I typically would recommend abemaciclib simply because longer follow-up data from the monarchE trial are available. It is exciting that with longer follow-up from monarchE, the absolute difference in iDFS between treatment arms continues to increase.

For patients who do not fit the eligibility criteria for the monarchE trial such as those with intermediate-risk EBC, I typically opt for ribociclib since we have data from the NATALEE trial for this patient population. Overall, it is very important to individualize treatment decisions. So, if a patient is on a drug that causes QT prolongation, for example, I will recommend abemaciclib. If a patient has elevated LFTs at baseline, abemaciclib may be favored over ribociclib. For patients with underlying gastrointestinal issues where they have intermittent diarrhea, my preference will be ribociclib over abemaciclib. Of importance, individual patient characteristics should be used to personalize and tailor treatment to each patient. 

We are awaiting more data from monarchE and NATALEE with even longer follow-up. These data will help to better understand the benefits of abemaciclib and ribociclib in this setting. However, these data will not be able to provide definitive information about the optimal duration of CDK4/6 inhibition in the HR-positive, HER2-negative EBC setting since we cannot compare across different trials and, particularly because the patient populations in these trials were different.

Finally, there are patients with HR-positive, HER2-negative EBC for whom the use of CDK4/6 inhibitors will be of limited benefit. There are also patients for whom CDK4/6 inhibitor-based therapy will be of significant benefit. These are exciting times and as the different ongoing phase III trials of CDK4/6 inhibitors like the ADAPTlate, POETIC, POLAR and ADAPTcycle studies continue to accrue and progress, we will hopefully get more data that will help us to better personalize the use of CDK4/6 inhibitor–based treatments for our patients with HR-positive/HER2-negative EBC.

A 57-year-old postmenopausal woman presents with a palpable mass in her right breast. Mammogram/ultrasound showed a >5 cm mass with enlarged, suspicious ALN. Core biopsy reveals grade 1 invasive lobular carcinoma, ER-positive/PR-positive/HER2-negative disease, and lymph node biopsy showed node-positive carcinoma. CT staging and germline testing are negative. The patient has preexisting QT prolongation.


Right breast mastectomy and ALN dissection were performed and reveal 5.2 cm mass, grade 1 invasive lobular carcinoma with 2/3 positive lymph nodes. She received adjuvant chemotherapy with dose-dense doxorubicin plus cyclophosphamide followed by 12 weeks of paclitaxel. She undergoes radiotherapy to the right chest wall and regional nodes.

Based on the patient’s tumor characteristics, predictive biomarkers and existing comorbidities, which of the following would you recommend as the most appropriate systemic adjuvant therapy for this patient?

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