CE / CME
Pharmacists: 1.00 contact hour (0.1 CEUs)
Nurses: 1.00 Nursing contact hour
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: August 31, 2023
Expiration: August 30, 2024
Is There a Role for CDK4/6 Inhibition in Early-Stage HR+ Disease?
Next, we focus on evaluating and managing high-risk HR-positive/HER2-negative EBC without germline BRCA mutations. There has been a lot of interest in CDK4/6 inhibitors in this setting given the significant benefit seen in the metastatic setting.24
This figure shows hazard curves based on annual hazard ratio for recurrence of breast cancer, stratified by disease stage.25 Superimposed on this figure are the treatment duration of various CDK4/6 inhibitors (palbociclib, abemaciclib, and ribociclib) as adjuvant therapy from large phase III clinical trials. The patient populations from each of these trials are described on the right.
Reported CDK4/6 Inhibitor Adjuvant Trials
This table goes into greater detail about large phase III clinical trials of CDK4/6 inhibitors in the adjuvant setting for patients with HR-positive/HER2-negative EBC. The PENELOPE-B and PALLAS trials were negative studies that looked at the addition of palbociclib (1-year or 2-year duration of treatment, respectively) to adjuvant ET.26,27 The monarchE trial demonstrated benefit for adjuvant abemaciclib when added to standard-of-care (SoC) ET.28 The ongoing NATALEE trial has suggested a potential benefit for adjuvant ribociclib when added to ET.29
Now we are going to dive into these last 2 studies in a bit more detail.
monarchE: Study Design
The randomized, open-label phase III monarchE trial looked at adjuvant SoC ET with or without abemaciclib in 5637 patients with HR-positive/HER2-negative, node-positive EBC.28 Patients were divided into 2 cohorts in this particular trial. The first cohort (91% of patients) had ≥4 positive axillary lymph nodes or 1-3 positive nodes plus grade 3 disease and/or tumor size ≥5 cm. The second cohort (9% of patients) had 1-3 positive lymph nodes and Ki-67 ≥20%. All patients received ET for 5-10 years as indicated, with or without 150 mg abemaciclib twice daily for up to 2 years.
The primary endpoint was iDFS, with key secondary endpoints including iDFS in the Ki-67 high (≥20%) population, distant relapse-free survival (DRFS), OS, and safety.
monarchE: Baseline Patient Characteristics
All patients had ≥1 node involved. With approximately 60% of patients having ≥4 lymph nodes involved, this is a high-risk population.28
monarchE: iDFS in ITT Population at 4 Years (Interim Analysis 2)
With a median follow-up of 42 months, the 4-year iDFS with abemaciclib plus ET was improved (85.8% vs 79.4%; hazard ratio: 0.664; 95% CI: 0.578-0.762; P <.0001) compared with ET alone.28 In fact, the iDFS benefit seems to be improving over time.
monarchE: Outcomes by Ki-67 Status in Cohort 1
An important thing we learned from this study is that Ki-67 is prognostic but not predictive of who will benefit from adjuvant abemaciclib. In patients from cohort 1, there was no difference in magnitude of benefit to iDFS, DRFS, or OS from abemaciclib seen between patients with Ki-67 high (≥20%) and Ki-67 low (<20%).28 Although a patient’s risk may be higher with a higher Ki-67, the relative benefit from addition of abemaciclib was unchanged.
Ki-67 Requirement Dropped From Abemaciclib Indication for High-Risk, Node-Positive, HR+/HER2- EBC
Based on the updated results of the monarchE trial, the previous requirement for Ki-67 ≥20% was removed from the FDA indication for abemaciclib.
Currently, abemaciclib is approved 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.30
monarchE: Safety
The main AEs seen with adjuvant abemaciclib plus ET compared with ET alone include gastrointestinal toxicity (any grade diarrhea: 84% vs 9%; grade ≥3 diarrhea: 8% vs <1%) and fatigue (any grade: 41% vs 18%; grade ≥3: 3% vs <1%).28 There were also higher rates neutropenia (any grade: 46% vs 6%; grade ≥3: 20% vs 1%) and leukopenia (any grade: 38% vs 7%; grade ≥3: 11% vs <1%). Approximately 62% of patients required a dose hold, approximately 44% required a dose reduction, and approximately 19% discontinued abemaciclib because of AEs.
It is worth mentioning that within this trial, patients who received a lower dose of abemaciclib still experienced clinical benefit. When the trial cohort was divided into 3 equally sized subgroups by relative dose intensity during the duration of treatment, 4-year iDFS rates were generally consistent regardless of dose intensity (lowest to highest relative dose intensity groups: 87.1% vs 86.4% vs 83.7%).31 Something that I mention to my patients is that even if they require a dose reduction for some reason, they may still see a benefit from the addition of abemaciclib to ET.
monarchE: Treatment-Emergent AEs of Special Interest
Looking at some AEs of special interest from the monarchE trial, the addition of abemaciclib to ET increased the risk of venous thromboembolic events: 2.5% vs 0.6% (including pulmonary embolism: 1.0% vs. 0.1%), which were uniquely seen with abemaciclib.32 There was also a numerically higher rate of alopecia (11.2% vs 2.7%) and a slightly increased risk of interstitial lung disease (3.2% vs 1.3%), which we see with various CDK4/6 inhibitors. There was also a slightly increased risk of elevated aspartate aminotransferase (any grade: 11.8% vs 4.9%; grade ≥3: 1.9% vs 0.5%) and alanine aminotransferase (any grade: 12.3% vs 5.6%; grade ≥3: 2.8% vs 0.7%), which we see with other CDK4/6 inhibitors including ribociclib.
NATALEE: Study Design
Initial data from the highly anticipated randomized phase III NATALEE trial were presented at ASCO 2023.29 This study is a little different from monarchE in that patients with HR-positive/HER2-negative EBC are receiving ≥5 years of ET (nonsteroidal AI) with or without ribociclib for 3 years. Patients could not receive tamoxifen because of the known QTc prolongation with that combination.33 The other unique feature of this study is that it includes some patients with relatively moderate risk (ie, patients with stage IIA disease could either be N0 with grade 2 disease and a high Ki-67 [≥20%], a high 21-gene recurrence score [≥26] or high risk via genomic risk profiling, or N0 with grade 3 disease).
The primary endpoint of this study was iDFS, with key secondary endpoints including recurrence-free survival, DDFS, OS, and safety.
NATALEE: iDFS (Primary Endpoint)
At a median follow-up of 27.7 months, we see an iDFS benefit with the addition of ribociclib to ET (hazard ratio: 0.748; 95% CI: 0.618-0.906; P = .0014) compared with ET alone and an improvement in 3-year iDFS rate (90.4% vs 87.1%).29 Most patients are still receiving adjuvant ribociclib (only 20% of patients have completed 3 years of ribociclib). There is certainly a need for additional maturity of follow-up from this study.
NATALEE: DDFS and OS
We also saw an improvement in 3-year DDFS rate (90.8% vs 88.6%; hazard ratio: 0.739; 95% CI: 0.603-0.905; P = .0017), but it is premature to think about OS.29
NATALEE: Safety
Neutropenia was more common in patients receiving ribociclib plus ET (any grade: 62.1% vs 4.5%; grade ≥3: 43.8% vs 0.8%) compared with ET alone, which we see across the CDK4/6 inhibitors.29 Some QTc prolongation was seen (any grade: 5.2% vs 1.2%; grade ≥3: 1.0% vs 0.5%; increase from baseline of >60 ms: 0.8% vs 0.1%). Hepatotoxicity was also more common in patients treated with ribociclib plus ET (any grade: 25.4% vs 10.6%; grade ≥3: 8.3% vs 1.5%) compared with ET alone. Ribociclib was discontinued in 19% of patients because of AEs, with most occurring early in treatment (median: 4 months). The most common AEs leading to ribociclib discontinuation were liver-related AEs (8.9% vs 0.1%) or arthralgia (1.3% vs 1.9%).
Key AEs With CDK4/6 Inhibitors: Monitoring and Prevention
This slide is an overview of the different AEs we can see with CDK4/6 inhibitors, along with some general management strategies.30,34,35 Diarrhea is most associated with abemaciclib, although it occurs to some extent with the entire class. Hepatobiliary toxicity is seen with abemaciclib and numerically higher with ribociclib. QTc prolongation is seen with ribociclib, and neutropenia is seen across all of the CDK4/6 inhibitors, although less frequently seen with abemaciclib. Venous thromboembolism is seen with abemaciclib and interstitial lung disease/pneumonitis with all of the CDK4/6 inhibitors.
Practical Management Strategies: Diarrhea With Abemaciclib
Diarrhea is the main toxicity that we see with abemaciclib, and it is important to dose modify and use antidiarrhea medications such as loperamide.30
Dose Modifications for Abemaciclib
Abemaciclib can be taken with or without food.30 The medication should be taken at approximately the same time each day, avoiding concomitant use of strong CYP3A4 inhibitors and inducers. The recommended starting dose of abemaciclib in combination with ET is 150 mg twice daily. If a dose reduction is warranted, first reduce the dose to 100 mg twice daily, and the lowest dose for which we have data is 50 mg twice daily.
An Approach for High-Risk HR+/HER2- EBC
This is a summary of our current approach for high-risk HR-positive/HER2-negative EBC. If high-risk patients have a BRCA mutation, we should consider giving adjuvant olaparib. If they are BRCA wild type, they should receive ET with a CDK4/6 inhibitor—right now, that is abemaciclib because ribociclib is not approved. For high-risk patients, we talk about ovarian function suppression if they are premenopausal. Again, if ribociclib is approved in the adjuvant setting, it would be with an AI.
A common question is how to choose between olaparib and abemaciclib if patients have a BRCA mutation. I usually start with olaparib, and then if patients are up for additional targeted therapy upon that completion, then I would initiate abemaciclib after, but never together with olaparib. Of course, patients would still be receiving ET throughout that time period.
ESR1 Mutations: Primary vs Metastatic
Next, I discuss mutations to the ESR1 gene, which develop as an acquired ET resistance mechanism in metastatic breast cancer, particularly after AI use.36 Approximately one third of patients treated with AIs in the metastatic setting develop an ESR1 mutation.37
Targeting ESR1 Mutations With SERDs
There are data that suggest patients who have ESR1 mutations do not benefit from AIs and may benefit more from selective estrogen receptor downregulators (SERDs).38,39 For some time, all we had was fulvestrant, which is a potent SERD that is given intramuscularly.40 However, its efficacy is limited by poor bioavailability, and there has been great enthusiasm about the potential role for oral SERDs, as they may have greater availability and activity in the setting of endocrine resistance.41
Oral SERDs for EBC: Select Clinical Trials
Oral SERDs have been evaluated and shown efficacy in the metastatic breast cancer setting. One of these, elacestrant, is approved for treatment of postmenopausal women or adult men with estrogen receptor–positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following ≥1 line of ET.42
Now numerous ongoing studies are looking at the utility of oral SERDs in the EBC setting, both in the neoadjuvant and adjuvant space; these include giredestrant, camizestrant, and imlunestrant and have the potential to change how we treat patients with HER2-negative EBC.
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