CE / CME
Nurses: 1.50 Nursing contact hours
Physicians: maximum of 1.50 AMA PRA Category 1 Credits™
Pharmacists: 1.50 contact hours (0.15 CEUs)
Released: October 19, 2023
Expiration: October 18, 2024
Current Approach to Newly Diagnosed HR-Positive/HER2-Negative MBC
I would like to provide our reader with a bird’s-eye view of how we currently manage MBC. I am going to start with HR-positive/HER2-negative disease, beginning with first-line therapy.
It is important to note that we always want to biopsy that first metastatic event to ensure that breast cancer is present and repeat standard markers (eg, ER, PgR, HER2).5 We may send that biopsy for next-generation sequencing to see if there happens to be a PIK3CA mutation or an ESR1 mutation. We also can assess for somatic mutations in BRCA1 or BRCA2, which may remind us to obtain germline testing if we have not already done so. I always send biopsy tissue for next-generation sequencing in patients with de novo metastatic disease so that I know in advance the biomarkers that may be relevant for treatment decision-making down the road.
First‑line therapy for HR-positive/HER2-negative MBC involves endocrine therapy (ET).5,6 This typically consists of an AI plus an LHRH agonist if the patient is premenopausal in combination with a CDK4/6 inhibitor—preferably either ribociclib or abemaciclib because those agents are associated with documented or anticipated improvements in overall survival (OS). By contrast, palbociclib may be the CDK4/6 inhibitor of choice for certain patients when toxicity considerations are paramount and the patient likely has ET-sensitive disease.
At the time of metastatic disease progression on first-line therapy, one should obtain a liquid biopsy to test circulating tumor DNA (ctDNA) for presence of an ESR1 mutation to determine whether the patient may be a good candidate to receive elacestrant in the second‑line setting.5 I will talk more about this and cover the other second-line options are as we go forward.
Summary Data for First-line Combinations of CDK4/6 Inhibitors and ET in HR-Positive/HER2-Negative Breast Cancer: PFS and OS
In MONALEESA-2 and MONALEESA-7, ribociclib in combination with ET yielded a statistically significant improvement in OS compared with ET alone (hazard ratios in both trials: 0.76).7,8 MONALEESA-3 included a first-line cohort evaluating ribociclib plus fulvestrant and showed significantly improved OS with ribociclib plus fulvestrant compared with fulvestrant alone (median OS: 67.6 vs 51.8 months; hazard ratio: 0.67).9
MONARCH-3, the trial evaluating abemaciclib as part of first-line therapy, has not yet shown a statistically significant improvement in OS. An interim analysis of survival has been reported for abemaciclib plus AI compared with AI alone (median OS: 67.1 vs 54.5 months; hazard ratio: 0.754), which looks very promising based on what we have seen in MONALEESA-2.10 However, we are awaiting the final statistical analysis from MONARCH-3, which is anticipated by the end of 2023.
Unfortunately, the PALOMA-2 trial with first-line palbociclib plus letrozole did not yield a survival advantage compared with letrozole alone (median OS: 53.9 vs 51.2 months; hazard ratio: 0.956).11 Nonetheless, certain subsets of patients do very well with palbociclib-based treatment, including older women, patients with bone-only disease, and patients with more ET-sensitive disease. As such, palbociclib is not an unreasonable choice for patients when ribociclib and abemaciclib are not ideal options.5
postMONARCH: Abemaciclib + Fulvestrant vs Placebo + Fulvestrant in HR-Positive/HER2-Negative MBC After CDK4/6 and ET
What do we do after disease progression on a first-line CDK4/6 inhibitor?
We are awaiting the results of the postMONARCH trial (NCT05169567), where patients (N = 350) who progress on first-line CDK4/6 inhibitor therapy consisting of either palbociclib or ribociclib in combination with an AI are then randomized to receive abemaciclib plus fulvestrant or placebo plus fulvestrant.12 All patients switch from an AI to fulvestrant, and then one half receive abemaciclib twice per day for up to 2 years or placebo twice per day indefinitely. The primary endpoint of the study is PFS by investigator. Secondary endpoints include OS, PFS by blinded independent central review (BICR), objective response rate (ORR), safety, and patient-reported outcomes.
Patients who get to the 2-year mark with abemaciclib are likely to be able to continue the treatment indefinitely until they have disease progression. Thus, postMONARCH is asking the very important question of whether introducing abemaciclib, which has a broader mechanism of action as a CDK4/6 inhibitor, can benefit patients after they have progressed while receiving palbociclib or ribociclib.
RIGHT Choice: Ribociclib + ET vs Combination CT in Aggressive HR-Positive/HER2-Negative ABC
I also would like to briefly mention the results from the RIGHT Choice trial, which illustrated just how efficacious the CDK4/6 inhibitors are when selected as first-line therapy and when compared with combination chemotherapy.
RIGHT Choice was a randomized, open-label, multinational phase II study conducted in pre- or perimenopausal women with aggressive disease defined as symptomatic visceral metastases, rapid disease progression or impending visceral compromise, or markedly symptomatic nonvisceral disease (N = 222).13 Patients were randomly assigned to receive full-dose ribociclib plus ET (letrozole or anastrozole plus goserelin) or to investigator’s choice of combination chemotherapy. The primary endpoint was PFS assessed locally per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints included time to treatment failure (TTF), 3-month treatment failure rate, time to treatment resistance, OS, and ORR. Patients could receive treatment until disease progression or death.
RIGHT Choice: PFS and Time to Treatment Failure
The primary endpoint of PFS doubled from 12.3 months with combination chemotherapy to 24.0 months with ribociclib-containing treatment (hazard ratio: 0.54; P = .0007).13 When patients have borderline visceral crisis, I am always very motivated about inducing a rapid response. We always have turned to chemotherapy to get that response. However, looking at the data on TTF, you can see that the chance of disease progression in the first 3 months of treatment was higher with combination chemotherapy than it was with ribociclib plus ET (median TTF: 8.5 vs 18.6 months; hazard ratio: 0.45).13
These data really drove home to me that there are few patients who should not receive a CDK4/6 inhibitor plus ET in the first-line metastatic setting. The only time I would deviate from that is if a patient had frank hepatic failure, where the bilirubin, transaminases, and alkaline phosphatase already have reached very high levels. For those patients, I will judiciously use chemotherapy to drive down those liver values. I have learned over many years how to elicit a response with careful doses of chemotherapy, and then, as liver function improves, I increase the chemotherapy dose. By contrast, I simply do not have experience with the CDK4/6 inhibitors in that context, although one could theoretically use a CDK4/6 inhibitor instead of chemotherapy.
RIGHT Choice: Responses and Tolerability
In this trial, the ORR (65.2% vs 60.0%) and clinical benefit rate (CBR; 80.4% vs 72.7%) were modestly higher with ribociclib plus ET vs combination chemotherapy.13 However, the PFS data really were the most remarkable based on the doubling in median values, as stated earlier. Time to response also was improved for ribociclib plus ET vs chemotherapy (hazard ratio: 0.78).
Regarding treatment tolerability, the patients who received ribociclib plus ET vs chemotherapy experienced a similar number of all-grade and grade 3/4 AEs but had fewer treatment-related serious AEs, treatment-related AEs leading to discontinuation, and dose reductions due to high-grade AEs.
Key AEs With CDK4/6 Inhibitors: Monitoring and Prevention
There can be serious AEs associated with CDK4/6 inhibitors that we as healthcare professionals need to be aware of and know how to manage appropriately.
We need to advise patients about the possibility of diarrhea, particularly for abemaciclib.14 For either grade ≥3 diarrhea or persistent grade 2 diarrhea that does not resolve within 24 hours, we want to suspend abemaciclib treatment until the toxicity improves to grade ≤1, and then restart abemaciclib at a reduced dose.14 For grade 2 diarrhea that does not resolve within 24 hours with antidiarrheal agents, suspend abemaciclib treatment until the toxicity improves to grade ≤1, and then restart abemaciclib at the same dose level. For grade 1 diarrhea, no dose modifications are required, and I often tell patients they can take one half to a full dose of loperamide once per day and continue therapy without suspending treatment.
Hepatotoxicity should be carefully monitored prior to the start of therapy with a CDK4/6 inhibitor and while patients are receiving abemaciclib or ribociclib therapy.14,15 Monitoring for hepatotoxicity involves liver function test assessments every 2 weeks for the first 2 months and then as indicated in the prescribing information for the different agents. In patients experiencing hepatotoxicity with abemaciclib, no dose modification is required for grade 1 or 2 alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation without increase in bilirubin above 2 times the upper limit of normal (ULN). Patients who experience persistent or recurrent grade 2 ALT/AST elevation or grade 3 ALT/AST elevation without an increase in bilirubin should hold abemaciclib until the toxicity resolves to grade 1 or baseline levels and then resume with a dose reduction. Patients with ALT/AST elevation >3 times the ULN with an increase in bilirubin or those with a grade 4 ALT/AST increase should discontinue the CDK4/6 inhibitor.14
Neutropenia appears to be more common with palbociclib (83%) vs ribociclib (17%-41%) and abemaciclib (37%-46%).14-16 Monitoring of blood counts is recommended by all manufacturers at the beginning of each cycle, as well as subsequent cycles, and as clinically indicated.14-16
In patients receiving abemaciclib, the prescribing information recommends monitoring complete blood counts every 2 weeks for the first 2 months, then monthly for the following 2 months and as clinically indicated.14 No dose adjustments are required for grade 1 or 2 neutropenia. If grade 3 neutropenia develops, suspend treatment until neutropenia resolves to grade ≤2, and then resume at the same dose. If there is recurrent grade 3 neutropenia or a first instance of grade 4 neutropenia, suspend drug until neutropenia resolves to grade ≤2, and then resume treatment at the next lower dose.
No dose adjustment is required for grade 1 or 2 neutropenia with palbociclib.16 If grade 3 neutropenia is observed, we need to suspend treatment, repeat blood count testing within 1 week, and when recovered to grade ≤2, start the next cycle at the next lower dose; if grade 4 on Day 22, we need hold treatment until recovered to grade ≤2 and then resume at the next lower dose level.
In patients receiving ribociclib, the prescribing information recommends monitoring complete blood counts every 2 weeks for the first 2 cycles, after the subsequent 4 cycles, and as clinically indicated.15 No dose adjustments are required for grade 1 or 2 neutropenia. If grade 3 neutropenia develops, suspend treatment until neutropenia resolves to grade ≤2, and then resume at the same dose. If there is recurrent grade 3 neutropenia or febrile neutropenia (with single episode of fever of >38°C or above 38°C for more than 1 hour and/or concurrent infection), stop treatment until neutropenia resolves to grade ≤2, and then resume at the next lower dose level. If grade 4 neutropenia develops, stop treatment until neutropenia resolves to grade ≤2, and then resume treatment at the next lower dose level.
I will tell you, however, that I do not always go by the prescribing information, because I find that dose reduction does not always reverse grade 3 neutropenia. I do dose reduce for grade 4 neutropenia, but I generally will tolerate grade 3 neutropenia, whereas the prescribing information says to reduce the dose for grade 3 neutropenia that persists over several cycles.14-16
Venus thromboembolic events (VTEs) can occur with any of the CDK4/6 inhibitors but mostly have been reported with abemaciclib (2%-5%), so we need to be aware of and plan for that.14 VTEs include deep vein thrombosis, pulmonary embolism, pelvic venous thrombosis, cerebral venous sinus thrombosis, subclavian and axillary vein thrombosis, and inferior vena cava thrombosis, all of which potentially can lead to death. Based on the prescribing information, patients receiving abemaciclib need to be monitored and educated to recognize signs and symptoms of venous thrombosis and pulmonary embolism (eg, pain or swelling in arms or legs, shortness of breath and/or chest pain, rapid breathing, or rapid heart rate).14 For grade 1 or 2 VTEs in patients with MBC, no dose modification is required. Dose interruption is recommended for patients with advanced/metastatic breast cancer experiencing grade 3 or 4 VTEs. For recurrent grade 3 or new-onset grade 4 VTEs, suspend dose and treat VTEs as clinically indicated, and then resume abemaciclib when the patient is clinically stable.
Interstitial lung disease (ILD) can occur with any of the CDK4/6 inhibitors but is very rare. Patients should be educated about and monitored for pulmonary symptoms indicative of ILD or pneumonitis, such as hypoxia, cough, or dyspnea, and new or worsening respiratory symptoms.14-16
In patients receiving abemaciclib with confirmed ILD, of grade 1 or 2, the prescribing information indicates that no dose modification is required.14 For persistent or recurrent grade 2 ILD that does not resolve with maximal supportive measures within 7 days to baseline or grade 1, suspend treatment until ILD resolves to baseline or grade ≤1, and then resume at the next lower dose. If grade 3 or 4 ILD develops, discontinue treatment with abemaciclib.
In patients receiving palbociclib with confirmed ILD of grade 1 or 2, the prescribing information indicates that no dose modification is required.16 For grade ≥3 persisting ILD that does not resolve with supportive measures, suspend treatment until ILD resolves to grade ≤1 or ≤2 (if not considered a safety risk to the patient), and then resume at the next lower dose. If grade 3 or 4 ILD develops, discontinue treatment with palbociclib. Palbociclib should be permanently discontinued in patients deemed to be suffering from severe ILD.
In patients receiving ribociclib with confirmed grade 1 ILD (asymptomatic), no dose interruption or modification is required, and ILD can be managed with appropriate medical therapy and clinical monitoring.15 If grade 2 ILD (symptomatic) develops, the prescribing information indicates dose interruption until ILD recovers to grade ≤1 and then resuming ribociclib at the next lower dose. If ILD of grade 2 recurs, or ILD is of grade 3 (severe symptomatic) or grade 4 (life-threatening), ribociclib should be discontinued permanently.
Interactive Tool for Managing AEs With Oral Targeted Therapy for HR-Positive/HER2-Negative Breast Cancer
I wanted to bring your attention to this interactive tool for managing AEs in patients receiving oral targeted therapies for HR-positive/HER2-negative breast cancer.
This tool is available through clinicaloptions.com/Breast2021HROralTool or by searching for AliCEA in the app store on your mobile device.
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