CME
Physicians: Maximum of 0.50 AMA PRA Category 1 Credit™
Released: March 07, 2025
Expiration: September 06, 2025
Considerations for First-line Treatment of HR+/HER2- MBC
When a patient is diagnosed with incurable HR-positive/HER2-negative MBC, a number of factors should be considered when making the first-line treatment decision.1 These should include a discussion with the patient about treatment preference, goals of care, comorbid conditions, and concomitant medications. The considerations should take into account the level of symptoms that the patient is experiencing from the disease and the disease burden. It is important to evaluate the site(s) of metastatic disease because this may affect treatment recommendations. For a patient with bone metastasis, the use of an antiresorptive agent such as a bisphosphonate or a receptor activator of nuclear factor kappa-Β (RANK) ligand inhibitor should be considered and discussed with the patient. Brain metastasis or central nervous system disease is fairly uncommon in the first-line HR-positive/HER2-negative MBC setting. For patients with localized recurrence, locoregional therapy to the sites of metastases should be considered. In almost all cases, women with HR-positive/HER2-negative MBC should be offered a CDK4/6 inhibitor plus endocrine therapy (ET) as first-line therapy. If premenopausal, ovarian suppression/ablation should be added to maximally suppress the estrogen receptor pathway. Patients with visceral crises are traditionally started on chemotherapy. However, this approach is falling out of favor because of mounting evidence supporting the use of a CDK4/6 inhibitor–based therapy, which is associated with improved efficacy outcomes and a better and more manageable toxicity profile compared with chemotherapy. So, even in the rare situation where a patient has visceral crisis, a CDK4/6 inhibitor–based approach may be considered.
As treatment decisions are made in concert with patients, it is important to keep the patient’s goals of care in mind and involve a multidisciplinary team of healthcare professionals as needed. This is particularly crucial for older patients who may have preexisting comorbid conditions such as diabetes, cardiovascular disease, or electrolyte abnormalities that require the use of concomitant medications. Some of these medications have the potential to alter a patient's ability to safely take certain anticancer therapy. Thus, the integration of referrals and communication with the necessary subspecialty partners in medicine are important facets of decision-making in the planning and institution of an optimal first-line treatment regimen for patients.
First-line Trials of ET ± CDK4/6i vs ET in HR+/HER2- MBC: Results
There have been 4 large randomized, phase III clinical trials that have evaluated the use of a CDK4/6 inhibitor plus ET in the front-line setting for patients with HR-positive/HER2-negative MBC. PALOMA-2 evaluated palbociclib, MONALEESA-2 and MONALEESA-7 evaluated ribociclib, and MONARCH 3 evaluated abemaciclib.2-8 All of these studies demonstrated a statistically significant and clinically relevant improvement in progression-free survival (PFS) with the addition of a CDK4/6 inhibitor to ET. These studies demonstrated that the median PFS in the front-line setting with any of these CDK4/6 inhibitors plus ET is at least 2 years. It is important to note that overall survival (OS) was significantly improved with the addition of ribociclib to ET in MONALEESA-2 (63.9 months vs 51.4 months; HR: 0.76; P = .008) and MONALEESA-7 (58.7 months vs 48 months; HR: 0.76; P value not reported).4,6 There was a strong trend toward statistical significance with respect to OS in MONARCH 3, which demonstrated a 13.1-month improvement with the addition of abemaciclib to ET (66.8 months vs 53.7 months).8 However, in this trial, the numeric advantage with the addition of abemaciclib to ET did not reach statistical significance (HR: 0.804; P = .0664). In PALOMA-2, there was no statistical significance in OS with the addition of palbociclib to ET (HR: 0.96; P = .34).3
The common grade 3 or higher adverse events (AEs) associated with the use of CDK4/6 inhibitors include neutropenia and a decreased white blood cell count.9-11 Neutropenia is very common with palbociclib and ribociclib. Approximately 60% to 70% of patients who receive either of these agents in these trials experienced grade 3 or higher neutropenia.2-7 This is why palbociclib and ribociclib are administered on a 3 weeks on, 1 week off schedule.
On the other hand, the incidence of grade 3 or higher neutropenia with abemaciclib is approximately 25%, which is less than that seen with palbociclib and ribociclib.8 In contrast to palbociclib and ribociclib, abemaciclib is administered on a twice daily continuous schedule. Complete blood counts for all patients receiving any of these CDK4/6 inhibitors should be performed with appropriate monitoring for neutropenia. Abemaciclib is associated with diarrhea with approximately 10% of patients experiencing grade 3 or higher diarrhea.
First-line Trials of CDK4/6i + ET vs CT in HR+/HER2- MBC: Results
Multiple studies have been conducted to interrogate whether or not patients should be preferentially treated with chemotherapy for symptomatic or high-risk HR-positive/HER2-negative MBC in the front-line setting. Such studies include the phase III PADMA trial and the phase II RIGHT Choice trial.
The phase II RIGHT Choice study investigated ribociclib plus ET and ovarian suppression vs investigator’s choice of chemotherapy as first-line therapy for young patients with aggressive advanced or MBC. The study demonstrated a statistically significant improvement in PFS with the addition of ribociclib to ET and ovarian suppression (21.8 months vs 12.8 months; HR: 0.611; P = .003).12 OS data from RIGHT Choice are currently immature. The phase III PADMA trial investigated induction therapy with palbociclib plus ET vs investigator’s choice of chemotherapy with or without maintenance ET for patients with higher-risk advanced breast cancer (ABC) with indication for single-agent chemotherapy. Patients were eligible if they did not have asymptomatic bone-only, oligometastatic disease. The results from this trial were recently reported.13 Similar to RIGHT Choice, PADMA showed that the use of a CDK4/6 inhibitor plus ET significantly prolonged the primary endpoint of time to treatment failure (17.2 months vs 6.1 months; HR: 0.46; 95% CI: 0.31-0.69; P <.001) vs chemotherapy. In addition, PFS was significantly prolonged with palbociclib plus ET vs chemotherapy (18.7 months vs 7.8 months; HR: 0.45; P <.001). In PADMA, there was a numeric improvement of 9.3 months in the median OS in favor of palbociclib plus ET (46.1 months vs 36.8 months). These data from the PADMA and Right Choice trials suggest that even for patients with high-risk, aggressive HR-positive/HER2-negative MBC, the use of a CDK4/6 inhibitor–based treatment approach as first-line therapy yields improved outcomes compared with upfront chemotherapy.
HR+/HER2- MBC: Second- and/or Subsequent-line Therapy
If a CDK4/6 inhibitor was not previously used in the first-line setting, one may be used in combination with fulvestrant in the second- or later-line setting for pre- or postmenopausal patients with HR-positive, HER2-negative MBC.1 After exhausting CDK4/6 inhibitor–based therapy, there are several other options. Genomic sequencing of the tumor to detect alterations such as a PIK3CA mutation, AKT1 mutation, PTEN loss or ESR1 mutation may be used to select therapy. If no such mutation is detected, the combination of exemestane with everolimus may be used.14
INAVO120: Palbociclib + ET ± Inavolisib in PIK3CA-Mutant HR+/HER2- Advanced Breast Cancer
The phase III INAVO120 study evaluated the use of the PI3 kinase pathway inhibitor inavolisib in combination with palbociclib and fulvestrant for patients with PIK3CA-mutated, HR-positive/HER2-negative locally advanced or MBC with disease progression during or within 12 months of completing adjuvant ET.15 No previous systemic therapy for advanced disease was allowed. Since targeting the PI3 kinase pathway can lead to hyperglycemia, there were strict criteria for entry relating to diabetes. Patients were required to have a glycated hemoglobin (A1C) less than 6.0% and a fasting glucose level less than 126 mg/dL to be eligible. Patients with type II diabetes requiring ongoing systemic therapy at the time of enrolment or those with any history of type I diabetes were excluded from participating in the study.
The addition of inavolisib to palbociclib and fulvestrant demonstrated a statistically significant improvement in PFS vs placebo plus palbociclib and fulvestrant (15 months vs 7.3 months; HR: 0.43; P <.0001). At the time of analysis, OS data were immature. The addition of inavolisib to palbociclib and fulvestrant resulted in an objective response rate of 58.4% vs 25% with palbociclib and fulvestrant alone. Overall, the combination of inavolisib with palbociclib and fulvestrant was fairly well tolerated with grade 3 or higher neutropenia, hyperglycemia, stomatitis/mucosal inflammation, and diarrhea reported in 80.2%, 5.6%, 5.6%, and 3.7%, respectively.
Based on the results of INAVO120, the FDA approved inavolisib plus palbociclib and fulvestrant for adults with endocrine-resistant, PIK3CA-mutated, HR-positive, HER2-negative, locally advanced or MBC on October 10, 2024.16 Of note, this combination has since become a standard of care for patients with disease progression during or within 12 months of completing adjuvant ET. It is important to recall that patients were highly selected for entry into this study. These entry criteria should be kept in mind when applying these data in a clinical setting. The combination of inavolisib with palbociclib and fulvestrant is not appropriate for patients with insulin-dependent diabetes or those with an A1C of 6.0% or greater. It may be necessary to involve a multidisciplinary team to help manage the associated side effects of treatment.
Personal Perspectives and Insights
It is important to note that, for the most part, prospective, randomized controlled trials involve the inclusion of patients who are highly selected. The eligibility criteria tend to include patients who are younger with relatively few preexisting comorbidities, a good performance status, and who are not receiving concomitant medications that have a risk of drug–drug interactions. In addition, patients with kidney, liver, or cardiac dysfunction tend to be excluded from enrollment. Therefore, when new agents receive FDA approval based on their efficacy and safety in randomized controlled trials, very little data are available regarding how to best utilize these agents in real-world clinical settings in patients who may not have been eligible for the trial. For this reason, we heavily rely on real-world evidence to provide information relating to the safety and effectiveness of new therapies.
It is not uncommon to be treating patients with HR-positive, HER2-negative MBC who have preexisting conditions such as hypertension, thyroid abnormalities, kidney disease, diabetes, or glucose intolerance. Some patients have also been previously exposed to agents like anthracyclines for early-stage breast cancer and thus may have a higher risk of cardiomyopathy. Polypharmacy also heightens the risk of drug–drug interactions. To optimize patient safety, it is important to work closely with pharmacists, advanced practice providers, and subspecialty colleagues involved in the care of the patients we treat.
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