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Optimizing Tx of HRpos HER2neg MBC

CME

Optimizing Treatment for Patients With HR-Positive/HER2-Negative MBC

Physicians: Maximum of 0.50 AMA PRA Category 1 Credit™

Released: March 24, 2025

Expiration: September 23, 2025

Sara A. Hurvitz
Sara A. Hurvitz, MD, FACP
CME/CE Information

Activity

Progress
1 2
Course Completed

PALOMA-2: Letrozole ± Palbociclib in HR+/HER2- ABC

The randomized phase III PALOMA-2 trial was the first phase III study to demonstrate that adding a CDK4/6 inhibitor to ET improves long-term outcomes (NCT01740427). Postmenopausal patients with ER-positive/HER2-negative advanced breast cancer and an ECOG PS of 0-2 who had not received any prior treatment for advanced disease were eligible.9,23 Prior (neo)adjuvant letrozole or anastrozole with a disease-free internal ≤12 months from treatment completion were exclusion criteria. Eligible patients were randomly assigned to receive an NSAI (letrozole) alone (n = 222) or in combination with palbociclib (n = 444). The primary endpoint was PFS by investigator assessment, with secondary endpoints including OS, response, safety, and tolerability. 

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PALOMA-2: PFS and OS Outcomes in ITT Population

There was a statistically significant improvement in the median PFS with the addition of palbociclib to letrozole vs letrozole alone (27.6 months vs 14.5 months; HR: 0.563; 95% CI: 0.461-0.687; P <.0001). However, even after a median follow-up of approximately 90 months, there was no significant difference in OS observed between the treatment arms (53.9 months vs 51.2 months; HR: 0.96; 95% CI: 0.78-1.18; P = .34).

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PALOMA-2: Select AEs

The most common adverse event (AE) associated with the addition of palbociclib to letrozole on this trial was any grade neutropenia, which was reported in 81.8% of patients including approximately 70% who experienced grade 3 or higher neutropenia. It should be noted, however, that palbociclib-associated neutropenia is not frequently associated with fever or infection. Given the incidence of this AE, patients are treated with palbociclib on a 3 weeks on/1 week off schedule, with therapy resuming once neutrophil counts are at least 1000/mm3.24 

Palbociclib is associated with diarrhea. Any grade diarrhea was reported in 28.4% of patients on the PALOMA-2 trial, but grade 3 or higher diarrhea was uncommon (1.4%). Approximately 12% of patients experienced any grade alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation, with only 3% grade 3 or higher transaminase elevation reported in the patients on this trial. Grade 5 AEs associated with palbociclib plus letrozole included pneumonia/respiratory failure, which was reported in only 1 patient.

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MONALEESA-2, MONALEESA-3, and MONALEESA-7: ET ± Ribociclib in HR+/HER2- ABC

The double-blind, randomized MONALEESA-2 (NCT01958021), MONALEESA-3 (NCT02422615), and MONALEESA-7 (NCT02278120) trials evaluated ET alone or in combination with ribociclib for patients with HR-positive, HER2-negative advanced breast cancer. Both MONALEESA-2 and MONALEESA-7 included patients with ET-naive advanced disease.3-7 MONALEESA-2 included patients who had previously received (neo)adjuvant NSAI with a disease-free interval greater than 12 months from treatment completion (N = 668), and MONALEESA-7 allowed patients who had previously received (neo)adjuvant ET but did not allow prior ET in the advanced setting (N = 672). On the other hand, MONALEESA-3 included a cohort of patients with treatment-naive advanced disease. It also included those who had previously received up to 1 line of therapy for advanced disease, and those who had experienced a relapse during or within 12 months of completing (neo)adjuvant ET (N = 726).10,11 For all 3 studies, the primary endpoint was PFS by investigator assessment. The secondary endpoints included OS, response, safety and tolerability.

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MONALEESA-2, MONALEESA-3, and MONALEESA-7: PFS and OS Outcomes

MONALEESA-2, MONALEESA-3, and MONALEESA-7 demonstrated a statistically significant improvement in PFS with the addition of ribociclib to ET compared with ET alone yielding similar hazard ratios ranging from 0.55 to 0.593 (P <.001). With regard to OS, all 3 trials demonstrated a significant improvement in the median OS with the addition of ribociclib to ET with a hazard ratio of approximately 0.76.

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MONALEESA-2, MONALEESA-3, and MONALEESA-7: Select AEs on Ribociclib + ET Arm

Like palbociclib, ribociclib is also associated with a relatively high risk of neutropenia, with any grade events reported in approximately 70% or more of patients on these trials, including more than 50% who experienced grade 3 or higher neutropenia. As with palbociclib, ribociclib-associated neutropenia is not commonly associated with infection or fever. Ribociclib is also given on a 3 weeks on/1 week off schedule in order to allow for neutrophil count recovery.25 Approximately 14% of patients treated with ribociclib experienced grade 3 or higher hepatobiliary toxicity on these trials. Thus, liver function tests should be performed before initiating ribociclib, every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated.

QTc prolongation is an AE that is associated with ribociclib. Any grade QTc prolongation was reported in approximately 10% of patients on the MONALEESA trials. Because tamoxifen can also cause prolongation of the QTc, it should not be given with ribociclib. 

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MONARCH 3: ET ± Abemaciclib in HR+/HER2- ABC

MONARCH 3 is a randomized phase III study evaluating the addition of abemaciclib to ET in the frontline setting of advanced breast cancer (NCT02246621). Patients with HR-positive, HER2-negative locally advanced or MBC were enrolled on the trial (N = 493), and randomly assigned to receive an NSAI (either anastrozole or letrozole) in combination with either abemaciclib or placebo.8 The primary endpoint was PFS by investigator assessment and the secondary endpoints included OS, response, and safety.

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MONARCH 3: PFS and OS Outcomes in ITT Population

After a median follow-up of 8.1 years, there was a statistically significant improvement in the median PFS with the addition of abemaciclib to NSAI (29 mo) vs placebo plus NSAI (14.8 mo) (HR: 0.535; 95% CI: 0.429-0.668; P <.0001). Of note, the hazard ratios for PFS associated with all 3 CDK4/6 inhibitors in the first-line MBC setting are quite similar.

The median OS with abemaciclib was 66.8 months vs 53.7 months with placebo when used in combination with an NSAI (HR: 0.804; 95% CI: 0.637-1.015). However, the numeric improvement of 13.1 months with abemaciclib was not statistically significant (P = .0664). 

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MONARCH 3: Select AEs

The most notable AE associated with abemaciclib is diarrhea, with more than 80% of patients experiencing any grade diarrhea, and approximately 10% of patients experiencing grade 3 or higher diarrhea. In contrast with palbociclib and ribociclib, the rate of neutropenia seen with abemaciclib is lower, with an incidence of 46.8% of patients experiencing any grade neutropenia, including grade 3 or higher events in 27.5% of patients. Given the lower rate of neutropenia associated with abemaciclib, it may be given on a continuous twice daily schedule.26

Other AEs to be aware of with abemaciclib include anemia (any grade: 35.2%), leukopenia (any grade: 24.5%), increased ALT (any grade: 22%), and increased AST (any grade: 21.4%). Of note, an artifactual elevation in blood creatinine levels can be seen with abemaciclib (any grade: 25.1%). If observed, blood samples should be collected and tested for cystatin C, which will help to distinguish whether the patient truly has kidney function alteration. 

All 3 CDK4/6 inhibitors are associated with a low risk of interstitial lung disease (ILD)/pneumonitis. Grade 3 or higher ILD was reported in 1.5% of patients on MONARCH 3. Grade 3 or higher venous thromboembolism (VTE) was also reported on the abemaciclib arm (4.0%).

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