Neelam Desai, MD, is a breast medical oncologist and hematologist at the Atrium Health Levine Cancer Institute in North Carolina.

Dr Desai on Research Informing Upfront CDK 4/6 Inhibitor Use in HR+/HER2– Breast Cancer

"There [are several] pivotal trials for [ribociclib, abemaciclib, and palbociclib] in metastatic HR-positive, HER2-negative breast cancer…all of [which] show a consistent improvement in progression-free survival [PFS]. [Accordingly], all 3 of these drugs are approved in the metastatic setting."

Neelam Desai, MD, a breast medical oncologist and hematologist at the Atrium Health Levine Cancer Institute, highlighted the current body of research supporting upfront use of CDK 4/6 inhibitors in combination with endocrine therapy for patients with metastatic hormone receptor. (HR)–positive, HER2-negative breast cancer.

Desai noted that multiple pivotal trials have guided the choice among the three approved CDK4/6 inhibitors for metastatic HR-positive, HER2-negative breast cancer.

These include the phase 3 PALOMA-2 trial (NCT01740427), the phase 2 PARSIFAL trial (NCT02491983), and the phase 2 Young-PEARL trial (NCT02592746) for palbociclib (Ibrance); the MONALEESA trials evaluating ribociclib (Kisqali), and the phase 3 MONARCH 3 trial (NCT02246621) evaluating abemaciclib (Verzenio).

All of these studies demonstrated a consistent and statistically significant progression-free survival (PFS) benefit, Desai reported. Beyond PFS, the studies investigating ribociclib also demonstrated a statistically significant improvement in overall survival (OS) vs the control regimen. Although the MONARCH 3 trial for abemaciclib did not meet the threshold for statistical significance in its OS end point, it nevertheless presented a clinically meaningful OS benefit of 13.1 months, Desai added.

Similarly, studies evaluating palbociclib did not show a statistically significant improvement in OS, a result that has drawn some criticism regarding the methodology of data collection, Desai noted. However, she pointed out that real-world studies have since provided evidence of improvement in both PFS and OS with palbociclib. These findings collectively reinforce the established role of all 3 CDK 4/6 inhibitors, which are fully approved for use in the metastatic setting, as a cornerstone of treatment for this specific patient population, Desai concluded.

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Neelam Desai, MD, discusses the current body of evidence for CDK 4/6 inhibitor use in metastatic HR-positive, HER2-negative breast cancer. 

Neelam Desai, MD, highlights the phase 3 PATINA study evaluating a palbociclib-based regimen in HR-positive/HER2-positive metastatic breast cancer.

Dr Desai on the PATINA Study of a Palbociclib-Based Regimen in HR+/HER2+ Metastatic Breast Cancer

“In this trial, at that juncture of maintenance therapy, patients were [randomly assigned] to [receive trastuzumab, pertuzumab], and endocrine therapy with or without palbociclib. What this study showed was that the addition of palbociclib [to this regimen] led to a 15-month improvement in progression-free survival.”

Neelam Desai, MD, a breast medical oncologist and hematologist at the Atrium Health Levine Cancer Institute, highlighted the phase 3 PATINA study (NCT02947685) that evaluated the efficacy and safety of palbociclib (Ibrance) plus anti-HER2 therapy and endocrine therapy for the treatment of patients with hormone receptor–positive/HER2-positive metastatic breast cancer.

The randomized, international, open-label study specifically assessed the efficacy and safety of palbociclib added to trastuzumab (Herceptin) with or without pertuzumab (Perjeta), plus endocrine therapy with an aromatase inhibitor or fulvestrant (Faslodex); ovarian suppression required for patients who are premenopausal. Patients in the control arm received anti-HER2 therapy plus endocrine therapy alone.

For patients with hormone receptor–positive/HER2-positive metastatic breast cancer, the current standard of care is induction taxane with trastuzumab plus pertuzumab, Desai began. Furthermore, after 6 to 8 cycles, she noted that taxane is stopped as trastuzumab and pertuzumab are continued. For those with hormone receptor–positive disease, endocrine therapy is then added, she said.

In PATINA, the addition of palbociclib demonstrated an improvement in progression-free survival (PFS) of approximately 15 months, although the overall survival data were not yet mature, Desai said. At the data cutoff of October 15, 2024, and at a median follow-up of 53 months, the median PFS was 44.3 months (95% CI, 32.4-60.9) compared with 29.1 months (95% CI, 23.3-38.6) in the palbociclib and control arms, respectively (HR, 0.74; 95% CI, 0.58-0.94; 1-sided 

 = .0074). Moreover, the confirmed objective response rate was 29.2% vs 22.2% (

 = .0458) in the respective arms, with a clinical benefit rate of 89.3% vs 81.3%, which favored the palbociclib arm (2-sided 

Neelam Desai, MD, discusses the role of a palbociclib-containing regimen in HR-positive, HER2-positive metastatic breast cancer.

Dr Desai on the Role of Palbociclib in HR+, HER2+ Metastatic Breast Cancer

“The data are compelling—I certainly would consider adding palbociclib in the maintenance phase for patients who [have] both hormone receptor–positive and HER2-positive metastatic disease.”

Neelam Desai, MD, a breast medical oncologist and hematologist at the Atrium Health Levine Cancer Institute, discussed the role of palbociclib (Ibrance) plus anti-HER2 therapy and endocrine therapy (ET) in patients with hormone receptor (HR)–positive, HER2-positive metastatic breast cancer.

phase 3 AFT-38 PATINA trial (NCT02947685)

 are compelling, as the investigators concluded that the combination of palbociclib, anti-HER2 therapy, and ET could represent a new standard of care for patients with HR-positive, HER2-positive metastatic breast cancer, Desai began. Following these findings, she noted that this regimen could be one she considers as maintenance therapy for her patients with HR-positive, HER2-positive metastatic breast cancer.

At a data cutoff of October 15, 2024, patients (n = 518) were randomly assigned to either receive palbociclib plus trastuzumab (Herceptin) or pertuzumab (Perjeta) and ET (n = 261), or anti-HER2 therapy plus ET alone (n = 257). Of note, the final progression-free survival (PFS) analysis was performed after 262 events and 53 months of median follow-up. Data demonstrated that palbociclib plus anti-HER2 and ET significantly improved PFS (HR, 0.74; 95% CI, 0.58-0.94; 1-sided 

 = .0074). Notably, the median PFS was 44.3 months (95% CI, 32.4-60.9) vs 29.1 months (95% CI, 23.3-38.6) in the palbociclib and control arms, respectively. The confirmed objective response rate was 29.2% compared with 22.2% (

 = .0458), with a clinical benefit rate of 89.3% vs 81.3% (2-sided 

Adverse effects occurred most frequently in patients in the palbociclib arm, specifically grade 3 neutropenia (63.2%). More patients from the palbociclib arm also experienced grades 2 and 3 fatigue (grade 2, 22.9%; grade 3, 5.4%), stomatitis (17.2%; 4.2%), and diarrhea (25.4%; 11.1%).

Treatment with palbociclib was generally well-tolerated in the study, and there were no new safety signals, which demonstrated a potential option for the respective patient population, Desai concluded.

Neelam Desai, MD, breast medical oncologist, hematologist, Levine Cancer Institute, Atrium Health, discusses the toxicity profile of fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) in HER2-positive breast cancer.

Pivotal results from the phase 3 DESTINY-Breast03 (NCT03529110) and DESTINY-Breast02 (NCT03523585) trials have solidified the status of T-DXd as the standard of care in HER2-positive breast cancer after one or two prior lines anti-HER2-based regimens in the metastatic setting.

Although the agent was shown to be safe and tolerable across all trials, there are several adverse effects (AEs) that are attributed to this regimen that should be noted, Desai begins.

According to Desai, the most common AEs seen in more than 20% of patients receiving T-DXd are blood and lymphatic system disorders, including decreased platelet count, decreased white blood cell count, and gastrointestinal disorders such as nausea, vomiting, constipation, and diarrhea, as well as skin disorders, like alopecia. Moreover, anemia and neutropenia are more common than thrombocytopenia, and other prevalent AEs include fatigue and headache.

In terms of cardiotoxicity, a low percentage of patients had grade 1 or 2 left ventricular dysfunction, Desai adds. However, this AE is not a major concern for patients treated with T-DXd, she states.

A less common, yet potentially severe AE associated with this agent is drug-related pneumonitis, or interstitial lung disease (ILD), Desai continues. In the DESTINY-Breast03 trial, ILD was seen in 15% of patients. However, less than 1% of events were characterized as grade 3, and there were no grade 4 or grade 5 drug-related ILD or pneumonitis events. The majority of patients with HER2-positive breast cancer who experience ILD will have grade 1 or 2 severity, Desai notes.

The identification of early indicators for ILD, such as coughing or trouble breathing, can allow for quicker treatment, and prevent the AE from worsening, Desai states. Therefore, the recognition and management of ILD remains an important area of interest, she emphasizes. The incidence of ILD should be confirmed through imaging before drug administration is paused and corticosteroids are administered to decrease inflammation, Desai says. Treatment discontinuation is recommended for patients with symptomatic ILD, as continued use may worsen this AE and lead to a potentially fatal outcomes.

Neelam Desai, MD,  discusses the toxicity profile of fam-trastuzumab deruxtecan-nxki in HER2-positive breast cancer.

Neelam Desai, MD

Articles

Dr Desai on Research Informing Upfront CDK 4/6 Inhibitor Use in HR+/HER2– Breast Cancer

Dr Desai on the PATINA Study of a Palbociclib-Based Regimen in HR+/HER2+ Metastatic Breast Cancer

Dr Desai on the Role of Palbociclib in HR+, HER2+ Metastatic Breast Cancer

Dr Desai on Toxicities Associated with T-DXd in HER2+ Breast Cancer