44 Months of Progression-Free Survival With Palbociclib in HR-Positive, HER2-Positive Breast Cancer

The treatment of hormone receptor-positive (HR+), HER2-positive metastatic breast cancer has been transformed by targeted therapies. Among these, palbociclib (Ibrance), a CDK4/6 inhibitor, shows promise when combined with anti-HER2 and endocrine therapies. Results of the phase 3 AFT-38 PATINA trial, presented at the 2024 San Antonio Breast Cancer Symposium, demonstrated significant improvements in progression-free survival (PFS), strengthening the possibility of this combination becoming a new standard of care.

Targeting a Mixed Tumor

HER2 (Human Epidermal Growth Factor Receptor 2) is a cell-surface protein regulating growth and proliferation. When overexpressed, it can drive more aggressive growth in tumors such as breast cancer. Effective HER2-targeted drugs such as trastuzumab and pertuzumab have transformed treatment of this biological subgroup, substantially improving survival and quality of life.

Approximately 10-15% of breast cancers are both hormone receptor-positive (estrogen [ER] and/or progesterone [PR]) and HER2-positive . Tumors in this double-positive group are biologically heterogeneous because of the aggressive nature of HER2 positivity and the generally favorable disease-course characteristics associated with hormone receptor positivity. Treatment strategies must address both biological targets.

Palbociclib combined with endocrine therapy is already considered standard treatment for hormone receptor-positive, HER2-negative metastatic breast cancer. However, this is the first time palbociclib has been tested in large clinical trials of HER2-positive tumors. The PATINA trial was conducted to explore whether adding palbociclib to HER2-targeted and endocrine therapies could overcome resistance and prolong progression-free survival. Its results suggest that the combination could play an important role in treating HER2-positive, hormone receptor-positive breast cancer.

Striking Results: Better Disease Control With Palbociclib

PATINA demonstrated a statistically and clinically significant improvement in median PFS when palbociclib was added to standard treatment.

When palbociclib was combined with trastuzumab or trastuzumab plus pertuzumab and endocrine therapy, median PFS was 44.3 months (95% CI, 32.4-60.9), well above the control group's 29.1 months(95% CI, 23.3-38.6) (HR, 0.74; 95% CI, 0.58-0.94; unstratified 1-sided P = 0.0074).

This improvement of 15.2 months highlights the clinical importance of adding palbociclib to the regimen.

Mechanism: Targeting Resistance

Palbociclib acts by inhibiting the cyclin D1-CDK4 axis, which is critical to tumor growth in HER2-positive cancers. This pathway also mediates resistance to HER2-targeted therapies. Combining CDK4/6 inhibition with anti-HER2 treatment confirmed, through PATINA, the synergy and profound antitumor activity observed in preclinical models.

Study Design and Participants

The open-label, phase 3 AFT-38 PATINA trial, in HR+, HER2+ metastatic breast cancer, enrolled 518 patients .

Participants

1. received palbociclib + anti-HER2 and endocrine therapies in one arm, or
2. anti-HER2 and endocrine therapies alone in the other, following 1:1 randomization.

Key eligibility criteria included completion of induction chemotherapy and no evidence of cancer progression before enrollment.

Key Endpoints

• Primary Endpoint: Investigator-assessed progression-free survival (PFS).

• Secondary Endpoints: Overall survival, objective response rate, clinical benefit rate, and safety.

Efficacy Results: Subgroups and Overall Analysis

Subgroup analyses further supported palbociclib's benefit:

• Patients With Previous Anti-HER2 Treatment: Treatment reduced the risk of disease progression by 24% in these patients.
• Patients Without Previous Anti-HER2 Treatment: This group benefited even more, with a 32% reduction in the risk of progression.
• Patients With a Complete or Partial Treatment Response: The risk of disease progression was also reduced by 24% in this group.
• Patients With Stable Disease: In patients with stable disease, the risk of progression was reduced by 28%.

The confirmed overall response rate was 29.9% with palbociclib, compared with 22.2% in the control arm (P = 0.046).

The clinical benefit rate was 89.3% in the experimental group and 81.3% in the control group (P = 0.01).

Interim Overall Survival Analysis

The interim overall survival analysis showed:

• Median overall survival was not evaluable (NE) in the palbociclib arm (95% CI, 71.6-NE), compared with 77 months in the control arm (95% CI, 72-NE) (HR, 0.86; 95% CI, 0.60-1.24).

• Three-year overall survival rates: 87% in the experimental arm and 84.7% in the control arm.

• Five-year overall survival rates: 74.3% and 69.8%, respectively.

Adverse Effects

Palbociclib's adverse-effect profile was consistent with previous studies. Neutropenia was the most common adverse effect:

• Grade 2 (mild) neutropenia: 19.9% in the palbociclib arm and 4.0% in the control arm.

• Grade 3 (moderate) neutropenia: 63.2% and 4.4%.

• Grade 4 (severe) neutropenia: 4.6% and 0%.

Other notable adverse effects included a reduced white blood cell count, diarrhea, stomatitis, and fatigue. Among palbociclib recipients, 7.5%discontinued treatment because of adverse effects. No grade 5 (fatal) adverse effects were reported.

Commentary

PATINA supports adding palbociclib to first-line anti-HER2 treatment in advanced hormone-positive, HER2-positive breast cancer. This treatment prevents tumors from becoming resistant and offers an effective way to prevent disease progression. The study found that progression was held off for approximately 15 months longer in patients receiving the palbociclib combination.

This is also a generally well-tolerated option with manageable adverse effects, preserving quality of life and providing long-term benefit. Palbociclib combined with anti-HER2 treatment could become a new standard for breast cancer and offers a promising approach to managing the disease.

This treatment not only slows cancer progression but may also provide a foundation for new treatment strategies. These findings point to a promising future for patients and doctors.