Key Clinical Summary: Optimizing Maintenance in HER2+ Metastatic Breast Cancer

This is a micro-learning module summary of the session by Sarah Sammons, MD, which you can find here. Before participating, please read our CME and disclosure information which can be found here.

Acknowledgment: This program is supported by an independent education grant from Pfizer Global Medical Grants. This online education program has been designed for healthcare professionals globally.

Introduction

This summary explores the evolving treatment paradigm in human epidermal growth factor receptor 2 (HER2)‑positive metastatic breast cancer (MBC), focusing on recent trial data that may redefine first‑line standards of care. It reviews the impact of antibody–drug conjugates (ADCs), particularly trastuzumab deruxtecan (T‑DXd), the role of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors in hormone-receptor (HR)‑positive disease, and strategies for managing central nervous system (CNS) involvement. The report highlights biomarker‑driven patient selection, quality‑of‑life considerations, and the importance of tailoring therapy to disease progression rate and patient goals.

Evolution of First‑Line Standards: DESTINY‑Breast09

• For more than a decade, the CLEOPATRA regimen, docetaxel plus trastuzumab and pertuzumab, was the established first‑line standard.
• The DESTINY‑Breast09 trial introduced a potential paradigm shift, evaluating T‑DXd plus pertuzumab, T‑DXd alone, and the CLEOPATRA regimen.
• Results demonstrated a striking improvement in progression‑free survival (PFS): approximately 41 months with T‑DXd plus pertuzumab versus 27 months with taxane plus trastuzumab/pertuzumab.
• Benefits were consistent across subgroups, including patients with brain metastases, PIK3CA mutations, and both de novo and recurrent disease.
• Response rates and complete responses favored the ADC‑based regimen.
• While regulatory approval is awaited, these findings suggest T‑DXd plus pertuzumab may soon replace taxane‑based induction as the frontline standard.

Toxicity Profile of T‑DXd

• Key toxicities of T‑DXd include fatigue, nausea, and alopecia, with the drug classified as highly emetogenic. Prophylaxis with three‑drug antiemetic regimens and short courses of steroids is recommended.
• Interstitial lung disease (ILD) occurs in 10–15% of patients; early recognition and management with high‑resolution computed tomography and corticosteroids are critical. Current guidelines permit rechallenge after grade 1 pneumonitis but recommend permanent discontinuation after grade ≥2 events. These risks necessitate careful patient counseling and monitoring.

Maintenance and Quality‑of‑Life Considerations

• Traditional first‑line therapy allowed finite chemotherapy induction followed by antibody maintenance, often yielding durable disease control with excellent quality of life.
• In contrast, DESTINY‑Breast09 employed continuous ADC therapy until progression or toxicity. This raises concerns about long‑term tolerability, given the cytotoxic payload of T‑DXd.
• Maintenance strategies that preserve quality of life, such as finite induction followed by antibody or endocrine therapy (ET), remain highly valued.
• Future trials are expected to explore induction with ADCs followed by maintenance regimens incorporating HER2 antibodies, ET, or CDK4/6 inhibitors.

Patient‑Centered Decision‑Making

• Treatment selection increasingly requires individualized approaches:
• While T‑DXd plus pertuzumab may become the new standard, taxane plus trastuzumab/pertuzumab remains appropriate for many patients, particularly those with de novo disease, HER2 IHC 3+ tumors, absence of brain metastases, and no PIK3CA mutations.
• For HR‑positive patients, integration of ET and CDK4/6 inhibitors is supported by the AFT-38 PATINA trial, which demonstrated a median PFS of 44 months with palbociclib added to trastuzumab/pertuzumab and ET.
• Patient preferences, comorbidities, and lifestyle factors, such as avoidance of alopecia or tolerance for oral versus intravenous therapy, should guide regimen choice.

CNS Disease Management

• Brain metastases remain a major challenge in HER2‑positive MBC. Two regimens demonstrate robust intracranial activity:
• HER2CLIMB regimen: Tucatinib plus trastuzumab and capecitabine improved intracranial PFS, response rates, and OS in patients with active or stable brain metastases. The regimen avoids alopecia but requires management of diarrhea, nausea, pill burden, and hepatotoxicity.
• T‑DXd: DESTINY‑Breast12 confirmed high intracranial response rates (~70%) and a 12-month CNS PFS of ~60% in patients with brain metastases. While highly effective, risks include ILD and alopecia, necessitating careful patient selection.
• Choice between these regimens should consider rate of disease progression, CNS burden, comorbidities, and patient priorities. For example, patients with underlying lung disease may be better suited to tucatinib‑based therapy, while those requiring rapid intracranial response may benefit from T‑DXd.

Patient Case Studies

Early Relapse with Brain Metastases: A 45-year-old woman relapsed 18 months after adjuvant trastuzumab emtansine, presenting with brain metastases and hilar lymphadenopathy. Post-radiosurgery, systemic options included trastuzumab/pertuzumab/taxane (THP) rechallenge versus T-DXd. DESTINY-Breast09 showed superior PFS with T-DXd + pertuzumab, though regulatory approval is pending. Toxicities included nausea, fatigue, and interstitial lung disease risk, requiring vigilant monitoring.

ER+/HER2+ Maintenance Strategy: A 63-year-old woman with de novo estrogen receptor (ER)-positive/HER2-positive disease achieved a partial response after THP induction. The AFT-38 PATINA trial demonstrated that adding palbociclib to trastuzumab/pertuzumab plus ET extended median PFS to 44 months versus 29 months. This supports integrating CDK4/6 inhibitors into maintenance for ER-positive/HER2-positive patients, with manageable hematologic toxicity.

CNS-Driven Progression: A 49-year-old woman with stable extracranial disease developed recurrent brain metastases after prolonged trastuzumab/pertuzumab maintenance. Options included tucatinib/trastuzumab/capecitabine (HER2CLIMB) or T-DXd (DESTINY-Breast12). Both regimens have shown strong intracranial activity, but patient preference against alopecia favored tucatinib. Shared decision-making emphasizes tailoring therapy to CNS risk, comorbidities, and quality-of-life priorities.

Conclusions

HER2‑positive metastatic breast cancer is entering a new era of frontline management. DESTINY‑Breast09 positions trastuzumab deruxtecan plus pertuzumab as a likely new standard, offering unprecedented PFS across diverse patient subgroups, including those with brain metastases. At the same time, the PATINA trial highlights the value of integrating ET and CDK4/6 inhibitors for HR‑positive disease, extending durable control well beyond prior benchmarks. For patients with CNS involvement, both tucatinib‑based regimens and T‑DXd demonstrate meaningful intracranial activity, enabling tailored approaches based on biology, comorbidities, and patient preferences. Future directions will emphasize balancing efficacy with quality of life, refining maintenance strategies, and adopting biomarker‑guided personalization to optimize outcomes in HER2‑positive MBC.

Content is accurate as of the date of release on 6 January 2026.