Sequencing Antibody-Drug Conjugates (ADCs) for Metastatic HER2-Low Breast Cancer: A Complex Decision-Making Process

Core Concepts

While Antibody-Drug Conjugates (ADCs) offer promising treatment options for metastatic HER2-low breast cancer, the optimal sequencing of these agents remains unclear due to limited data on resistance mechanisms and the efficacy of subsequent treatments.

Abstract

This podcast transcript featuring Dr. Kathy Miller and Dr. Stephanie Graff discusses the complexities of sequencing Antibody-Drug Conjugates (ADCs) for patients with metastatic HER2-low breast cancer.

Defining HER2-low Patients and Available ADCs

The discussion begins by defining HER2-low patients, a relatively new category encompassing those previously considered HER2-negative. These patients exhibit low levels of HER2 expression and were historically excluded from HER2-targeted therapies. However, the emergence of ADCs like sacituzumab govitecan and trastuzumab deruxtecan (T-DXd) has shown promise in this patient population.

Challenges in Sequencing ADCs

The central challenge lies in determining the optimal sequence for using these ADCs. While both target HER2, they have different targets for specificity and delivery, and distinct side effect profiles. Factors such as prior treatments, patient preferences, and potential toxicities all contribute to the decision-making process.

Limited Data and Resistance Mechanisms

The lack of robust data on ADC sequencing poses a significant hurdle. While real-world evidence suggests reduced efficacy when using one ADC after another, these findings stem from small studies with limited generalizability. The mechanisms of resistance to ADCs are complex and may involve changes in the target receptor or the drug's payload.

Shared Decision-Making and Future Directions

Given the uncertainties, shared decision-making between clinicians and patients is paramount. Factors like dosing schedules, potential side effects, and individual patient preferences should guide treatment choices. The podcast emphasizes the need for further research, particularly clinical trials investigating ADC sequencing and biomarkers for predicting response and resistance. The emergence of new ADCs like datopotamab deruxtecan (Dato-DXd) further complicates the landscape, highlighting the need for ongoing research to optimize treatment strategies in this evolving field.

Stats

PFS with ADC 2 was much lower than PFS with ADC 1.
70%-75% of patients in a study of chemotherapy in HER2-negative patients who progressed on previous chemotherapy would be expected to be ER-positive.
Triple-negative breast cancer represents 10 to 15 to 20 percent of the total patient population with metastatic disease or breast cancer in general.

Quotes

"We have scant data, which is not the same as great data."
"I think at this time, we're all getting uncomfortable that the primary mechanism of resistance may not be target changing"
"It's almost as if, even though the ADCs are one drug, I think of it a bit like when we give someone hormone therapy with a CDK inhibitor and their disease is progressing. And we wonder, are they resistant to the hormone therapy or the CDK inhibitor?"

Key Insights Distilled From

Episode 5: Sequencing of ADCs for Metastatic HER2-Low Disease

by Kathy D. Mil... at www.medscape.com 11-21-2024

https://www.medscape.com/viewarticle/1001337

Deeper Inquiries

How might the development of personalized medicine and biomarker testing impact the future of ADC sequencing for HER2-low breast cancer?

Personalized medicine and biomarker testing hold immense potential for revolutionizing ADC sequencing in HER2-low breast cancer. Here's how:

Predictive Biomarkers for ADC Response: Identifying specific biomarkers that predict response or resistance to particular ADCs (like T-DXd or Sacituzumab Govitecan) will be crucial. This could involve:

Target Expression Levels: Moving beyond simple HER2-low classification to quantify HER2 expression levels (including HER2 ultra-low) and assess the expression of other potential targets like TROP2.
Resistance Mechanisms: Analyzing tumor biopsies to understand the mechanisms of resistance developed against a specific ADC. This could involve looking for mutations in the target receptor, alterations in the payload's pathway, or activation of alternative signaling pathways.
Tumor Microenvironment: Investigating the tumor microenvironment for factors that might influence ADC efficacy, such as immune cell infiltration or the presence of specific stromal components.

Tailored Sequencing Strategies: Biomarker data will enable the development of personalized ADC sequencing strategies:

Optimal First-Line ADC: Selecting the most effective first-line ADC based on a patient's individual tumor profile.
Predicting Resistance: Identifying patients at high risk of developing resistance to a particular ADC, allowing for proactive treatment switching or combination strategies.
Rational Combinations: Guiding the development of rational ADC combinations with other therapies (like immunotherapy or targeted agents) based on the specific molecular alterations present in a patient's tumor.

Clinical Trial Design: Biomarker-driven clinical trials will be essential to:

Enrich Trial Populations: Selecting patients most likely to benefit from a specific ADC or ADC sequence, leading to more efficient and successful trials.
Validate Biomarker Utility: Confirming the clinical significance of identified biomarkers and their ability to guide treatment decisions.
In essence, personalized medicine and biomarker testing will transition ADC sequencing from its current empirical state to a more precise and individualized approach, maximizing patient outcomes and minimizing unnecessary toxicities.

Could combining ADCs with other therapies, such as immunotherapy or targeted agents, offer a more effective strategy than sequential treatment?

Combining ADCs with other therapies, particularly immunotherapy or targeted agents, holds significant promise for improving outcomes in HER2-low breast cancer compared to sequential treatment alone. Here's why:

Synergistic Mechanisms of Action:

Immune Activation: ADCs, by inducing tumor cell death, can release tumor antigens and potentially promote an anti-tumor immune response. Combining them with immune checkpoint inhibitors (ICIs) could amplify this response, leading to more durable tumor control.
Targeting Multiple Pathways: Combining ADCs with agents that target different signaling pathways involved in tumor growth and survival could overcome resistance mechanisms and enhance efficacy. For example, combining an ADC with a CDK4/6 inhibitor in HR-positive/HER2-low breast cancer could provide a two-pronged attack on tumor cells.

Overcoming Resistance: Combination therapies could potentially delay or prevent the development of resistance by:

Multiple Mechanisms of Action: Simultaneously targeting different vulnerabilities within the tumor, making it harder for resistance to emerge.
Lowering the Threshold for Response: Potentially achieving tumor responses even if the tumor exhibits some degree of resistance to one of the agents in the combination.

Clinical Trial Evidence: Early clinical trials are exploring various ADC combinations:

ADC + ICI Combinations: Trials are investigating the combination of ADCs like T-DXd or Sacituzumab Govitecan with ICIs like pembrolizumab or atezolizumab in HER2-low breast cancer.
ADC + Targeted Therapy Combinations: Studies are evaluating the combination of ADCs with other targeted agents, such as PARP inhibitors in patients with specific mutations or CDK4/6 inhibitors in HR-positive/HER2-low disease.
While combination therapies offer great potential, careful consideration must be given to:

Increased Toxicity: Combining agents often leads to a higher risk of side effects. Carefully selecting patients and optimizing dosing schedules will be crucial to manage toxicity.
Trial Design and Biomarker Development: Well-designed clinical trials are essential to determine the optimal combinations, identify predictive biomarkers for response, and establish effective safety management strategies.

Given the complexities and uncertainties surrounding cancer treatment, how can healthcare providers better support patients in navigating difficult decisions and managing expectations?

Navigating cancer treatment, especially with evolving options like ADCs, can be overwhelming for patients. Healthcare providers play a crucial role in supporting them through shared decision-making and clear communication:

Active Listening and Empathy: Create a safe space for patients to express their fears, concerns, and priorities. Acknowledge the emotional burden of the diagnosis and treatment decisions.

Clear and Compassionate Communication:

Explain Complex Concepts: Break down complex medical information about ADCs, sequencing, potential benefits, and risks in a way that is understandable to someone without a medical background.
Visual Aids: Utilize diagrams, charts, or patient education materials to illustrate treatment options and potential outcomes.
Shared Decision-Making: Emphasize that treatment decisions are a partnership. Present options with their pros and cons, considering the patient's values, preferences, and goals.

Managing Expectations:

Realistic Outcomes: While ADCs offer hope, it's important to have realistic conversations about potential benefits, limitations, and the possibility of disease progression.
Side Effect Management: Provide comprehensive information about potential side effects, their severity, and strategies for management. Proactively address concerns and offer support resources.

Multidisciplinary Care Coordination:

Integrate Support Services: Connect patients with support groups, mental health professionals, financial counselors, and other resources to address their holistic needs.
Nurse Navigators: Nurse navigators can play a vital role in guiding patients through the healthcare system, coordinating appointments, and providing education and support.

Open Communication and Follow-Up:

Encourage Questions: Emphasize that no question is too small and encourage patients to reach out with any concerns between appointments.
Regular Check-Ins: Schedule regular follow-up appointments to monitor treatment response, manage side effects, and address any emerging issues or anxieties.
By prioritizing open communication, shared decision-making, and comprehensive support, healthcare providers can empower patients with HER2-low breast cancer to navigate the complexities of their treatment journey with greater confidence and a sense of control.