Adjuvant Atezolizumab in TNBC: What Recent Trials Reveal About Its Role

Abstract

The management of early TNBC has witnessed great strides with the introduction of immune checkpoint inhibitors. Although neoadjuvant pembrolizumab combined with chemotherapy has been associated with significant clinical benefits for certain high-risk patients, more recent data indicate adjuvant atezolumab does not improve rates of recurrence or survival. This trial of adding atezolizumab to adjuvant chemotherapy in resected patients with stage II to III TNBC failed to show an overall survival benefit. This article describes the current scenario of immunotherapy in TNBC, discussing the latest clinical trial results, biological hypotheses for the observed variability in response across studies, and future strategies in optimizing immune-based approaches to the treatment of breast cancer.

Introduction

Triple-negative breast cancer (TNBC) is a highly aggressive and heterogeneous subtype of breast cancer, lacking estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. It still has very few targeted therapy options, and hence systemic chemotherapy continues to be the mainstay treatment for TNBC. The latest addition of immunotherapy, though, has shifted the landscape and has opened many new avenues of treatment, primarily in the neoadjuvant setting.

Although pembrolizumab, a PD-1 inhibitor, demonstrated clinical benefit when used in combination with chemotherapy before surgery, the role of adjuvant immunotherapy is not well established. Atezolizumab, a PD-L1 inhibitor, was expected to have similar benefits in the adjuvant setting, but the latest results of trials have disputed this hypothesis. This review is intended to address the current knowledge of adjuvant atezolizumab in early TNBC, discuss the implications of recent clinical findings, and highlight areas for future research.

Immune Checkpoint Inhibition in TNBC: The Current Landscape

Immunotherapy has fundamentally altered the landscape of the treatment paradigm for TNBC, mainly in metastatic and neoadjuvant settings. Studies such as KEYNOTE-522 show that adding pembrolizumab to neoadjuvant chemotherapy is very effective at boosting pathological complete response rates and even EFS for patients diagnosed with high-risk TNBC. For these reasons, the FDA granted pembrolizumab an accelerated approval when combined with chemotherapy in specific subgroups of patients diagnosed with early-stage TNBC.

However, whether adjuvant immune checkpoint inhibition has a place in this framework remains uncertain. Neoadjuvant pembrolizumab having succeeded to reduce recurrence and improve long-term outcomes, atezolizumab after curative intent surgery may prevent recurrence further.

The Atezolizumab Adjuvant Trial: A Critical Examination

A recent randomized controlled trial investigated the efficacy of adjuvant atezolizumab in combination with chemotherapy in patients with stage II to III TNBC who had completed surgery. The study aimed to determine whether continued immune checkpoint blockade post-surgery could enhance survival outcomes and reduce recurrence risk. Key findings include:

• No significant improvement in recurrence-free survival (RFS) with adjuvant atezolizumab compared to chemotherapy alone.

• No overall survival (OS) benefit in the atezolizumab-treated cohort.

• Comparable toxicity profiles between the two groups, but no added clinical advantage for adjuvant immune checkpoint inhibition.

These results suggest that, unlike in the neoadjuvant setting, immune checkpoint blockade may not provide additional benefit after surgical resection in TNBC.

Potential Biological Explanations for the Lack of Adjuvant Benefit

Several factors may explain why adjuvant atezolizumab failed to show efficacy in early TNBC:

1. Tumor Microenvironment Changes Post-Surgery: The immunological landscape of TNBC may shift after surgical resection, potentially altering the tumor’s ability to respond to immune checkpoint inhibition. The absence of an intact tumor mass may reduce antigen presentation, limiting the efficacy of checkpoint inhibitors.

2. Differential Mechanisms of Immunotherapy in the Neoadjuvant vs. Adjuvant Setting: Neoadjuvant immune checkpoint inhibitors may exert their greatest effects when combined with chemotherapy in the presence of a tumor, enabling a more robust immune response before surgery. In contrast, the adjuvant setting lacks this dynamic interaction, potentially diminishing the therapeutic impact.

3. Patient Selection Criteria: The trial may not have adequately stratified patients based on PD-L1 expression levels, tumor-infiltrating lymphocytes (TILs), or other predictive biomarkers. It is possible that a subset of TNBC patients could still derive benefit from adjuvant immunotherapy if selected based on more refined criteria.

4. Chemotherapy-Induced Immune Modulation: The immunosuppressive effects of prior chemotherapy regimens may influence the efficacy of subsequent checkpoint inhibition in the adjuvant setting. Unlike in the neoadjuvant phase, where chemotherapy may help prime an immune response, post-surgical immune suppression may hinder further therapeutic benefit.

Clinical Implications and Future Directions

The results of this trial suggest that adjuvant atezolizumab should not be routinely used in early-stage TNBC. Instead, future research should focus on:

• Refining Patient Selection: Identifying biomarkers that can predict which patients may benefit from continued immune checkpoint blockade post-surgery.

• Exploring Alternative Immunotherapy Strategies: Investigating novel immune modulatory agents, combination therapies, and maintenance strategies that could enhance the efficacy of checkpoint inhibitors in TNBC.

• Optimizing Neoadjuvant Approaches: Given the success of neoadjuvant pembrolizumab, additional studies should explore optimal sequencing strategies and whether extending immunotherapy beyond the neoadjuvant phase may benefit select patient groups.

• Understanding Resistance Mechanisms: Further research into the molecular and immune-related mechanisms underlying resistance to adjuvant immunotherapy may provide insights for developing more effective treatment strategies.

Conclusion

While immunotherapy has revolutionized the treatment of TNBC, its role in the adjuvant setting remains uncertain. The recent trial evaluating adjuvant atezolizumab in early TNBC did not demonstrate a survival benefit, suggesting that checkpoint inhibition may be more effective in the neoadjuvant phase. These findings reinforce the need for continued research to refine immunotherapy strategies, optimize patient selection, and explore novel therapeutic approaches for TNBC. Until further data become available, adjuvant atezolizumab should not be used outside of clinical trials, and treatment decisions should be guided by existing evidence supporting neoadjuvant immunotherapy for high-risk TNBC patients.

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