Progress and pitfalls in the use of immunotherapy for patients with triple negative breast cancer

ABSTRACT

Introduction

Triple negative breast cancer (TNBC) is an area of high unmet medical need in terms of new effective treatment strategies. Although breast cancer is traditionally considered a ‘cold’ tumor type, TNBC is the most appropriate subtype for immunotherapeutic strategies; this is due to the high level of tumor infiltrating lymphocytes, PD-L1 expression, and tumor mutational burden compared to other breast cancer subtypes.

Areas covered

This review examines the available evidence on the use of immunotherapeutic strategies in early and advanced TNBC, discusses the pitfalls and limitations often encountered in clinical research, and summarizes data on novel promising immunomodulatory approaches that have been explored in early-phase trials.

Expert opinion

PD-1-blockade is approved for stage II/III TNBC and for first-line treatment of PD-L1-positive TNBC patients with metastatic disease and should be considered standard of care. However, question marks and difficulties remain; these include the identification of predictive biomarkers to select patients who benefit from the addition of PD1-blockade and the balance between efficacy and long-term toxicity for an individual patient. Numerous treatment combinations and new immunotherapeutic strategies beyond PD1 blockade are being evaluated, thus reflecting a promising evolution towards a more personalized approach, and extended clinical benefit in TNBC.

Abbreviations:Triple-negative breast cancer (TNBC); breast cancers (BCs); estrogen receptor (ER); progesterone receptor (PgR); human epidermal growth factor-2 (HER-2); basal-like 1 (BL1), basal-like 2 (BL2); mesenchymal (MES); mesenchymal stem-like (MSL); immunomodulatory (IM); luminal androgen receptor (LAR); basal-like immunosuppressed (BLIS); basal-like immune-activated (BLIA); tumor-infiltrating lymphocytes (TILs); tumor mutational burden (TMB); immune cells (ICs); immunohistochemistry (IHC); overall response rate (ORR); overall survival (OS); progression-free survival (PFS); intention-to-treat (ITT); hazard ratio (HR); confidence interval (CI); Food and Drug Administration (FDA); European Medicines Agency (EMA); immune checkpoint inhibitors (ICI); Combined Positive Score (CPS); disease control rate (DCR); neoadjuvant chemotherapy (NACT); pathological complete response (pCR); event-free survival (EFS); disease-free survival (DFS); residual cancer burden (RCB); San Antonio Breast Cancer Symposium (SABCS); antibody-drug conjugates (ADCs); PARP inhibitors (PARPi); clinical benefit rate (CBR); Histone deacetylase inhibitors (HDACi); Dendritic cell (DC); talimogene laherparepvec (TVEC); granulocyte-macrophage colony-stimulating factor (GM-CSF); mismatch repair deficiency (dMMR).

KEYWORDS:

• Atezolizumab
• durvalumab
• immune-checkpoint inhibitors
• immunotherapy
• nivolumab
• pembrolizumab
• triple negative breast cancer

Article Highlights

• Triple-negative breast cancer (TNBC) is an area of high unmet medical need in terms of development of new effective treatment strategies.

• Immunotherapy represents a promising approach in TNBC, due to its relatively higher level of tumor infiltrating lymphocytes, PD-L1 expression, and tumor mutational burden compared to other breast cancer subtypes.

• Pembrolizumab, in combination with chemotherapy, has been approved by the Food and Drug Administration (FDA) for patients with high-risk early TNBC as (neo)adjuvant treatment, and for first-line treatment of patients with advanced TNBC whose tumors express PD-L1 (Combined Positive Score [CPS] ≥10)

• Atezolizumab, in combination with chemotherapy, is no longer FDA-approved for the treatment of patients with advanced TNBC whose tumors express PD-L1 (Immune Cell score ≥ 1%), yet holding this indication according to the European Medicines Agency (EMA)

• Ongoing studies aim to extend the clinical benefit of immunotherapy, evaluating new treatment combinations able to overcome resistance to PD-(L)1 blockade

• Several new immunotherapeutic strategies beyond PD-(L)1 blockade are currently being tested, reflecting a promising evolution towards a more personalized approach in TNBC

• Several unmet needs remain to be fulfilled, including a deeper understanding of TNBC heterogeneity, the identification of reliable predictive biomarkers of response to immune checkpoint inhibitors, the definition of the most appropriate endpoints to evaluate their activity in clinical trials and investigation of less-explored potential long-term toxicities (e.g. on fertility, sexuality, and pregnancy)

This box summarizes key points contained in the article.

Declaration of interest

Elisa Agostinetto: Speaker fee: Eli Lilly. Support for attending medical conferences from: Novartis, Roche, Eli Lilly, Genetic, Istituto Gentili (all outside the submitted work).

Agnese Losurdo: Speaker fee: Eli Lilly, Novartis (all outside the submitted work).

Guilherme Nader Marta: Travel grants: Roche, Bayer (all outside the submitted work).

Armando Santoro: Advisory Board: Bristol-Myers-Squibb (BMS), Servier, Gilead, Pfizer, Eisai, Bayer,

Merck Sharp & Dohme (MSD). Consultancy: Arqule, Sanofi, Incyte. Speaker<apos;>s Bureau: Takeda, BMS,

Roche, Abb-Vie, Amgen, Celgene, Servier, Gilead, Astrazeneca, Pfizer, Arqule, Lilly, Sandoz, Eisai,

Novartis, Bayer, MSD (all outside the submitted work)

Kevin Punie: Travel support from AstraZeneca, Pfizer, PharmaMar and Roche (outside the submitted work).

His institution received honoraria for advisory/consultancy roles for AstraZeneca, Eli Lilly, Gilead

Sciences, Novartis, Pfizer, Pierre Fabre, Roche, Teva and Vifor Pharma, Speaker fees for Eli Lilly,

Medscape, MSD, Mundi Pharma, Novartis, Pfizer and Roche, and Research funding from MSD and Sanofi

(all outside the submitted work).

Romualdo Barroso: Speaker bureau fees from AstraZeneca, Daichi-Sankyo, Eli Lilly, Pfizer, Novartis,

Merck, and Roche. He has also served as a consultant/advisor for AstraZeneca, Daichi-Sankyo, Eli Lilly,

Libbs, Roche, Merck and has received support for attending medical conferences from Astrazeneca, Roche,

Eli Lilly, Daichi-Sankyo, and Merck (all outside the submitted work).

Lazar Popovic: Speaking fee and/or advisory board: Roche, MSD, BMS, Astra Zeneca, Pfizer, Novartis,

Gilead, Sandoz, Takeda, Astellas, Janssen, Sanofi, Abbvie (all outside of submitted work)

Cinzia Solinas has no conflicts of interest to declare.

Marleen Kok: Advisory board: AZ, BMS, Daichii, Medscape, MSD and Roche (outside the submitted

work). Institutional research funding: AZ, BMS and Roche (all outside the submitted work)

Evandro de Azambuja: honoraria and advisory board: Roche/GNE, Novartis, Seattle Genetics, Zodiacs,

Libbs and Pierre Fabre; travel grants: Roche/GNE, GSK/Novartis. Research grant for his institute:

Roche/GNE, Astra-Zeneca, Novartis, and Servier (all outside the submitted work)

Matteo Lambertini acted as a consultant for Roche, Pfizer, Lilly, MSD, Seagen, Gilead, AstraZeneca and

Novartis, and received honoraria from Sandoz, Takeda, Ipsen, Roche, Lilly, Pfizer and Novartis (all outside

the submitted work).

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One reviewer receives research funding from Roche and Pfizer. He/shes receive speakers fees from Gilead, Pfizer, Lily and AstraZeneca, has a place on the Advisory Board for Daichi Sankyo and receives conference support from Astra Zeneca, Lily, and Daichi Sankyo. Peer reviewers on this manuscript have no otheir relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded.