The emerging role of immune checkpoint inhibitors for the treatment of breast cancer

ABSTRACT

Introduction

Breast cancer has traditionally been viewed as immunogenically ‘cold,’ but two immune checkpoint inhibitors have been approved in combination with chemotherapy for PD-L1 positive advanced triple-negative breast cancer (TNBC), and pembrolizumab was also recently approved for early stage TNBC. As the landscape is rapidly evolving, a comprehensive review of checkpoint inhibitors in breast cancer is needed to aid clinicians in selecting appropriate candidates for therapy, and to highlight ongoing promising studies in this area and topics in need of further investigation.

Area covered

This review summarizes the latest evidence from completed and ongoing trials of immune checkpoint inhibitors. Ongoing studies were identified using a search of ClinicalTrials.gov with the term ‘breast cancer’ along with specific checkpoint inhibitor agents.

Expert opinion

A number of novel combination strategies are under investigation to enhance response and overcome resistance to immunotherapy, with promising preliminary data from checkpoint inhibitors targeting TIGIT, combinations with small molecule inhibitors such as lenvatinib, and injectable agents directly influencing the immune microenvironment. As immunotherapy enters into the curative setting, biomarkers predictive of immunotherapy benefit are needed, as PD-L1 status has not been a helpful discriminator in completed trials in early-stage breast cancer.

KEYWORDS:

• Atezolizumab
• breast cancer
• checkpoint inhibitors
• durvalumab
• immunotherapy
• small-molecule inhibitors
• PARP inhibitors
• pembrolizumab
• triple negative breast cancer

Article highlights

• Response to checkpoint inhibition in advanced breast cancer is enriched in patients with untreated, PD-L1 positive, triple-negative disease

• Atezolizumab and pembrolizumab were approved for the treatment of PD-L1 positive triple-negative breast cancer in combination with chemotherapy on the basis of the IMpassion130 and KEYNOTE-355 trials, although the U.S. approval for atezolizumab was withdrawn given the conflicting results of IMpassion131

• Pembrolizumab was recently approved in combination with neoadjuvant chemotherapy and as a single agent in the adjuvant setting for early-stage high-risk triple-negative breast cancer, based on improvements in pathologic complete response and event-free survival seen in KEYNOTE-522

• Unlike in the metastatic setting, PD-L1 status and other immunotherapy biomarkers have not identified patients with early-stage disease who benefit from immunotherapy

• Ongoing studies are evaluating PD-1/PD-L1 blockade in combination with novel immune checkpoint inhibitors, PARP inhibitors, small-molecule inhibitors, and intratumoral injections of immunomodulatory therapeutics

This box summarizes key points contained in the article.

Declaration of interest

R Nanda is on Advisory Boards for Aduro, Cardinal Health, Clovis, Fujifilm, G1 Therapeutics, Genentech, Immunomedics/Gilead, Ionis, iTeos, MacroGenics, Merck, Oncosec, Pfizer, and Seattle Genetics. N Nanda is also on the data safety monitoring board for G1 Therapeutics.

R Nanda also receives funding from Arvinas, AstraZeneca, Celgene, Corcept Therapeutics, Genentech/Roche, Immunomedics/Gilead, Merck, OBI Pharma, Odonate Therapeutics, OncoSec, Pfizer, Seattle Genetics, Taiho

A Pearson is on the Advisory board for Prelude Therapeutics

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.

Additional information

Funding

All authors received salary support from the University of Chicago. F Howard also reports support from NIH grants 1F32CA265232-01 and 5T32CA009566-33.