Combination of HER2-targeted agents with immune checkpoint inhibitors in the treatment of HER2-positive breast cancer

ABSTRACT

Introduction

Human epidermal growth factor receptor 2 (HER2)-positive breast cancers account for approximately 15 to 20% of breast cancer diagnoses. Historically, HER2-positive breast cancers had been associated with poorer prognosis. The addition of HER2-targeted agents to treatment regimens has significantly improved outcomes for patients with HER2-positive breast cancer. Despite this, relapses continue to occur in about 20% of patients. Newer therapeutic strategies are needed. The role of immunotherapy in the treatment of HER2-positive breast cancer is currently under clinical investigation.

Areas Covered

This article will focus on the clinical trial data evaluating immune checkpoint inhibitors, including pembrolizumab, atezolizumab, avelumab, durvalumab, and nivolumab in the treatment of HER2-positive breast cancer.

Expert opinion

The incorporation of immunotherapy in the treatment of HER2-positive breast cancer is a reasonable strategy. Clinical trials of checkpoint inhibitors with HER2-targeted agents show clinical activity in HER2-positive breast cancer tumors that are programmed cell death-ligand 1 (PD-L1) positive and also when used as an earlier line of therapy in the metastatic setting. Treatment of HER2-positive breast cancer with immunotherapy and HER2-targeted agents warrants continued clinical investigation.

KEYWORDS:

• Human epidermal growth factor receptor 2
• immunotherapy
• immune checkpoint inhibitor
• pembrolizumab
• atezolizumab
• avelumab
• durvalumab
• nivolumab

Article highlights

• The rationale to evaluate immunotherapy for the treatment of HER2-positive breast cancer is based on preclinical studies showing that HER2-positive breast tumors are immunogenic and trastuzumab has an immune-based mechanism of action. Clinical trials have been conducted to determine the role of checkpoint inhibitors, such as programmed cell death (PD-1) and PD-L1 inhibitors, in the treatment of HER2-positive breast cancer.

• The phase Ib/II PANACEA trial evaluated the combination of pembrolizumab and trastuzumab in HER2-positive metastatic breast cancer patients that progressed after receiving trastuzumab. There was a 15% overall response rate and 24% disease control rate in patients with PD-L1-positive, HER2-positive tumors. In the randomized phase II KATE2 trial, atezolizumab in combination with trastuzumab emtansine (T-DM1) did not show an improvement in progression-free survival (PFS) compared to T-DM1 alone in metastatic HER2-positive patients. An exploratory analysis suggested an improvement in PFS in the PD-L1-positive subset, but further confirmatory studies are needed.

• Preliminary results of a phase Ib study (DS8201-A-U105) of nivolumab in combination with fam-trastuzumab deruxtecan-nxki in metastatic HER2-positive patients showed an overall response rate of 59.5%. Continued follow-up is ongoing. Several clinical trials combining immunotherapy with various chemotherapies and HER2-targeted agents are being evaluated in different settings including localized disease and advanced disease with and without brain metastases.

Disclosure statement

A Tan has received honoraria from Astra-Zeneca, Genentech and Merck. 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 apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.