Checkpoint inhibitor therapy for metastatic triple-negative breast cancer

Abstract

Immunotherapy has become a mainstay of cancer treatment in many malignancies, though its application in breast cancer remains limited. Of the breast cancer subtypes, triple-negative breast cancers (TNBCs) are characterized by immune activation and infiltration and more commonly express biomarkers associated with response to immunotherapy. Checkpoint inhibitor therapy has shown promising activity in metastatic TNBC. In 2019, the US FDA granted accelerated approval of atezolizumab, a programmed death-ligand 1 (PD-L1) inhibitor, in combination with nab-paclitaxel for unresectable locally advanced or metastatic PD-L1-positive TNBC, based on the results of the phase III IMpassion130 trial. In 2020, the FDA also granted accelerated approval of pembrolizumab, a PD-1 inhibitor, in combination with chemotherapy for locally recurrent unresectable and metastatic PD-L1-positive TNBC, based on results of the phase III KEYNOTE-355 trial. Additional combination strategies are being explored in the treatment of metastatic TNBC, with the goal of augmenting antitumor activity. In this review, the clinical development of checkpoint inhibitors in the treatment of metastatic TNBC will be discussed, including clinical outcomes with monotherapy and combination therapy regimens, biomarkers that may predict for benefit, and future directions in the field.

MitoQ Prevents Human Breast Cancer Recurrence and Lung Metastasis in Mice

“…In particular, secondary tumors are often more resistant to conventional treatments than primary tumors [1], and local treatments are usually not an option for metastatic patients. In addition, immunotherapy using checkpoint inhibitors only generates a modest response in breast cancer [2]. Despite progress for HER2+ breast cancer [3], polymetastatic breast cancer is still a largely incurable disease [4].…”

Precision Medicine and Triple-Negative Breast Cancer: Current Landscape and Future Directions

“…Another phase II study of abemaciclib (selective ATP-competitive inhibitor of CDK4 and CDK6 kinase activity) for TNBC is also ongoing (Clinicaltrials.gov: NCT03130439). CDK inhibitors (mainly CDK4/6) augment anti-tumor immunity through T-cell activation, supporting the rationale for combination with immunotherapy [108,144,145]. A phase Ib clinical breast cancer study of pembrolizumab with abemaciclib demonstrated tolerability with clinical benefits [108].…”

“…CDK inhibitors (mainly CDK4/6) augment anti-tumor immunity through T-cell activation, supporting the rationale for combination with immunotherapy [108,144,145]. A phase Ib clinical breast cancer study of pembrolizumab with abemaciclib demonstrated tolerability with clinical benefits [108].…”

“…A recent paper described details about clinical trials involving PD-1/PD-L1 blockade either as monotherapy, in combination with chemotherapy, or with other targeted therapies [108]. Gagliato et al also described the success and challenges of PD-1/PD-L1 immunotherapy for TNBC patients [109].…”

Therapeutic progress and challenges for triple negative breast cancer: targeted therapy and immunotherapy

“…In a phase III clinical trial (KEYNOTE-355), the other ICI, pembrolizumab plus chemotherapy distinctly improved the PFS of patients with metastatic TNBC, compared with placebo plus chemotherapy [ 142 ]. And therefore, Pembrolizumab, was approved in 2020 to treat metastatic TNBC patients with PD-L1-expressing in combination with chemotherapy [ 143 ]. In addition to combining chemotherapy, the combination of ICIs and targeted agents in the treatment of TNBC also has great clinical potential.…”