Emerging Immunotherapy Combination Strategies for Breast Cancer: Dual Immune Checkpoint Modulation, Antibody–Drug Conjugates, and Bispecific Antibodies

Breast cancer has long been thought to be immune-suppressive.¹ PD-L1 expression and/or tumor-infiltrating lymphocytes in the tumor microenvironment have been found in a small percentage of breast tumors in multiple investigations over the past 10 to 15 years.¹ The PD-1 inhibitor pembrolizumab has been licensed by the US Food and Drug Administration for the first-line treatment of patients with metastatic PD-L1–positive, triple-negative breast cancer (TNBC) in combination with chemotherapy, and the PD-L1 inhibitor atezolizumab has also shown clinical activity.¹ With the inclusion of immunotherapy, the median progression-free survival for pembrolizumab or atezolizumab paired with chemotherapy rose by 4.1 months and 2.5 months, respectively.¹

Immune checkpoint blockade is now used as a first- or second-line treatment for a variety of malignancies, but it is still difficult to determine which patients would benefit the most. Because of its link to improved response rates to PD-1/PD-L1 blockage in patients with metastatic TNBC, PD-L1 expression is commonly employed as a prognostic biomarker.² In patients with metastatic TNBC treated with immune checkpoint inhibitor monotherapy or, in some circumstances, a chemotherapeutic combination, higher PD-L1 positivity has been linked to greater overall response rates, progression-free survival, and overall survival. These findings underscore the need for less confusing, more repeatable immune checkpoint inhibitor prediction indicators.²

Despite this progress, there is still more to be studied. The clinical benefit is minimal. Only approximately 40% of TNBC tumors are PD-L1 positive, and immunotherapy is still not licensed for advanced PD-L1–negative TNBC, HER2-positive breast cancer, or estrogen receptor–positive breast cancer.¹ In breast cancer, it is conceivable that redundant immune suppression mechanisms are active, or that key immune activation pathways remain mute.¹ Studies are investigating how dual immune checkpoint inhibition, bispecific antibodies, and antibody–drug conjugates can be used to target several pathways of immunoregulation in metastatic breast cancer.¹

References

1. Roussos Torres ET, Emens LA. Emerging combination immunotherapy strategies for breast cancer: dual immune checkpoint modulation, antibody-drug conjugates and bispecific antibodies. Breast Cancer Res Treat. 2021 Oct 30. Epub ahead of print.
2. Thomas R, Al-Khadairi G, Decock J. Immune checkpoint inhibitors in triple negative breast cancer treatment: promising future prospects. Front Oncol. 2021;10:600753.