Immunotherapy for triple-negative breast cancer

The FDA has granted accelerated approval for the combination of atezolizumab with nab-paclitaxel for locally advanced or metastatic triple-negative breast cancers that cannot be surgically resected and express programmed death ligand-1 (PD-L1).

Triple-negative breast cancers, which account for about 15% of breast cancers, lack detectable expression of three molecules- estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2 (HER2). Drugs targeting ER and HER2 are approved and available for subgroups of patients whose breast tumors express these molecules. However, few options outside of standard chemotherapy exist for patients with triple-negative breast cancer.

The majority of chemotherapy drugs target non-specific processes, such as DNA synthesis or cell division, which are increased in cancer cells but also occur in many normal cells. Because of this non-specific effect on normal cells, many chemotherapy drugs cause debilitating side effects, such as nausea, fatigue, hair loss, and increased risk of infection. In an attempt to improve tumor-targeting and reduce non-specific toxicities, cancer researchers have developed many classes of molecularly targeted agents, including those that target ER and HER2 as mentioned above.

Immunotherapy is a relatively new cancer therapy approach that attempts to stimulate the patient’s immune response against cancer cells. There are many types of immunotherapies in development or approved for other types of cancer. Atezolizumab is an antibody that targets a molecule called PD-L1, which is expressed on some cancer cells. PD-L1 normally interacts with a group of immune cells, inhibiting their function. By blocking PD-L1, atezolizumab disrupts cancer-immune cell interactions, theoretically allowing immune cells to function and kill cancer cells.

This week’s drug combination approval is based on results from a phase 3 trial of atezolizumab combined with the chemotherapy agent nab-paclitaxel (1). The trial included more than 900 patients with previously untreated metastatic triple-negative breast cancer. The combination showed a statistically significant increase in median progression-free survival of about 2 months, including among those with PD-L1-positive tumors, compared with the chemotherapy plus a placebo. Although this increase in progression-free survival may appear modest, metastatic triple-negative breast cancer currently carries a poor overall survival rate.

Progression-free survival is viewed as a potential marker of overall survival. The FDA grants accelerated approvals to agents that show promise based on a marker of clinical benefit, such as progression-free survival, in patients with serious diseases. Ongoing trials will seek to determine whether the combination successfully extends overall survival of patients with advanced or metastatic triple-negative breast cancer compared with chemotherapy alone.

(1) Schmid et al. N Engl J Med. 2018 Nov 29;379(22):2108-2121