Immunotherapy is emerging as a new treatment option in breast cancer, with improved understanding of immune evasion by cancer cells and the discovery of selective immune checkpoint inhibitors creating novel opportunities for treatment.
Single-drug therapies with monoclonal antibodies against programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) have shown little efficacy in patients with metastatic breast cancer, in part because of the low number of tumor-infiltrating lymphocytes (TILs) in most breast cancers. That led researchers to design trials of combinations of immunotherapy and molecularly targeted therapies for metastatic breast cancer.
Currently, there are two immunotherapies approved by the Food and Drug Administration to treat breast cancer. The first is the anti-PD-L1 antibody atezolizumab combined with nab-paclitaxel in patients with metastatic triple-negative breast cancer (TNBC) that cannot be removed by surgery. Atezolizumab is approved only for breast cancers that test positive for the PD-L1 protein. The anti-PD-1 antibody pembrolizumab is approved to treat metastatic cancer or cancer that cannot be removed by surgery and that has microsatellite instability-high or DNA mismatch repair deficiency.
"We have had an initial success for immunotherapy in breast cancer that has led to FDA approvals," Elizabeth Mittendorf, MD, PhD, of Dana-Farber/Brigham and Women's Cancer Center in Boston, told the Reading Room. "Many ongoing trials are investigating other strategies to include combining immuno-oncology with targeted agents -- for example, PARP inhibitors in patients with BRCA mutations, which are based on strong preclinical data and have shown encouraging preliminary results. There is tremendous excitement in the field."
Mittendorf and co-authors wrote a recent review of clinical trials conducted to date evaluating immunotherapeutic agents and strategies in breast cancer, as well as ongoing studies and the preclinical and clinical rationales for immunotherapy in breast cancer.
Initially, TNBC was chosen for investigation for several reasons, Mittendorf explained: "There is a clinically unmet need for TNBC treatment and it is the most immunogenic of the different subtypes of breast cancer -- that is, it has the most TILs. This suggests that an endogenous immune response could be augmented with immunotherapeutic agents, such as checkpoint blockade."
The clinical trial that led to the approval of atezolizumab plus nab-paclitaxel in patients with metastatic TNBC enrolled patients in the first line. "Additional trials are evaluating immuno-oncology strategies in this same population," she said.
The study examined the addition of atezolizumab to a standard chemotherapy with protein-bound paclitaxel in 902 patients with metastatic TNBC who had not previously received treatment for their cancer. The results showed that adding immunotherapy to chemotherapy prolonged progression-free survival for a PD-L1-positive subgroup of patients. Adverse events were consistent with the known safety profiles of each agent. This treatment combination was approved by the FDA in March 2019.
Managing Side Effects
One of the challenges of immunotherapy is the potential for substantial side effects, including life-threatening ones, noted Norah Lynn Henry, MD, PhD of the University of Utah, Charles L. Loprinzi, MD, of the Mayo Clinic, and Lidia Schapira, MD, of Stanford University, writing on ASCO's Cancer.Net about whether to consider immunotherapy as an option in breast cancer.
They noted that the most common immunotherapy side effects are skin reactions, such as redness and blistering, and flu-like symptoms, including fever, nausea, weakness, and body aches. Different types of immunotherapy can cause different side effects.
Mittendorf said although managing the side effects of immune checkpoint blockade agents has been a concern, clinicians are becoming more familiar with managing these agents now that more of them are being approved for more indications.
"In breast cancer, the approval and success of therapy in the metastatic setting has led to increased enthusiasm for investigating these agents in earlier-stage disease to include the neoadjuvant setting," she added. "In this before-surgery setting, in which a number of patients will be cured with standard therapies, there is increased concern about the potential toxicity we could be introducing."
She noted that other immuno-oncology strategies, such as chimeric antigen receptor T-cell therapy, are associated with different toxicities, but these strategies are not being investigated in breast cancer at this time.
The Cancer.Net piece noted that another challenge is the high cost, which insurance companies may not cover.
Researchers are starting to get some clues from clinical trials about which patients may benefit from immunotherapy. "Immunotherapy may be more likely to work in people whose breast cancer has more gene mutations or whose tumor cells have higher levels of PD-L1. In addition, there is some information that suggests immunotherapy may work better if it is given early during treatment," wrote Henry, Loprinzi, and Schapira, who also have editorial positions with Cancer.Net as associate editor for breast cancer, associate editor for psychosocial oncology, and editor in chief, respectively.
Mittendorf noted that new information about breast cancer immunotherapy is expected in the near future from ongoing clinical trials being conducted across the U.S. and around the world to evaluate combinations with immunotherapy drugs. "The breast cancer community is anticipating the reporting out of data from other large trials evaluating immune checkpoint blockade plus chemotherapy in patients with metastatic TNBC, as well as in earlier stage patients with TNBC who are receiving these agents in the neoadjuvant setting prior to surgery," she said.
More research is needed to determine which types of breast cancers are most likely to respond to combinations with immunotherapy. "Outside of that approval -- of atezolizumab plus nab-paclitaxel -- breast cancer patients should be considered for immunotherapy if they are potentially eligible for a clinical trial evaluating an immunotherapy agent," said Mittendorf.
Mittendorf reported financial relationships with AstraZeneca, EMD Serono, Galena Biopharma, Genentech/Roche, Merck, Peregrine Pharmaceuticals, SELLAS Life Sciences, TapImmune, and the Physician Education Resource.
Source : https://www.medpagetoday.com/reading-room/asco/immunotherapy/80019