Immunotherapy's Role in TNBC May Be in Combination

Hatem Soliman, MD

Immunotherapy has had a challenging journey breaking through the breast cancer treatment landscape. Recently, responses have been seen in some patients with triple-negative breast cancer (TNBC), signaling a potential role for immunotherapy in this tumor type.

TNBC is a heterogeneous group of breast cancer that is made up of several subtypes. It is traditionally defined as breast cancer with <1% staining of estrogen receptor and progesterone receptor, and it is negative for amplification or overexpression of HER2.

Hatem Soliman, MD, a medical oncologist specializing in breast cancer at The Center for Women’s Oncology at Moffitt Cancer Center, says that calling this entire group of patients as having TNBC is an “oversimplification.” The majority of these patients have invasive ductal carcinoma, but there are also patients with lobular, metaplastic, and adenoid cystic carcinoma, and each of these subtypes has its own real-world therapeutic implications.

“It also seems like TNBC is enriched [with] the types of breast cancers that are likely going to respond to immunotherapy. Many of these tumors tend to be under-infiltrated by immune cells and tend to be relatively bland immunologically,” said Soliman during a presentation at the 2018 OncLive^® State of the Science Summit^TM on Breast Cancer.

However, a TNBC subset exists that is heavily infiltrated with lymphocytes and is already inflamed and activated—the subset just needs to be identified, he added. This group represents patients who will respond more favorably to immunotherapy, particularly checkpoint inhibitor monotherapy. Although response rates hover around 20%, these signals of activity serve as proof-of-concept data that can be built on to target a particular patient population, said Soliman.

The most predominant biomarker for immunotherapy is PD-L1 staining in the tumor. Those that stain for PD-L1 are believed to be the most inflamed tumors and the ones that will be the most responsive to checkpoint inhibitors. Soliman explained that investigators are seeking ways to potentially identify other molecular markers for selecting patients for immunotherapy.

“At Moffitt [Cancer Center], we have been looking at chemokine signatures,” said Soliman. “We were able to demonstrate that breast cancers that have a very high chemokine score tend to attract very high numbers of these aggregates of lymphocytes within their tumor tissue. These tumors are highly inflamed, and they tend to be clustered—more so in tumors that are high-grade, triple-negative, and HER2-positive versus chemokine-low tumors that are very bland and don’t have a lot of lymphocytes in them.”

Using immunotherapy earlier in the treatment course may be beneficial. If immunotherapy is given in the third- or fourth-line setting, a patient’s immune system may be too weak as a result of prior multiple systemic therapies. Data supporting this idea are early but compelling, Soliman said.

Additionally, combinations with immunotherapy may be better approaches than monotherapy, Soliman explained.

“Only a minority of patients are going to respond to monotherapy with checkpoint treatment,” he said. “We don’t think that is the path going forward. It is probably likely that we will have to use a series of rational combinations to prime the tumor, to get it more stimulated. Then, we follow up with a checkpoint inhibitor to see if it will sustain the benefit and keep up the immune attack on the tumor.”

Researchers are exploring immunotherapy in combination with chemotherapy; chemotherapy can have immune-stimulating properties if it is dosed in the appropriate schedule.

One ongoing trial is testing the combination of pembrolizumab (Keytruda) and eribulin (Halaven; NCT03051659). Early results showed an overall response rate of 33.3%, higher than what is historically seen with eribulin monotherapy. Atezolizumab (Tecentriq) with nab-paclitaxel (Abraxane) is being studied in 2 trials: One is investigating nab-paclitaxel with or without added atezolizumab in the frontline setting (IMpassion130; NCT02425891), and the other is examining paclitaxel with or without atezolizumab (IMpassion131; NCT03125902) for patients with no prior therapy for metastatic or locally advanced disease. Low-dose brief induction with chemotherapy followed by nivolumab (Opdivo) has shown encouraging response rates in TNBC, as well.

Soliman adds that ongoing work is combining immunotherapy with other biologics. The subsets of TNBC that are very susceptible to DNA-damaging agents may also respond to immunotherapy. Additionally, PARP inhibitors may be combined with other sensitizing agents to increase damage to tumor DNA, and targeting TNBC-enriched surface proteins with antibody—drug conjugates also appears to be an effective method. Currently, the maker of the antibody–drug conjugate sacituzumab govitecan (IMMU-132) is seeking an accelerated approval from the FDA.

“Immunotherapy has modest activity in a select group, but we do need to improve our patient selection and use sequential or combination approaches to sensitize tumors,” Soliman concluded.