Emerging TNBC Agents Show Improved Patient Outcomes

Sylvia Adams, MD

The metastatic triple-negative breast cancer (TNBC) space, which typically has a short survival prognosis, is advancing through the introduction of novel treatment strategies, involving antibody-drug conjugates, PARP inhibitors, and immunotherapy, said Sylvia Adams, MD.

"The landscape is very much changing in TNBC," said Adams. "Up until 1 or 2 years ago, we only had chemotherapy. With that, the outcomes were dismal with, 1 year, or maybe one and a half years, for survival; but now we have new agents."

In an interview with OncLive^® during the 2019 State of the Science Summit™ on Breast Cancer, Adams, director of the Breast Cancer Center, professor of medicine, Perlmutter Cancer Center at the NYU School of Medicine, discussed the biology of TNBC, data sparking excitement in the field, and intriguing trials on the horizon.

OncLive: What is the role of immunotherapy in this space?

Adams: Immunotherapy is interesting because compared with any other therapies we have—chemotherapy, hormonal therapy, etc.—immunotherapy has the potential for cure because once you stimulate your immune system to fight the tumor, [your immune system] can [fight]. It also has immune memory so metastases that pop up later can potentially be killed with the power of the immune system. It can lead to cures or long-term disease control even in metastatic patients. That is very special. Learning how to harness an immune response against cancer and apply it to patients who otherwise have a short life expectancy is very exciting.

In TNBC, what work is being done with immunotherapy?

For the last 5 to 10 years, we have looked at different immunotherapies in breast cancer. We found that many women already develop an immune response to their cancers, especially in TNBC. If you look inside the tumor, there are cells ready to kill, except the tumor is outsmarting [the cells] by putting up an invisible shield. Using immunotherapy drugs, such as anti—PD-1/PD-L1 agents, we can take that shield down and enable [a patient's] own immune response to kill the tumor. That is pretty exciting.

Over several years, we have studied single-agent immunotherapies in TNBC in the metastatic setting. We have seen responses that are durable, though not yet in the number of patients or [a large enough] percentage to get us very excited. However, there is proof of concept that you can actually control these tumors for the long-term with immunotherapy unlike chemotherapy, which has very short responses. The initial studies were with single agents. Later, we developed combination trials that utilized some immune activities of regular chemotherapies combined with immunotherapy. Those have been quite promising.

The IMpassion130, the largest immunotherapy trial in this country and globally, randomized 900 women with metastatic TNBC in the first-line setting with standard chemotherapy with nab-paclitaxel (Abraxane) with or without immunotherapy. What we saw is that the time of the tumor [progression] is delayed by the combination. Also, in certain patients that carried that PD-L1 marker in the tumor, there is a survival improvement of up to 10 months. That is a significant number for women whose survival otherwise is less than 2 years. We are seeing the first promising results of immunotherapy in TNBC with the updated survival analysis from this second interim analysis of IMpassion130.

What did that second analysis show?

It showed that women with the PD-L1 marker in their tumor have a 7- to 8-month increase in survival, which is clinically significant. Many of those patients are very young women with children, so any additional months or year are very meaningful.

Beyond immunotherapy, PARP inhibitors also have a big role in the treatment of patients with BCRA mutations. Could you discuss some of these agents and their data?

PARP inhibitors are very interesting. They are a very special type of drug that attack the Achilles’ heel of certain tumors that are related to BRCA. These tumors are very vulnerable to these medications, so in breast cancer specifically, that arises in women who are BCRA1/2 carriers. There is efficacy using these drugs as single agents.

There are two drugs approved now in the United States. One is olaparib (Lynparza) and the other is talazoparib (Talzenna). They are approved for women who carry the BRCA mutation and have metastatic HER2-negative breast cancer. The OlympiAD and the EMBRACA studies looked at these drugs versus standard chemotherapy, which we are currently using, and showed that they are as least as good, if not even better in women who carried this gene with less toxicities. [The PARP inhibitors] are oral, which is quite important to patients, otherwise they must come in for intravenous chemotherapy.

The other key player in this space are the ADCs. Could you elaborate on the role of these agents in the paradigm?

The ADCs are very smart drugs because they use a carrier antibody that attacks or binds right to the cancer cell because of an antigen that the cancer cell exposes. Because of that direct targeting of tumor cells, the load of the antibody, which is a cytotoxic chemotherapy, can be directly deployed to the cell. Therefore, it decreases the general toxicity that we see with chemotherapy. It is very effective.

In TNBC, there are no ADCs yet approved. In HER2-positive breast cancer, we have an approved drug with ado-trastuzumab emtansine (T-DM1; Kadcyla) but in TNBC, there are several promising trials that we have conducted in this country and globally, which are promising because these were done in women who were already treated with prior chemotherapy and had disease progression. Now, with these new agents, there is less toxicity and the potential for longer responses in a good subset of patients, because most of those antigens are expressed in the majority of breast cancers.

Could you highlight some of these ongoing trials?

We have only seen results from very early studies in breast cancer—phase I/II trials in metastatic TNBC. These ADCs are targeting agents for antigens, such as LIV-1. The results are impressive because you can see response rates of 40%, which is unheard of. Chemotherapy in the second-line setting would give you a very tiny response rate. This is very exciting, and we are waiting on the results from the big, randomized, phase IIIASCENT trial that is looking at an ADC [sacituzumab govitecan] as a comparator with standard of care chemotherapy in metastatic TNBC.

What is your take home message to you colleagues?

We have targeted therapies including PARP inhibitors for women who have a BRCA mutation, but immunotherapy is really exciting because there are women who can have durable, potentially cures from metastatic disease [from immunotherapy]. I have seen several women in my practice who have been on [immunotherapy] trials for three or four years using just one injection every three or four weeks and they are cancer-free despite metastatic disease. We have more to look forward to with ADCs, there will be combination therapies and we will try to harness the power, both of the immune response and these ADCs. We will have more results and more hope in the near future.

Is there any exciting work that is being done specifically at your institution that you wanted to highlight?

At NYU, we have done a lot of the immunotherapy research for TNBC. I have led several trials, not just in the United States but globally, that contributed to the knowledge that we have so far. Single-agent immunotherapy can be effective in some women but combinations with chemotherapy and immunotherapy became the standard of care for women now in the first-line setting. I am very proud of those achievements but we are still not there. We still need to look at different combinations. We need to study more about the immune system in these patients to learn more and to come up with even smarter conversations.

Is there a particular study that you are excited to see the results of this year?

Yes, I am excited to see the results of MK-3475-522/KEYNOTE-522 where patients received chemotherapy plus immunotherapy before surgery to shrink down their tumor. It was a positive readout so it must mean that there are higher chances of complete pathologic response, meaning disappearing of the tumor, at the time of surgery. We know that those women typically have a much better survival chance.