Immunotherapy Builds Momentum in Metastatic TNBC

Aditya Bardia, MD, MPH

Among treatment approaches, immunotherapy has generated the most excitement in metastatic triple-negative breast cancer (TNBC), having shown a frontline improvement in overall survival (OS), explained Aditya Bardia, MD, MPH. Now, researchers are looking for ways to extend the benefit of these agents.

“There are many exciting agents in metastatic TNBC,” said Bardia, an assistant professor of medicine at Harvard Medical School. “Hopefully, over the next few years, we'll continue to push the survival curves.”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Breast Cancer, Bardia, who is also an attending physician, Medical Oncology, at Massachusetts General Hospital, discussed the recent momentum in metastatic triple-negative breast cancer (TNBC) treatment.

OncLive: How has the management of metastatic TNBC changed in recent years?

Bardia: Over the past few years, there has been a change in the management of metastatic TNBC, particularly with regard to first-line therapy. The IMpassion130 trial demonstrated that the addition of the PD-1 inhibitor atezolizumab (Tecentriq) to nab-paclitaxel (Abraxane) resulted in improvements in not just progression-free survival (PFS), but also OS. This is the first time we saw an improvement in OS with a first-line agent in TNBC, which was very exciting. We had been waiting for immunotherapy to enter breast cancer. Now, we have an [immunotherapy] drug that we can use for patients with metastatic TNBC.

[In my presentation], I reviewed the rationale for immunotherapy as well as the data behind the approval of atezolizumab. I also covered targeted therapies, including AKT inhibitors, which are being tested in a subset of patients with TNBC—specifically, in tumors that have an upregulation in the PI3K/AKT/mTOR pathway.

Finally, I reviewed antibody-drug conjugates (ADCs); there's a lot of excitement with newer ADCs, including sacituzumab govitecan, ladiratuzumab vedotin (SGN-LIV1A), as well as [fam-] trastuzumab deruxtecan (DS-8201).

What is the rationale for immunotherapy in TNBC? Could you discuss the impact of the atezolizumab approval?

We generally use the term “immunotherapy” synonymously with “PD-1/PD-L1 inhibitors,” but immunotherapy could encompass any agent that targets the immune system; that could be PD-1/PD-L1, OX40, or LAG-1. You could even argue that CAR T cells fall under the bucket of immunotherapy. I focused on PD-1/PD-L1 inhibitors because those are the agents that have been FDA approved for use in solid tumors. In TNBC, atezolizumab is the only agent that has been approved, but there is interest in other PD-1/PD-L1 inhibitors as well, such as pembrolizumab (Keytruda), nivolumab (Opdivo), and durvalumab (Imfinzi).

The rationale for immunotherapy is that a subset of patients with TNBC express PD-1, and PD-1 is an antigen that puts the brakes on the immune system; this allows activated T cells to attack the cancer cell. When PD-1 is upregulated, [T cells] are unable to attack the cancer cells because it acts as a break for the activated T cells; it tells them not to attack any specific cell that expresses that antigen. With the use of a PD-1/PD-L1 inhibitor, you take that break away, allowing the activated T cells to attack the cancer cell. [The cancer cell] is considered foreign by the T cell because it expresses a number of neoantigens.

However, T cells need to be activated for immunotherapy to work; it needs to be a "hot" tumor. For PD-1 inhibitors to work, the immune microenvironment should express PD-1. If PD-1 is the mechanism by which the T cell is not able to attack the tumor cells, taking that away would induce [antitumor] efficacy. If there's some other mechanism that’s not dependent on PD-1, there's no point in using a PD-1/PD-L1 inhibitor. This is why the approval of atezolizumab is indicated for patients with a PD-L1 expression of 1% or higher.

Could you discuss the phase III KEYNOTE-119 trial with pembrolizumab?

There has been a lot of buzz related to KEYNOTE-119. This trial looked at pembrolizumab monotherapy versus chemotherapy in previously treated patients. Most trials in breast cancer are combining chemotherapy with immunotherapy. The bar was set very high. It was an unstratified patient population; anyone with metastatic TNBC was eligible to enroll. The press release reported that there was no improvement in OS with immunotherapy versus chemotherapy. We were not very surprised because it would be very difficult for single-agent immunotherapy to do better than chemotherapy, particularly in pretreated patients.

We know from prior studies that response to immunotherapy goes down in pretreated patients; that may be because some of the T cells get affected by chemotherapy. Even if the T cells had been activated, the chemotherapy could take that away, leaving no T cells to attack the tumor. Even if you take the breaks away, we wouldn’t have the ammunition or the T cells to attack the tumor. In general, the response to immunotherapy is lower in later lines of therapy; it's highest in the first-line setting.

The real excitement for immunotherapy is in early breast cancer. Specifically, in the neoadjuvant and adjuvant setting where the response to immunotherapy is likely going to be higher than what we've seen in the metastatic setting. However, immunotherapy is also associated with several adverse events. We treat patients with early breast cancer with curative intent, so you have to be very careful about managing immune-related adverse events (irAEs).

What is your advice for effectively managing these irAEs?

irAEs are different from what we've seen with chemotherapy. With chemotherapy, the common AEs include hair loss, nausea, vomiting, and drop in counts. The events from PD-1/PD-L1 inhibitors manifest from T cells attacking normal cells in the body. Our body has PD-1 as a mechanism to prevent activated T cells from attacking the normal cells. If there’s an imbalance, T cells can attack normal cells.

The common irAEs that have been reported with immunotherapy include an increase in liver enzymes by impacting the hepatocytes, as well as diarrhea, colitis, or other gastrointestinal issues, and endocrinopathies, including impact on the thyroid gland and the adrenal gland. Additionally, there can be an impact on the lungs that can cause pneumonitis. There’s a similar mechanism by which activated T cells can affect the lung parenchyma.

Finally, myocarditis is a rare but very serious irAE where immunotherapy can cause swelling of the myocardium. We have seen deaths from myocarditis as a result of immunotherapy. We have to be very careful with irAEs. In general, early recognition is key. Most irAEs are responsive to steroids. If you recognize the irAE early and initiate steroids, you can pretty much manage the events.

Could you expand on some exciting ongoing trials?

There are several trials in the first-line setting looking at immunotherapy with chemotherapy. Additionally, there are trials that are building on the backbone of nab-paclitaxel and atezolizumab with a third agent—most notably, PARP inhibitors. It's believed that PARP inhibitors and immunotherapy agents could be very synergistic. There are trials looking at the concept of maintenance immunotherapy or maintenance immunotherapy and PARP inhibition following 4 to 6 cycles of first-line chemotherapy. That could be a game changer in breast cancer. It's a concept that's used in ovarian cancer but has not been used in breast cancer before.

Targeted therapies are also exciting for a subset of patients. The combination of AKT inhibitors with chemotherapy is being studied in a phase Ib trial. One arm of the trial is testing the combination of a PD-L1 inhibitor with an AKT inhibitor and chemotherapy.

We’re also looking at ADCs. We're awaiting the results from the ASCENT trial, which is looking at sacituzumab govitecan versus chemotherapy in the third- or later-line setting. There are several planned ADC-based combination trials. There is a lot of excitement in the field of metastatic TNBC. Over the next 3 to 5 years, some of these trials will read out and could potentially change the landscape.

What key challenges need to be addressed with future research?

The second challenge is understanding the racial disparities related to TNBC. For years, we've known that African Americans have a higher incidence of TNBC, but we don’t know why. If we can understand the molecular underpinnings, we can develop specific therapies that can target that.

Finally, we need to develop biomarkers. There's no end to potential combinations. We need to be guided by biomarkers and by tumor biology, not just for selection but also monitoring. If we wait for the scans to show progression, it’s too late. We need early and sensitive biomarkers so that we can change therapy if a patient is not responding to a certain regimen.

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One key challenge is defining TNBC. Currently, it's a definition of exclusion; it's defined by tumors that do not express the estrogen receptor, progesterone receptor, or HER2. However, TNBC is a mixed bag in which you can have tumors that are basal versus those that are luminal but are still triple-negative. Tumors that express the androgen receptor would be more on the luminal side but are still called triple-negative.