Immunotherapeutic Agents Expand Treatment Landscape for Triple-Negative Breast Cancer

Elizabeth Mittendorf, MD, PhD

Patients with advanced or metastatic PD-L1—positive triple-negative breast cancer (TNBC) can now be treated with the FDA-approved combination of atezolizumab (Tecentriq) plus nab-paclitaxel (Abraxane) in the frontline setting, based on data from the phase III IMpassion130 trial (NCT02425891). According to Elizabeth Mittendorf, MD, PhD, this is a monumental improvement for the treatment of patients with TNBC.

The addition of the PD-L1 inhibitor with nab-paclitaxel reduced the risk of disease progression or death by 40% compared with the chemotherapy alone in the IMpassion130 trial. The median progression-free survival (PFS) with the combination versus the monotherapy was 7.4 months versus 5.0 months (HR, 0.60; 95% CI, 0.48-0.77;P<.0001), and the 1-year PFS rate was 29% (95% CI, 22%-36%) versus 16% (95% CI, 11%-22%), respectively. These&nbsp;results led to the FDA&rsquo;s decision to approve this treatmentin March 2019.

At the 2019 San Antonio Breast Cancer Symposium (SABCS), two key topics of discussion were immunotherapeutic options and how to sequence these treatments. A number of presentations included data for immunotherapy options, as well as targeted agents and other treatments for patients with TNBC, such as a phase I/II study (NCT02489448) that demonstrated promising responses with neoadjuvant durvalumab (Imfinzi).

According to theposter presentation at SABCS, the addition of neoadjuvant durvalumab tonab-paclitaxel (Abraxane) and the AC regimen of doxorubicin and cyclophosphamide inpatients with TNBC led to a 44% rate of pathologic complete response (pCR; 95% Cl, 30%-57%). Forty-six percent of patients, 26 out of 59 in the phase II portion of the study, achieved a pCR after completing surgery. The pCR rate was also 59% in patients who were PD-L1—positive (95% Cl, 0.39-0.76), and 32% with PD-L1&ndash;negative disease (95% CI, 0.12-0.56).

In an interview withTargeted Oncology, Mittendorf, director of the Breast Immuno-Oncology Program at Dana-Farber/Brigham and Women's Cancer Center, discussed the highlights from the 2019 SABCS for the treatment of patients with TNBC, as well as those withHER2-positive breast cancer. She also shared her thoughts on the key takeaways from the 2019 meeting.

TARGETED ONCOLOGY: What did you discuss at the 2019 SABCS, and what else is important to highlight from this meeting?

Mittendorf:This wasamomentous year for the field of breast cancer because we had an FDA approval for an immunotherapeutic agent, specifically atezolizumab with nab-paclitaxel in patients with metastatic TNBC. This comes on the heels of the IMpassion130 trial that had been published in late 2018. If you go through the numbers of how many patients are diagnosed every year, how many have triple-negative disease, and how many recur, there are only about 23,000 patients that are going to have metastatic TNBC annually. Of that, only about 8,755 would be eligible for this combination therapy because of their PD-L1 status. The question is, how do we make immunotherapy work in other tumor types, in tumors that are PD-L1—negative, or in patients who are not responding to that combination.

We discussed several strategies were based on improved understanding of the cancer immunity cycle. Tumors must release antigens, and those antigens must be presented to T cells, which are then stimulated, and then move to and into the tumor. Once there, they have to actually kill. We talked about ways in which we can use therapeutic strategies to enhance the different nodes of the cancer immunity cycle. One of the things we focused on was what our standard of care therapies are doing. We talked about immunogenic cell death induced by some therapeutic agents and how that may be why the combination of atezolizumab plus nab-paclitaxel works.

We also focused on 3 of our more commonly used targeted therapies in breast cancer. CDK4/6 inhibitors have shown increased antigen presentation, so that would not suggest a response to atezolizumab. This may mean it should be combined with immunotherapy. We spoke about PARP inhibitors, and there is a whole body of literature now showing PARP inhibitors augment what is referred to as an innate response to the STING pathway. That should also lead to an immune response that you can drive further by combining with immunotherapy. We also spoke about trastuzumab (Herceptin), which is a monoclonal antibody we have used in breast cancer for a long time now. In some ways, it actually could be considered 1 of the first successful immunotherapeutics because 1 of its major actions is through antibody-dependent cellular toxicity. We spoke about a few strategies to enhance that [treatment].

TARGETED ONCOLOGY: With emergence of immunotherapy in breast cancer, how is it effecting sequencing of treatments?

Mittendorf:That is a question that we are asking a lot and was asked several times during the meeting. The sequencing is critically important, and thereare[MOU3]&nbsp;preclinical data that shows if you look at an OX40 and PD-L1 combination, whether you sequence or give concomitantly, it is critically important, but the sequence matters as well. In 1 way, it works, and in another way, it doesn&rsquo;t. We have the same thoughts that we have to have in clinical practice. There is some interesting data that was presented by the German group at ASCO 2018 and published in 2019 that showed when they gave durvalumab before chemotherapy, patients had a little bit of a better response in respect to achieving or experiencing a pCR.

These are questions that we are all now aware need to be answered. It is going to take both laboratory-based work, likely animal models, and observations from appropriately designed clinical trials.

TARGETED ONCOLOGY: What is your main takeaway from your presentation?

Mittendorf:I believe we have to understand the tumor microenvironment, and we have to understand what our standard therapies do to that microenvironment. We have things that work in breast cancer, so we have to figure out how we can augment those therapies that work by adding immunotherapy. I think what we will learn in breast cancer is it is not going to be just T cells. We need to keep our minds open to the fact that there are other immune cell types that we may want to target.

TARGETED ONCOLOGY: What is your main take home message from the 2019 SABCS?

< < For more information from the 2019 San Antonio Breast Cancer Symposium.

Mittendorf:This was an exciting meeting with some interesting data presented to include in [our practice] This includes several trials looking at HER2-targeted agents that were presented. It is likely we will have some changes in our standard practice based on theHER2-positive stories. I think the additional data presented on the KEYNOTE522 of immunotherapy, pembrolizumab, in the early-stage, preoperative setting will potentially change practice. The take-home message from SABCS is to look at the data that is going to change the practice in theHER2-positive population, as well as the TNBC setting.