Immunotherapy Combos, Immune Agonists Part of Future TNBC Paradigm

Hope Rugo, MD

The role of immunotherapy is slated to become more refined in triple-negative breast cancer (TNBC), as phase III data showcasing the combination of a checkpoint inhibitor with chemotherapy are eagerly awaited, explained Hope S. Rugo, MD.

The phase III IMpassion130 trial, findings of which will be presented at the 2018 ESMO Congress, evaluated frontline treatment with the PD-L1 inhibitor atezolizumab (Tecentriq) combined with nab-paclitaxel (Abraxane) in patients with metastatic or unresectable locally advanced TNBC. Genentech (Roche), the developer of atezolizumab, reported in a news release that the regimen significantly reduced the risk of disease progression or death versus nab-paclitaxel alone.

IMpassion130 follows a phase Ib trial of the combination, which demonstrated a 66.7% overall response rate in the first-line setting.

Beyond immunotherapy/chemotherapy combinations, Rugo said checkpoint inhibitors added to PARP and CDK4/6 inhibitors are also under investigation, as well as studies focused on biomarkers and immune agonists.

“The field of immunotherapy in breast cancer is exploding,” said Rugo. “It is of great interest.”

OncLive^®: How would you describe the state of immunotherapy in TNBC?

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Breast Cancer, Rugo, professor of medicine, director of the Breast Oncology Clinical Trials Program, University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, discussed the highly anticipated studies of immunotherapy in TNBC and where the class of agents optimally fits in the landscape.Rugo: It is actually a really exciting area where we are learning more and more about predictors of response. It is enhanced by the recent press release for data that will be presented at the 2018 ESMO Congress from the IMpassion130 study. This trial looked at nab-paclitaxel as first-line chemotherapy for metastatic TNBC with either the checkpoint inhibitor atezolizumab or placebo. It was reported in the press release that it met its primary endpoint in terms of progression-free survival (PFS), and it was also reported that there were encouraging overall survival (OS) results in the overall population and in the PD-L1—positive subset. These are actually very exciting data that we expect to lead to the first checkpoint inhibitor approval for breast cancer.

That has led to, based on the lower response rates for single-agent checkpoint inhibitors in the second- or later-line setting, an interest in moving checkpoint inhibitors earlier into treatment, as well as an explosion of neoadjuvant, adjuvant, and post-neoadjuvant trials as well. [It has led us to] look at what agents we can use as immune enhancers, such as agonists—whether that is standard chemotherapy or radiation therapy. There is one trial—the TONIC trial—that looked at a burst of little agents and found that doxorubicin, given in 2 doses, seemed to enhance the response to a checkpoint inhibitor. These are small data being tested now in a larger trial. There are other antibodies being tested as either an initial lead-in or a lead-in followed by a combination. It may be that the [sequence] is important; all of these are under active investigation.

There are studies looking at checkpoint inhibitors combined with other agents in hormone receptor (HR)-positive disease, such as CDK4/6 inhibitors, which has very big interest based on fascinating preclinical work. Then, in HER2-positive disease, there are a number of studies looking at combinations with checkpoint inhibitors.

The thing we are going to learn in addition to the right combinations is whether there are specific biomarkers—whether it is PD-L1 positivity, tumor-infiltrating lymphocytes (TILs), or other factors that help us understand who responds [to immunotherapy]. The one thing I have definitely learned is how the cancer becomes more resistant to therapy and has a higher tumor mutational burden (TMB), or potentially [has] more mutations in the wrong pathways. They become more resistant to immunotherapy along with everything else. We need to be tackling treatment earlier.

Our neoadjuvant data in the I-SPY trial was really encouraging with a tripling of the pathologic complete response (pCR) rate in the TNBC population, and a near tripling in the pCR rate in the HR-positive, high-risk population. This was when pembrolizumab (Keytruda) was combined with neoadjuvant paclitaxel, then followed by cyclophosphamide and doxorubicin (AC). Therefore, our next-generation studies have actually included the idea of enhancing the immune response by adding the PARP inhibitor olaparib (Lynparza) with the checkpoint inhibitor durvalumab (Imfinzi) and paclitaxel.

It also brings up the question of, “If a patient has a great response to pembrolizumab and paclitaxel, do patients really need an anthracycline?” The idea is that patients who are responding to pembrolizumab and paclitaxel will get 4 more doses of pembrolizumab, not get AC, and see what their response is at the time of surgery. There are a lot of areas of investigation there.

What immunotherapy combinations have the most promise?

What is the goal of immunotherapy in TNBC?

Some studies have shown less of a dramatic response to neoadjuvant checkpoint inhibitor, but a lot of it has to do with the patient population that is selected and how the pCR is defined and reported.The first combinations that will be approved [will be] with chemotherapy and are certainly the easiest. The next generation of trials with pembrolizumab and atezolizumab will look not only at nab-paclitaxel and paclitaxel, but also gemcitabine and carboplatin, so that will be interesting. The next-generation combinations are immune agonists—sort of a short induction chemotherapy or radiation exposure, and then [there will be combinations with] novel targeted agents, such as PARP inhibitors or CDK4/6 inhibitors and other agents.The goal of any treatment for TNBC, or any breast cancer subset, is to cure more patients with that cancer so they don’t develop metastatic disease. For the metastatic population, [the goal is] to help people live as long as possible. Therefore, survival is a key endpoint. In the neoadjuvant and adjuvant settings, our goal is to cure more cancer.

What are the selection criteria for immunotherapy, and how could it evolve over the years?

To me, any TNBC bigger than 1.5 cm should be treated in the neoadjuvant setting, because it is only then that we can estimate prognosis and treat patients based on their own tumors’ response. [That might involve] giving everybody a checkpoint inhibitor upfront, but maybe we don’t need to do that. Perhaps we need to select the patients who aren’t having a fabulous response and treat those patients with a checkpoint inhibitor—we don’t really know yet. We have to do sequential therapies with a goal of pCR to really understand that.Right now, we are waiting for the IMpassion130 data to be presented. There will also be neoadjuvant data with atezolizumab and pembrolizumab that you’ll hear a lot more about in little bits and pieces.

However, there will be data with atezolizumab from Dr Elizabeth Mittendorf that has a robust correlative aspect as well. We also have correlative studies in our I-SPY network and in the pembrolizumab studies, so we are going to see a lot of data coming back. A lot of that is going to be driven by whatever biomarkers predict response in IMpassion130. Certainly, TILs and PD-L1 are the major markers that we are looking at. In some ways, it will be a lot easier to use PD-L1 to select patient tumors that are most likely to respond if they express PD-L1. [This is] rather than TILs, which are more of an immune host response, which require more effort and are difficult to standardize. Nonetheless, it may be that both of these characteristics are important. It is a great unknown.

Adams S, Diamond J, Hamilton E, et al. Safety and clinical activity of atezolizumab (anti-PDL1) in combination with nab-paclitaxel in patients with metastatic triple-negative breast cancer. In: Proceedings from the 2015 San Antonio Breast Cancer Symposium; December 8-12, 2015; San Antonio, Texas. Abstract P2-11-06.