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Immunotherapy Combos, Immune Agonists Part of Future TNBC Paradigm

Gina Columbus @ginacolumbusonc
Published: Tuesday, Oct 09, 2018

Hope Rugo, MD

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.”

In an interview during the 2018 OncLive® State of the Science SummitTM 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.

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

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.


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