IMpassion130 Trial Takes Immunotherapy to Forefront of TNBC

Eleni Andreopoulou, MD

Findings from the phase III IMpassion130 trial, which demonstrated that atezolizumab (Tecentriq) combined with nab-paclitaxel (Abraxane) improved progression-free and overall survival (OS) in triple-negative breast cancer (TNBC), are changing standard practice, explained Eleni Andreopoulou, MD.

The 2-year OS rate in all patients was 42% for nab-paclitaxel/atezolizumab versus 39% for nab-paclitaxel/placebo. The 2-year OS rate was higher in the PD-L1—expressing population at 51% in the atezolizumab arm versus 37% in the placebo arm. The median progression-free survival (PFS) was 7.2 months versus 5.5 months in all patients with atezolizumab and placebo, respectively; it was 7.5 months versus 5.0 months in PD-L1–expressing patients.

Following these data, immunotherapy arrived as a treatment option for patients with metastatic TNBC, specifically for those with a PD-L1 expression of ≥1%, when it was approved by the FDA in March 2019.

"Now, with immunotherapy on board, we have a fifth modality in treating breast cancer in addition to surgery, chemotherapy, radiation therapy, and biologic treatment. For TNBC in particular, this is a significant step forward," said Andreopoulou, the Madeline and Stephen Anbinder Clinical Scholar in Hematology/Oncology, Medicine, associate professor of clinical medicine, Weill Cornell Medicine. "In the setting of TNBC, we're hoping that we see the implementation of immunotherapy at the very early stages, particularly in the neoadjuvant and adjuvant setting, where our goal is to cure the disease."

In an interview during the 2019 OncLive^® State of the Science Summit™ on Breast Cancer, Andreopoulou discussed the impact of the IMpassion130 trial on TNBC treatment and the use of immunotherapy in this patient population.

OncLive: How would you describe the use of TNBC treatment?

Andreopoulou: In our clinical practice, we're facing challenges with treating patients with advanced TNBC. Unfortunately, we are very limited in terms of options, with chemotherapy being the mainstay of treatment for a long time. Technology has enabled us to elucidate the biologic heterogeneity of breast cancer and gives us a better insight of the molecular underpinning of the disease, including TNBC. We also recognize that TNBC is heterogeneous itself. We are pleased to see that some subtypes have been well-defined. This has been extremely crucial because it gives us an opportunity to focus on druggable targets, which are indicated in driver pathways for this disease.

We have been also focusing on addressing the hallmarks of cancer. We have been very excited recently to see the extremely encouraging results from IMpassion130, the first phase III randomized clinical study to show that the addition of the PD-L1 checkpoint inhibitor atezolizumab in combination with nab-paclitaxel has benefit in terms of PFS and extending OS. It is opening a new avenue for the treatment of TNBC and shifting our practice to a new direction.

Additionally, there are many ongoing clinical studies addressing the effectiveness of immunotherapy. We have learned immunotherapy could potentially be effective at earlier stages of the disease when tumors are more immunogenic. TNBC is a subtype of breast cancer where there is potential [for] immunotherapy, given the immunogenic status.

What is the future of immunotherapy in this disease?

I believe there is potential for immunotherapy to become the future backbone of the disease. Tumor cells are starting to escape in surveillance by developing a “cloak;” they go invisible. Therefore, the discovery of the molecules with checkpoint inhibitors is the first step forward on addressing the importance of our immune system in controlling tumorigenesis, the development of breast cancer, and the progression of the disease.

In IMpassion130, the PFS and OS benefit was mainly seen in PD-L1—positive patients. Could further combinations with chemotherapy, targeted therapy, and PARP inhibitors extend immunotherapy's reach?

PD-L1 expression in the immune cells of 1% or more has been established as the biomarker through IMpassion130. The combination with modality therapy aims to increase immunogenicity and right there the tumors [are hotter]. As the disease progresses in a very dynamic way, it's adapting and what we potentially recognize as an integral part of this evolution is immunoediting, where the tumors become less immunogenic as the refractory heterogeneous clones continue to evolve and progress.

What clinical trials are you looking forward to seeing the results of?

Clinical trials of interest in the immunotherapy space are the ones that are investigating the role of checkpoint inhibitors at earlier stages of disease in the adjuvant and neoadjuvant setting, where our goal is to cure. Of particular interest to me is the SWOG S1418 study, which is exploring the role of immunotherapy in patients with TNBC who have received primary chemotherapy in the neoadjuvant setting with suboptimal outcome and high residual cancer burden.

We do recognize that these patients with significantly lower residual disease are at a higher risk for relapse. Up until now, there is no available treatment in the adjuvant setting for these patients except the option of capecitabine. The role of immunotherapy might give us an option to address micrometastatic disease, with these possibly inflected in the context of high-volume residual disease. It's a high priority to bring effective treatment in the clinic in order to cure patients with TNBC.

How is PD-L1 expression correlated with response in TNBC treatment?

The essence of personal medicine is being in a position to select treatment that addresses the tumors. Our main focus is to define the biomarkers of effectiveness because this will enable us to select patients appropriately.

At Weill Cornell Medicine, our breast center works very closely with the Englander Institute for Precision Medicine. We are focusing on addressing the disease longitudinally and getting snapshots of the evolution of the disease through the evolutionary lineage. Breast cancer is undoubtedly a very complex disease.

Recognizing the complexities—heterogeneity as well as the continuous evolution with acquired mutations, through the process and the history of the disease progression—is extremely important. We're focusing on utilizing the results of sequencing on selecting appropriate and approved treatment, but also channeling our patients on high priority studies and matching the results with vulnerabilities with investigational therapies. High priority is the NCI-MATCH study. We are enrolling on this study and we're at the forefront with precision medicine.

What are some advancements with PARP inhibitors in the TNBC setting?

Another area of significant interest in addressing TNBC is the role of PARP inhibitors. Exploiting the concept of synthetic lethality for patients who germline BRCA1/2 mutations. There are already 2 PARP inhibitors approved for the treatment of patients with advanced breast cancer with germline mutations. The OlympiAD study and the EMBRACA have shown improvement in PFS with acceptable safety profiles. These give us more options for our patients.

Schmid P, Adams S, Rugo HS, et al. IMpassion130: updated overall survival (OS) from a global, randomized, double-blind, placebo-controlled, phase III study of atezolizumab (atezo) + nab-paclitaxel (nP) in previously untreated locally advanced or metastatic triple-negative breast cancer (mTNBC). J Clin Oncol. 2019;37(suppl; abstr 1003). doi: 10.1200/JCO.2019.37.15_suppl.1003