Novel Combo Promising in Advanced HER2-Negative Breast Cancer

At the European Society for Medical Oncology (ESMO) virtual meeting, researchers presented the results of a study evaluating the combination of entinostat, nivolumab (Opdivo), and ipilimumab (Yervoy) in patients with advanced HER2-negative breast cancer. At the recommended phase II dose, this combined approach was associated with expected immune-related adverse events in advanced HER2-negative breast cancer.

In this exclusive MedPage Today video, study author Evanthia Roussos Torres, MD, of the Norris Comprehensive Cancer Center at the University of Southern California in Los Angeles, describes the background of the study and what is next to come.

Following is a transcript of her remarks:

Thank you for the opportunity to give you a summary of what we presented at ESMO. What we discussed was actually a study that was specifically for patients with breast cancer.

Just to give a little background, patients with breast cancer, the indications currently for immune checkpoint inhibition are somewhat limited to those who have high-risk, early-stage disease or metastatic triple-negative disease with high CPS [combined positive score] or high tumor mutational burden, so there’s a lot of improvement for expanded indications. So combination therapies have been studied as a way to prime the tumor micro-environment to improve response rates and clinical benefit from these agents. And we and others have investigated whether the epigenetic modulation using the histone deacetylase inhibitor entinostat could actually prime the tumor micro-environment and improve response to immune checkpoint inhibition. And our preclinical data supported this growing body of work that found that there was improved survival in preclinical models that were treated with entinostat and anti-PD-1 and anti-CTLA-4.

So this is what we used to base our design on a phase I trial to test the safety and novel combination in patients. And the first part of the clinical trial was in advanced solid tumors. And what we presented at ESMO is actually the results from our planned expansion cohort in patients with HER2-negative breast cancer.

So in this dose expansion cohort, patients with advanced HER2-negative breast cancer did not have prior exposure to immune checkpoint inhibition. They were treated with a recommended phase II dose, which included 5 mg of weekly entinostat for a 2-week run-in period, and then 3 mg/kg of nivolumab every 2 weeks and 1 mg/kg of ipilimumab every 6 weeks.

And we had done blood and tissue biopsies collected prior to the entinostat run-in, after the 2-week run in, and then at 8 weeks after the addition of checkpoint inhibition.

So we had 18 patients from the dose expansion cohort, and then six patients that we included with breast cancer from the dose escalation cohort, to bring us to a total of 24 patients who received the combination of entinostat plus nivolumab and ipilimumab. The patients enrolled were about 55 years old, half of them had hormone receptor-positive breast cancer and half had triple-negative breast cancer. And just to note this is a patient population that was heavily pretreated with the median of 6.5 prior therapies.

We observed possible immune-related events that were similar to those reported in the dose escalation. Notably, there were only two patients who had higher grade adverse events, which included a grade 4 increasing lipase and a grade 5 respiratory failure, but these were presumed to actually be not immune related.

So the exciting part of our presentation noted an objective response rate of 30% with the response observed in both hormone-receptor positive and triple-negative subtypes, and the majority of these responses occurred in patients with triple-negative breast cancer. And one patient actually had a complete response at the 6-month timepoint. The duration of response ranged from less than 2 months to the longest response ongoing at greater than 24 months after the initiation of our treatment.

Median progression-free survival was short at 2.5 months, and the overall survival was 7.7 months in all patients, 24.4 months in patients with triple-negative breast cancer, and 5.9 months in patients with hormone-receptor positive disease. Of note, those driving improved overall survival are the patients who experienced response.

We also discussed some of our correlative studies that investigated immunohistochemical staining of T-cells, and that demonstrated the ratio of CD8 T effector cells over FoxP3 regulatory cells, increased after therapy from baseline to timepoint one and to timepoint two. And this is primarily as a result of increased CD8 infiltration. And this was most notable from patients with triple-negative breast cancer.

We also mentioned there’s no obvious trend in abundance of tumor infiltrating lymphocytes at baseline across the breast cancer subtypes or with treatment, and so this is not likely going to be a reliable biomarker of response in this setting.

So just to summarize, the combination of entinostat, nivolumab, and ipilimumab administered at the recommended phase II dose was associated with expected immune-related adverse events. An objective response rate of 30% suggests this combination really should be evaluated further in a phase II setting in advanced HER2-negative breast cancer. And correlative results suggest an increase in CD8-to-FoxP3 ratio after treatment and should be investigated in future studies as both a mechanism and potential predictor of response.

Future investigations for potential biomarkers and mechanisms of response are ongoing and include bulk RNA sequencing as well as imaging mass cytometry to investigate other important immune cell infiltrates such as myeloid-derived suppressor cells. And future clinical trials are planned to investigate this promising therapeutic combination in a large cohort of patients with breast cancer.

It was great to have the opportunity to discuss this and, of course, we always thank the patients and their families who contributed to making the study possible…Dr. Roisin Connolly and Dr. Vered Stearns, as well as my mentor from Johns Hopkins Dr. Elizabeth Jaffee, supported all of this work, as we continue to really dive deep into the correlatives that we hope to teach us more about the responders in the study.