New promising combo in advanced HER2-negative breast cancer

At the virtual meeting of the European Society for Medical Oncology (ESMO), 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 the expected immune system-related adverse reactions in advanced HER2-negative breast cancer.

In this exclusivity MedPage today video, author of the study Evanthia Roussos Torres, MD, from the Norris Comprehensive Cancer Center at the University of Southern California at Los Angeles, describes the background of the study and what will follow.

Here is a transcript of his remarks:

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

Just to give a bit of background, in breast cancer patients, the indications currently for immune checkpoint inhibition are somewhat limited to those with high risk early stage disease or disease. triple negative metastatic with high CPS [combined positive score] or high tumor mutational load, so there is a lot of improvement for the expanded indications. Thus, combination therapies have been investigated as a means of priming the tumor microenvironment to improve response rates and clinical benefits of these agents. And we and others investigated whether epigenetic modulation using the histone deacetylase inhibitor entinostat could actually prime the tumor microenvironment and enhance the response to immune checkpoint inhibition. And our preclinical data supported this growing body of work which revealed that there was an improvement in survival in preclinical models 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 the new combination in patients. And the first part of the clinical trial was in advanced solid tumors. And what we presented to ESMO were actually the results of our planned expansion cohort in patients with HER2-negative breast cancer.

Thus, in this dose extension cohort, patients with advanced HER2-negative breast cancer had not previously been exposed to immune checkpoint inhibition. They were treated with a recommended phase II dose, which included 5 mg of entinostat per week for a pre-inclusion period of 2 weeks, then 3 mg / kg of nivolumab every 2 weeks and 1 mg / kg of ipilimumab every 6 weeks.

And we had biopsies of blood and tissue taken before the entinostat break-in, after the 2-week break-in, and then 8 weeks after the checkpoint inhibition was added.

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

We observed possible immune events similar to those reported when increasing the dose. Notably, only two patients experienced higher grade adverse events, including grade 4 lipase elevation and grade 5 respiratory failure, but these were actually presumed not to be related to the immune system.

So, the exciting part of our presentation noted an objective response rate of 30% with the response observed in 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 after 6 months. The duration of the response ranged from less than 2 months with the longest ongoing response to more than 24 months after the start of our treatment.

Median progression-free survival was short at 2.5 months, and overall survival was 7.7 months in all patients, 24.4 months in patients with triple negative breast cancer, and 5.9 months. months in patients with hormone receptor positive disease. It should be noted that those who improved overall survival were the patients who had a response.

We also discussed some of our correlative studies which investigated the immunohistochemical staining of T cells, and which demonstrated that the ratio of CD8 T effector cells to FoxP3 regulatory cells, increased after treatment from baseline to time point one and time point two. And this is mainly due to increased infiltration of CD8. And this was most noticeable in patients with triple negative breast cancer.

We also mentioned that there was no obvious trend for the abundance of tumor infiltrating lymphocytes at baseline in breast cancer subtypes or with treatment, and therefore this is unlikely to be a reliable biomarker. response in this context.

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

Future research into potential biomarkers and response mechanisms is ongoing and includes bulk RNA sequencing as well as imaging mass cytometry to study other important immune cell infiltrates such as suppressor cells derived from myeloid. And future clinical trials are planned to study this promising therapeutic combination in a large cohort of breast cancer patients.

It was great to have the opportunity to discuss this and of course we always thank the patients and their families who helped make the study possible … Dr. Roisin Connolly and Dr Vered Stearns, as well as my Johns Hopkins mentor Dr Elizabeth Jaffee have supported all of this work, as we continue to delve deeper into the correlates that we hope we learn about the study stakeholders. .

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