Entinostat added to Nivolumab Plus Ipilimumab shows early efficacy / safety in advanced BC

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In a phase 1 study of entinostat (MS-275) combined with nivolumab (Opdivo) and ipilimumab (Yervoy), treatment resulted in an expected number of immune-related adverse events (irAEs) as well as ‘an objective response rate of 30% in patients with advanced HER2-negative breast cancer.

Eighteen patients received the recommended dose of phase 2 of the combination of 3 mg entinostat per week with nivolumab 3 mg / kg twice a week and ipilimumab 1 mg / kg twice a week. The cohort received a median of 2 cycles of treatment (range, 1-17).

At 24 weeks, the clinical benefit rate was 33% in the general population. Notably, the benefit in patients with triple negative breast cancer continued beyond the data cut-off point and the response continued after progression of treatment.

Safety analysis showed grade 3 and 4 anemia, decreased neutrophil count, and increased lipase in 17%, 13% and 8% of patients, respectively. The most common AEs were rash (29%), hypothyroidism (21%), and pneumonia (8%).

In an interview with Targeted Oncology ™, Evanthia Roussos Torres, MD, PhD, assistant professor of medicine at the Keck School of Medicine University of South California (USC), discussed the Phase 1 safety and efficacy of entinostat given in combination with nivolumab / ipilimumab for the treatment of advanced HER2-negative breast cancer.

TARGETED ONCOLOGY ™: Can you discuss the efficacy historically observed with the HDAC inhibitor, entinostat?

Torres: The efficacy of entinostat as monotherapy has mainly been studied in some of the liquid tumors such as leukemia and myeloma. I don’t know for sure what the extent of all these studies is, but as a monotherapy and especially in breast cancer, it was studied in combination with anti-endocrine therapies, anti-estrogen therapies to try to ‘improve response to endocrine therapies for unresponsive patients.

The idea was that entinostat would resensitize the tumor microenvironment to estrogen blockade in patients with estrogen receptor positive and progesterone receptor positive breast cancer. Next, several other epigenetic modulator drugs, as well as DNA methyltransferase inhibitors, have been studied in combination with checkpoint inhibition, not only in breast cancer, but in many different types of cancer in the body. part of a way to sensitize the tumor microenvironment.

These data came from preclinical models, primarily from a group at the Johns Hopkins University Oncology Center under the direction of Bret Vogelstein, MD as well as Roberto Pili, MD, who performed some of these studies. Essentially, they were studying what are the different changes of immune cells in the tumor microenvironment that are initiated by entinostat that could potentially enhance the checkpoint response.

These preclinical models and have helped to understand how it alters the tumor microenvironment by increasing the number of CD8 infiltrating T cells as well as altering the suppression of myeloid-derived suppressor cells, which are known and not just in breast cancer , but also in pancreatic cancer and other cancers to provide an immunosuppressed microenvironment. It is believed to be a mechanism by which there is intrinsic suppression and a lack of response to checkpoint inhibition

Can you explain the design of ETCTN-9844 and the methods used to conduct the study?

This was a phase 1 trial. The first part of the phase 1 trial was recently published in Clinical Cancer Research as a trial to test the safety of its new combination in patients with advanced solid tumors. Our recent publication of results reported that this treatment combination is associated with expected adverse events for these agents and a recommended phase 2 dose has been identified.

An overall response rate of 16% was observed in this initial cohort, including responses in triple negative breast cancer and hormone receptor positive breast cancer, and correlative studies from the initial phase. One shows that an increase in the CD8 T regulation ratio was noted after combination therapy.

The second part of the study presented to ESMO had a similar design, in which the cohort was specifically breast cancer. Thus, the cohort consisted of advanced HER2-negative breast cancers without prior inhibition or checkpoint. Then the patients were recruited and received a test we call running entinostat, which they received for 2 weeks, followed by the addition of nivolumab and ipilimumab. The combination of entinostat, nivolumab and ipilimumab was again administered at the recommended phase 2 dose which was determined from the first dose escalation cohort. We had 3 biopsies and blood tests. One was done before the start of the entinostat treatment, the other after the 2 week entinostat break-in and the other at the end of the 8 week treatment with the combination therapy. After that, we have the option to do some of the correlative analyzes.

What results did you present at ESMO?

First, the characteristics of the patients are important to note, we had a median age of 55 years, with a total of 24 patients. It should be noted that the patient cohort reported here includes 18 patients from this dose escalation cohort and which also includes 6 breast cancer patients from the dose escalation cohort. These patients all received the combination entinostat plus nivolumab and ipilimumab. Half of the cancers were positive for hormone receptors and half were triple negative. The patients were heavily pretreated with a median of 6.5 previous treatments.

Adverse events related to the immune system were similar to those reported in the dose escalation cohort. Notably, there were only 2 patients with higher grade adverse events, which were grade 4 lipase elevation and grade 5 respiratory failure both of which were presumed unrelated to the immune system.

We also reported that the objective response rate was 30%, with responses seen in hormone receptor positive and triple negative subtypes. However, the majority of these responses occurred in patients with triple negative breast cancer, and 1 patient experienced 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 treatment. The median progression-free survival for the overall cohort was short at 2.5 months, and the median 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 receptors. – positive disease.

It should be noted that those who improved overall survival were the patients who had a response. We also discussed correlative studies that investigated T cell immunohistochemical staining which demonstrates that the ratio of CD8 T effector cells to FOXP3 t regulatory cells increased after treatment from baseline at time point 1, which was the baseline versus intention to stop break-in and then to time point after combination therapy. This is mainly due to the increased infiltration of CD8-positive T cells, and this is particularly noticeable in biopsies from patients with triple negative breast cancer. There was also no obvious trend in the abundance of tumor infiltrating lymphocytes at baseline in breast cancer subtypes or with treatment.

This therefore indicates that tumor infiltrating lymphocytes are probably not a reliable biomarker of response in this setting. So. in conclusion, we reported that a combination of entinostat in combination with nivolumab / ipilimumab was associated with adverse events of immune origin expected in advanced HER-negative breast cancer. The objective response rate of 30% suggests that further evaluation is warranted in this setting, and the correlative results suggest an increase in the CD8 / FOXP3 ratio after treatment.

What are the next steps in this research?

We have a number of correlative results that we have just started to analyze. We will look at some of the bulk RNA sequencing and B-cell and T-cell receptor sequencing, as well as the use of imaging mass cytometry to study myeloid cell populations in patient samples. after intense data and after adding checkpoint inhibition. We believe that there are several other types of immune cells affected by therapy that are likely responsible for the responses we see.

In addition, we looked forward to planning the results of the next phase. Given the promising results we have seen here, we believe there are more breast cancer patients who can benefit from this new combination therapy.

I would also like to mention that I recently moved my lab from Johns Hopkins to USC and my lab is focusing on understanding the mechanisms of response to entinostat and checkpoint inhibition in cancer of the breast. breast. So we do a lot of the preclinical work that goes with what we do in clinical trials. We aim to better understand the specific molecular mechanisms that entinostat confers on some of these important immune cell types to potentially provide data that would support even more specific therapies or help with biomarkers select the patients most likely to respond.

With early research in mind, what other new therapies currently hold promise for breast cancer?

It is important to note that in breast cancer, in particular, we have tried to understand the tumor environment in more detail so that we can come up with more specific targets and biomarkers that will help improve response rates for this large population. of patients. And what strikes me as interesting is the suppressor cells that are increasingly characterized in the different breast cancer subtypes, especially myeloid-derived suppressor cells, as well as the differences between MI and M2 macrophages.

I think we’re starting to understand how these innate immune cells contribute to the lack of response to checkpoint inhibition, and that more specific targeting of these cell types has a lot of potential to improve responses. Much of the work is done in the field.

Reference:

Rousse ET, Leatherman J, Rafie C, et al. Entinostat, nivolumab and ipilimumab in advanced HER2-negative breast cancer (ETCTN-9844). Ann Oncol. 2021; 32 (suppl 5): S829-S866. doi: 10.1016 / advert / advert705


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