Evanthia Roussos Torres, MD, PhD

Evanthia Roussos Torres, MD, PhD, assistant professor of medicine at the University of Southern California Keck School of Medicine, discusses the follow-up research related to the phase 1 study (NCT02453620) of entinostat (MS-275) administered in combination with nivolumab (Opdivo) and ipilimumab (Yervoy) for the treatment of locally advanced, metastatic, unresectable, or HER2-negative breast cancer.

The phase 1 trial explored the use of entinostat, a histone deacetylase inhibitor which can reduce tumor growth by targeting enzymes, along with the CTLA-4 inhibitor ipilimumab and the PD-1 inhibitor nivolumab. The initial trial of 24 patients with multiple types of advanced breast cancer of determined a recommended safe dosage for the phase 2 trial and gathered other promising data on the efficacy and safety of the combination.

According to Torres, she and other investigators intend to analyze correlative results to evaluate the immune response. Areas of interest include bulk RNA sequencing, B-cell and T-cell receptor sequencing, and myeloid cell populations in patients before and after they received the combination including entinostat.

They intend to continue researching the immune cell types and molecular mechanisms that could be linked to the responses to the combination therapy as they work to expand the trial in phase 2. Better understanding of the mechanism of action could improve the targeting of therapies toward certain biomarkers, Torres explains.

 We have a number of correlative results that…we've just started analyzing. We're going to be looking at some of the bulk RNA sequencing and B-cell receptor and T-cell receptor sequencing as well as using imaging mass cytometry to investigate the myeloid cell populations in patient specimens after the entinostat and after the addition of checkpoint inhibition, because we feel that there are multiple other immune cell types that are affected by the therapy that are likely responsible for the responses that we're seeing. In addition, we were looking forward to planning the next phase results; given the promising results we've seen here, we think there are more patients with breast cancer who can benefit from this novel combination therapy.

 My lab is focusing on understanding the mechanisms of response to entinostat plus [immune] checkpoint inhibition in breast cancer. We're doing a lot of the preclinical work that goes along in parallel with what we're doing in the clinical trials, so that we can better understand specific molecular mechanisms that entinostat is imparting on some of these important immune cell types to potentially provide data that would support even more specific therapies or help with biomarkers to select patients who are most likely to respond.

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Evanthia Roussos Torres, MD, PhD, discusses the follow-up research related to the phase 1 study of entinostat administered in combination with nivolumab and ipilimumab for the treatment of locally advanced, metastatic, unresectable, or HER2-negative breast cancer.

Next Steps After Trial of Entinostat for Advanced Breast Cancer

Evanthia Roussos Torres, MD, PhD, assistant professor of medicine at the University of Southern California Keck School of Medicine, discusses the phase 1 study [NCT02453620] of the efficacy observed with entinostat (MS-275) administered in combination with nivolumab (Opdivo) and ipilimumab (Yervoy) for the treatment of locally advanced, metastatic, unresectable, or HER2-negative breast cancer.

Entinostat is a histone deacetylase inhibitor that is being investigated for its role in reducing tumor cell growth by blocking required enzymes. According to Roussos Torres, it has been studied previously as a monotherapy in blood cancers.

The phase 1 trial of 24 patients with advanced breast cancer investigated the safety and optimal dosage for entinostat and nivolumab when given with ipilimumab to patients with locally advanced, metastatic, or HER2-negative breast cancer. To determine the proper dosage, 6 patients received an escalating dose. Eighteen patients received the highest dose with acceptable toxicity, which was oral entinostat given at 5 mg weekly with a 2-week run-in before receiving nivolumab 3mg/kg twice per week and ipilimumab 1 mg/kg twice weekly.

The primary end point was assessing safety of the triplet combination. Patients with grade 3 and 4 adverse events (AEs) included 17% (n = 4) with anemia, 13% (N=3) who experienced a decreased neutrophil count, and 8% (n = 2) with increased lipase. The most common immune-related AEs included rash (n = 7, 29%), hypothyroidism (n = 5, 21%), and pneumonitis (n = 2, 8%). The objective response rate by RECIST (v1.1) was 30% (6/20 evaluable), including 1 complete response.

Based on the safety dosage identified and the 30% ORR, the investigators recommended further trials of the triplet combination.

The ORR was 30%, with response observed in both HER2-positive and triple-negative subtypes. The majority of these responses occurred in patients with triple-negative breast cancer [TNBC]. There was 1 patient who showed a complete response at the 6-month time point. The duration of response ranged from less than 2 months to the longest response ongoing at greater than 24 months after initiation of treatment. The median progression-free survival for the overall cohort was short, at 2.5 months, and the median overall survival [OS] was 7.7 months in all patients, 24.4 months in patients with TNBC, and 5.9 months in patients with hormone receptor-positive disease.

Of note, those driving improved OS are the patients who experienced [a] response. We're also going to discuss correlative studies that investigated immunohistochemical staining of T cells, which demonstrates that the ratio of CD8+ T effector cells over FOXP3 T regulatory cells increased after therapy from baseline to time point 1, which was the baseline compared to the entinostat run-in and then to time point 2 after combination therapy. This is primarily as a result of the increase in CD8+ T cells’ infiltration, and this is most notable in biopsies from patients with TNBC.

Evanthia Roussos Torres, MD, PhD, discusses the phase 1 study of the efficacy of entinostat administered in combination with nivolumab and ipilimumab  for the treatment of locally advanced, metastatic, unresectable, or HER2-negative breast cancer.

Evanthia Roussos Torres, MD, PhD | Authors

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