Triplet Therapy Shows Efficacy in Phase 1 Advanced Breast Cancer Trial

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.

TRANSCRIPTION:

0:08 | 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.