The second indication of chidamide in combination with exemestane to treat ER+ Her-2 late stage breast cancer


Disease background

Breast cancer is the most common cancer in women. Currently, it is primarily classified into three types, i.e., HR+, HER2, and triple negative breast cancer. HR+ patients account for 65–75% of all cases, the highest proportion among all types. These patients are positive for both estrogen receptor (ER) and progesterone receptor (PR) on the surface of cancer cells, which can usually be stimulated by hormones and undergo accelerated growth. Thus, the treatment of such patients mainly focuses on endocrine therapy. Although endocrine therapy can prevent the disease progression, most patients still develop disease progression, relapse, or resistance after 18–24 months. Therefore, endocrine resistance is an important problem and a major unsolved challenge.


Rationale for the use chidamide in the treatment of breast cancer

This is based mainly on the following studies:
(1) In 2007, G. Sabnis et al. showed that HDACi effectively reduced the resistance of breast cancer cells to AI and increased the sensitivity of the treatment;
(2) in 2011, CW Chou et al. indicated that HDACi inhibited the expression of EGFR in colorectal cancer cells;
(3) in 2013, BM Müller et al. showed that the higher expression of HDCA 1, 2, and 3 in patients with HR positive breast cancer than in HR-negative patients (P<0.05) influenced the disease progression, cancer metastasis, and reduced the survival rate. Chidamide is a subtype selective HDACi and its anti-cancer effect is mainly exerted by the inhibition of the expression of HDAC1, 2, 3, and 10. For the treatment of HR positive breast cancer, chidamide reduces the expression of HDCA 1, 2, and 3 in the tumor and has the potential to slow down the disease progression and prolong the survival of patients;
(4) Syndax’s (U.S.) product Entinostat combined with exemestane was used in patients with resistance to the non-steroidal AI or relapsed after the treatment to provide a new treatment opportunity for them. In September 2013, the drug combination received Breakthrough Therapy Designation from FDA and may be able to reverse the induced resistance due to long-term therapy with non-steroidal AI, regain the sensitivity to the drug for the relief of the disease. Entinostat and chidamide are highly similar with respect to the mechanism of drug action and the chemical structure.

Possible mechanisms of chidamide in combination with exemestane for the treatment of HR+ breast cancer

The trial is approved by TFDA (No. 1056076400). The Phase III clinical trial is divided into two parts: open-label and double-blinded trial. The open-label trial conducted in mainland China included 20 patients and the double-blinded trial contained 328 patients from mainland China and 60 patients from Taiwan.


Design of Phase III clinical trial

In the Phase III clinical trial of chidamide combined with Aromasin® (exemestane) to treat breast cancer, the design is as follows (this can be viewed in Clinical trial information: NCT02482753).


Preliminary response evaluation

At present, the open-label study was completed and published in ASCO in 2017, which showed that in 18 breast cancer patients treated with the combination of chidamide and exemestane, three patients achieved partial remission (PR), 12 patients had stable disease (SD), and three had progressive disease (PD). Of the 18 breast cancer patients, the median disease-free survival was 7.6 months. For safety, most adverse effects were controllable; drug-related and higher than Grade 3 adverse events occurred in two patients and mainly comprised neutropenia (35%), thrombocytopenia (30%), and leukopenia (20%). The double-blinded trial is currently in progress.