Chidamide Plus R-CHOP Approved in China for MYC/BCL2–Expressing DLBCL

China’s National Medical Products Administration has approved the novel oral subtype-selective histone deacetylase inhibitor chidamide (Tucidinostat; Epidaza) in combination with R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, and prednisone) for the treatment of patients with previously untreated diffuse large B-cell lymphoma (DLBCL) expressing MYC and BCL-2.¹

This regulatory decision was supported by interim findings from the phase 3 DEB trial (NCT04231448), which confirmed that the efficacy and safety indicators set by the protocol were achieved. The interim analysis, which was conducted by the Independent Data Monitoring Committee, showed that patients treated with first-line chidamide plus R-CHOP experienced significantly improved complete response (CR) rates vs those treated with R-CHOP alone, meeting a key secondary end point of the trial. A trend toward improved event-free survival, the trial’s primary end point, was also observed with the chidamide combination vs R-CHOP alone. Regarding safety, the chidamide combination’s toxicity profile is consistent with known risks, and no new significant safety signals were observed.

These results will be presented as a late-breaking abstract during the 2024 ASCO Annual Meeting.

“The classic R-CHOP regimen has been used as a first-line treatment for DLBCL for nearly 20 years, but its therapeutic effect is not satisfactory in populations with dual expression of BCL-2 and MYC proteins,” Xianping Lu, PhD, chairman and general manager of Chipscreen Biosciences, stated in a press release. “The combination of chidamide and R-CHOP is [being investigated in] the world’s first phase 3 registered clinical study that focuses on first-line therapy of dual-expressed DLBCL, and [is] the world’s first R-CHOP improvement study with significant benefits in CR rate. We believe that the approval of the new indication will bring new hope and better survival benefits to patients.”

Over one-third of patients with DLBCL will not achieve responses or will experience early recurrence when treated with standard-of-care R-CHOP in the first line. Moreover, approximately 30% of patients with DLBCL will display simultaneous overexpression of MYC and BCL-2 proteins. These patients often experience decreased efficacy and worse prognosis following R-CHOP treatment vs patients without MYC/BCL-2 overexpression. Accordingly, investigators are interested in combining novel agents, such as chidamide, with R-CHOP to bolster responses and safety in this population.

DEB was a randomized, double-blind, placebo-controlled, multicenter study evaluating the efficacy and safety of adding chidamide to R-CHOP vs R-CHOP alone in patients with newly diagnosed, MYC/BCL-2 double-expressed DLBCL, as selected by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH).² Patients with histologically or cytologically confirmed CD20-positive DLBCL who were no younger than 18 years of age and no older than 80 years of age were included in the study. No prior treatment for DLBCL was permitted, including hemotherapy, immunotherapy, radiotherapy (excluding local radiotherapy), monoclonal antibody therapy, and surgical treatment (excluding biopsy).

MYC overexpression was quantified as at least 40% by IHC; BCL-2 overexpression was quantified as at least 50% by IHC. Patients could not have a double (BCL-2 and c-MYC gene rearrangement) or triple (BCL-2, BCL-6, and c-MYC gene rearrangement) hit by FISH assessment. Other key inclusion criteria included the presence of at least 1 positive lesion according to the Lugano Classification by fluorodeoxyglucose PET-CT, a Lymphoma International Prognosis Index score of 2, 3, or 4, an ECOG performance score of 0 to 2, and an expected survival of at least 6 months. Patients with central nervous system involvement were ineligible for the study.

A total of 423 patients were enrolled onto the study. Patients received intravenous doses of 375 mg/m², 750 mg/m², 50 mg/m² and 1.4 mg/m² (maximum of 2 mg) of rituximab, cyclophosphamide, doxorubicin, and vincristine, respectively. These agents were administered with 100 mg of oral prednisone as the background therapy for 6 21-day cycles. Depending on the treatment arm, chidamide or placebo was administered orally at 30 mg following breakfast on days 1, 4, 8, and 11 in 21-day cycles for 6 cycles. After cycle 6, patients who achieved a CR received an additional 24 weeks of chidamide treatment following the same dosing schedule.

Additional secondary end points included progression-free survival, overall survival, disease-free survival, and safety. The study’s estimated completion date is March 1, 2025.

Chidamide has received global approval across multiple indications.¹ The agent is currently approved in China as a monotherapy for the management of recurrent/refractory peripheral T-cell lymphoma (PTCL) and in combination with an aromatase inhibitor for patients with estrogen receptor–positive, HER2-negative postmenopausal advanced or metastatic breast cancer. The agent is also approved in Taiwan, China for postmenopausal women with locally advanced or metastatic hormone receptor–positive, HER2-negative breast cancer who progressed or relapsed following endocrine therapy. In Japan, chidamide monotherapy is approved for both relapsed/refractory adult T-cell leukemia and relapsed/refractory PTCL.

In addition to an ongoing, phase 3 evaluation of chidamide in combination with nivolumab (Opdivo) for the first-line treatment of patients with melanoma, the agent is also being explored in combination with various immunotherapies across international clinical trials. This includes a phase 2 study (NCT05519865) of chidamide in combination with tislelizumab-jsgr (Tevimbra) in non–small cell lung cancer, as well as the phase 2 CAPAbility-01 trial (NCT04724239) of chidamide, sintilimab (Tyvyt) and bevacizumab (Avastin) for the third-line or later treatment of patients with microsatellite-stable, mismatch repair–proficient metastatic colorectal cancer.

References

1. National Medical Products Administration (NMPA) approves Chipscreen Bioscience’s chidamide (Epidaza) combined with R-CHOP for the treatment of diffuse large B-cell lymphoma. News release. Chipscreen Biosciences. April 30, 2024. Accessed April 30, 2024. https://www.prnewswire.com/news-releases/national-medical-products-administration-nmpa-approves-chipscreen-biosciences-chidamide-epidaza-combined-with-r-chop-for-the-treatment-of-diffuse-large-b-cell-lymphoma-302131654.html
2. Phase III study of tucidinostat in combination with R-CHOP in patients with newly diagnosed double-expressor DLBCL (DEB). ClinicalTrials.gov. Updated September 6, 2023. Accessed April 30, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT04231448