The first indication of chidamide --- treatment of peripheral T cell lymphoma


Comparison of efficacy in pivotal trials between chidamide and other HDACis on the global market

PTCL is a rare disease, which is classified into 22 subtypes according to the 2008 WHO classification. PTCL is highly heterogeneous and highly invasive. There are no standard drug treatments available in clinical practice, the response rate of the cancer to conventional chemotherapies is low, the tolerance is poor, relapse often occurs, and the overall 5-year survival rate is approximately 25%. Three new drugs, pralatrexate (Folotyn® ), romidepsin (FK228, ISTODAX® ), and belinostat (PXD101, BELEODAQ® ), were approved by the USFDA for relapsed and refractory PTCL in 2009, 2011, and 2014, respectively. In China, the new drug Epidaza® (chidamide) was approved by the CFDA in 2014 for the treatment of relapsed and refractory PTCL. Currently, among the four new drugs on the global market, only Folotyn®, a chemotherapeutic agent that inhibits folate metabolism, has entered into the Taiwan market; thus, for PTCL patients in Taiwan, the clinical need for effective and safe drugs for the treatment of PTCL is yet to be met.

Figure 3. The 5-year survival rate of peripheral T-cell lymphoma is 25%; the clinical needs are not satisfied.


Effectiveness evaluation

The main efficacy index of the clinical trial for chidamide in the treatment of relapsed and refractory PTCL was the Overall Response Rate (ORR), which was the same as those in pivotal trials for the other three new drugs overseas. In the Phase II pivotal trial at a dose of 30 mg twice per week, the ORR of chidamide determined by clinical investigators was 29.1% (23/79) (95% CI: 19.4–40.4%). Similar to the pivotal trials of the other three new drugs overseas, in the pivotal trial of chidamide for PTCL, in addition to the tumor response evaluation by clinical investigators, an independent review committee (IRC) was established to evaluate the major efficacy index (ORR). The ORRs of the four new drugs in the treatment of relapsed and refractory PTCL were 28%, 27%, 25%, and 26%, respectively. The comparison in the efficacy index for the same indication between the three new drugs overseas and chidamide was similar, as shown below.

In addition to the main efficacy index, the ORR, the Phase II pivotal trial of chidamide showed that the 3-month durable overall response rate (DORR) in the FAS population was 24.1% (19/79), which was much higher than pralatrexate (12%; 13/109), which indicated that chidamide may have a better durable efficacy than pralatrexate in the treatment of relapsed or refractory PTCL.

Table 2. Comparison in the treatment outcome of relapsed and refractory PTCL between chidamide and other HDACis on the global market


Response evaluation in different populations

Pathological subtypes

The data from 1314 cases of T cell lymphomas in 22 countries worldwide were collected by the International T-cell Lymphoma Project and showed that the frequency of the common pathological subtypes of PTCL occurred in the following order: PTCL-U, angioimmunoblastic T-cell lymphoma, ALCL, and NK-T cell lymphoma.

The subtypes of PTCL that have higher incidence in China are: PTCL-U, nasal type NK-T cell lymphoma, angioimmunoblastic T-cell lymphoma, enteropathy-associated T-cell lymphoma. Among these subtypes, the incidence of NK-T cell lymphoma in China was significantly higher than that of the Western populations and the subtype has a high incidence in Asia.

The subtypes included in the trial and their efficacy were compared between chidamide and two new drugs developed overseas. The subtypes included in pivotal trials of the four drugs and the ORRs of subtypes accounting for >10% of cases are shown below.

Table 3. Comparison in the pathological subtypes recruited in the trials between chidamide and other HDACis on the global market

Table 4. Comparison in the response rates of pathological subtypes accounting for >10% of all types of PTLC between chidamide and other HDACis on the global market


Benefit and risk assessment

Chidamide is a subtype selective HDAC inhibitor. The comparative analysis of the results of pivotal trials for relapsed or refractory PTCL indicated that, compared with three new drugs marketed overseas, chidamide may have a better efficacy, but had at least a comparable efficacy.


Convenience and compliance

Chidamide is orally administered twice per week; compared with the three intravenously administered new drugs marketed overseas, it offers a more convenient administration route, which is expected to have a higher compliance. Even with oral administration, the incidence and severity of toxic events and the severe adverse events (SAE) with digestive system manifestations, such as diarrhea and nausea, were much lower than those of the three intravenously administered drugs. The following table shows the adverse events of the four drugs.

Table 5. Adverse events of Chidamide and other HDACis on the global market