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Scientists share promising results of BET and EZH2 inhibitors for lymphoma

Researchers at the TAT (Targeted Anticancer Therapies) International Congress 2018 in Paris have presented new epigenetics compounds that show early activity in lymphoma patients.

BET-inhibitor-lymphoma

The compounds targeting epigenetics include BET inhibitors and EZH2 inhibitors and Dr Anastasios Stathis, head of the New Drugs Development Unit of the Oncology Institute of Southern Switzerland (IOSI), was one of the first oncologists to conduct research in this field. He has found that BET inhibitors have shown some activity in leukaemia, lymphoma and also NUT carcinoma – a rare and aggressive tumour driven by a translocation involving BET genes. His previous phase I research on the first-in-class BET inhibitor birabresib (OTX015/MK-8628) showed some activity in diffuse large B-cell lymphoma, providing proof-of-concept for this approach.

Subsequently, birabresib was used on a single-patient compassionate basis on four patients with NUT carcinoma.

Commenting on the outcome of this application, Stathis said: “This was the first evidence that preclinical findings with BET inhibitors in models of NUT carcinoma could be translated into activity in patients.”

Since then several additional BET inhibitors have been studied in clinical trials and preliminary results have confirmed that they may be effective in patients with diffuse large B-cell lymphoma and NUT carcinoma.

While general levels of tolerability have been good, some side effects have been observed that may limit treatment compliance. These include thrombocytopaenia (a decrease in the number of platelets in the blood, which can be dose-limiting but is reversible and not accompanied by major bleeding), fatigue and gastrointestinal symptoms.

Mid-infrared spectroscopy used to diagnose lymphoma and melanoma…

Regarding activity, patients do eventually progress on treatment but the duration of response is unknown. Commenting on the possibilities of BET inhibitors at this early stage, Stathis said: “It’s not clear what the real clinical impact of BET inhibitors could be. Compounds approved for lymphoma in the last five years had single-agent phase-I response rates above 30%, but activity with BET inhibitors is less than 30%. The hope is to identify the patients that would benefit most and test BET inhibitors in combination with other compounds. In addition, there are new classes of BET inhibitors in preclinical studies and we need to wait to see if they have better activity.”

Another area where clinical data is emerging relates to EZH2 inhibitors. EZH2 is a protein that exhibits relatively frequent mutations in lymphoma. Results from a study in patients with B-cell lymphoma show evidence of antitumour activity with an EZH2 inhibitor, which was well tolerated and had manageable toxicities.

Study author Dr Adrian Senderowicz of Constellation Pharmaceuticals, Cambridge, US, said: “If approved by health authorities, EZH2 inhibition may become a new treatment paradigm in relapse or refractory EZH2 mutant follicular lymphoma patients.”

A previous study showed that another EZH2 inhibitor, tazemetostat, induced objective response rates of 92% in patients with EZH2 mutant follicular lymphoma and 26% in those with the wild-type.

Commenting on the question posed by these differing response rates, Stathis said: “The question is whether it makes sense to treat patients without the mutation, since the response is so much lower. However, these patients do show some response and researchers want to know why.”