Abstract IA26: What do the results from the trials tell us?

Abstract

Abstract The relatively high prevalence of somatic mutations in several epigenetic modifying genes in germinal center lymphomas suggests a role in pathogenesis, with a variety of potential mechanisms for this. The first of these somatic changes to be successfully targeted by small-molecule inhibitors was the activating mutation of the enhancer of Zeste Homolog-2 (EZH2), which is found in up to a quarter of follicular lymphomas and germinal center-type diffuse large B-cell lymphomas, where it drives the methylation of histone H3 on lysine 27, inhibiting exit from the germinal center and accelerating lymphoma development in preclinical models. Two inhibitors of EZH2 have entered clinical trials, GSK2816126 and tazemetostat. GSK2816126 is a highly selective and potent inhibitor of wild-type (WT) and mutant (Y641N, A677G, and A687V) EZH2, with IC50 of 28–861 nM for proliferation in EZH2-mutant lymphoma cell lines. It is not orally bioavailable, but pharmacokinetic/pharmacodynamic studies suggested that therapeutic levels could be achieved with intravenous doses of between 900mg and 2,700mg twice a week. Tazemetostat is a similarly selective and orally bioavailable small-molecule inhibitor of EZH2 with an IC50 of 0.49-5800 nM for proliferation in EZH2-mutant lymphoma cell lines. Both of these molecules have been tested in phase I dose escalation studies. GSK2816126 was given by twice-weekly intravenous infusion at doses of up to 3,000mg, with dose-limiting liver enzyme rises at the highest dose, achieving trough levels of 410 ng/mL. No changes in H3K27me3 could be seen in peripheral blood mononuclear cells, and only one short-lived partial response was seen among 20 patients with B-cell lymphoma. Tazemetostat was given at doses of up to 1,600mg twice daily without reaching dose-limiting toxicity, although significant thrombocytopenia was seen at this dose level. The mean pre-dose trough level at the recommended phase II dose of 800mg bd was 75 ng/mL, and skin biopsies showed a reduction of H3K27me3 by approximately 40% from baseline. Tazemetostat has shown moderate efficacy as a single agent in relapsed/refractory follicular lymphoma (FL), with overall response rate (ORR) 33/43 (77%) and median duration of response (mDOR) 8.3 months in EZH2-mutant cases and ORR 18/53 (34%), mDOR 13 months in those without mutations. In relapsed/refractory diffuse large B-cell lymphoma (DLBL) the response rate was lower, ORR 6/36 (17%), mDOR 11+ months in mutant cases and 20/121 (17%), mDOR 7+ months in wild-type. In both studies the treatment was well tolerated, with the most frequently reported adverse events being thrombocytopenia, anemia, asthenia, vomiting, and fatigue, all in less than 5% of patients with FL and less than 20% in DLBL. Combination therapy of tazemetostat with atezolizumab did not increase the response rate in DLBL, but giving it with R-CHOP chemotherapy was well tolerated in a phase Ib study, and a dose of 800mg BD could be given without apparently increased toxicity over R-CHOP in patients between 60 and 80 years old, and without adverse effects on the pharmacology of the chemotherapy or tazemetostat. In keeping with many agents targeting a single molecular abnormality, inhibitors of EZH2 have demonstrated clear but transient efficacy, with the most promising results in follicular lymphoma. The higher response rate among cases with an activating mutation is notable, but wild-type lymphomas also show responsiveness in a minority of cases, indicating other potential mechanisms of action. The combination of tazemetostat with chemoimmunotherapy appears promising, although the relatively good prognosis for DLBL bearing an EZH2 mutation may make it difficult to demonstrate clear clinical benefit with this approach. Citation Format: Peter W. M. Johnson. What do the results from the trials tell us? [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr IA26.