June 20, 2015
Earlier today, Epizyme reported updated data from the ongoing open-label phase 1/2 trial, examining tazemetostat (EPZ-6438), a first-in-class EZH2 inhibitor, in subjects with relapsed/refractory B-cell lymphomas and advanced solid tumors (see company release here and investigator slides here). The lymphoma patients on study were heavily pre-treated with 85% having received three or more prior therapies. Oncology Discovery has covered Epizyme and EZH2 as an epigenetic cancer target previously, here and here. Tazemetostat continues to demonstrate favorable safety and tolerability. An additional update from this trial is expected in late 2015.
In B-Cell lymphomas an ORR of 60% demonstrates deepening responses over time. Nine of 15 evaluable Non-Hodgkin Lymphoma (NHL) patients achieved an objective response (7 PRs and 2 CRs). Figure 1 illustrates the maturation of response data over time (the x-axis changes from weeks to months when comparing the 2014 EORTC data to today’s ICML presentation). The bottom line: clinical responses have improved with continued therapy. For example, a Marginal Zone Lymphoma (MZL) patient exhibiting stable disease in the 2014 EORTC presentation has evolved to a PR in today’s presentation; a Follicular Lymphoma patient evolved from PR to CR, etc. The ORR of tazemetostat has evolved from 40% (4/10 evaluable patients) at EORTC to 60% (9/15 evaluable patients) with today’s ICML presentation. We anticipate that the continued evolution of response data will positively augment ORR in NHL.
Clinical prosecution of the mutant EZH2 hypothesis is underway. Tazemetostat was initially developed for use in mutant EZH2 NHL and pre-clinical data suggests an efficacy advantage against NHL cells carrying this genetic lesion when compared against their wildtype counterparts. Prior to this update, all tazemetostat responders were wildtype for EZH2. This observation serves as evidence towards broadened tazemetostat utility, and leaves the door open for enhanced efficacy against EZH2 mutant NHL. As of today, one of 14 patients evaluated for EZH2 mutation status possesses a Y646H mutation. This patient achieved a PR after 16 weeks of therapy and remains on study. Epizyme has disclosed that responses observed have occurred between two and 10 months of therapy, but the granular-level distribution is unknown. More data are required to determine if median time to response and ORR is improved for EZH2 mutant NHL patients; this is something to watch closely.
Tazemetostat continues to demonstrate a favorable tolerability and safety profile. Success beyond monotherapy hinges on the ability to combine with novel agents and standard of care. We believe the emerging tolerability profile of this agent will enable future combinations with complementary therapies to drive additional efficacy. The majority of adverse events were grade 1 or 2 within the evaluable for safety population of 45 patients with NHL and solid tumors. Five grade 3 or greater treatment-related events were observed (see Figure 2). As part of it’s phase 2 expansion plans for tazemetostat, Epizyme is enrolling an R-CHOP combination in DLBCL; pre-clinical company data indicate synergism between R-CHOP and tazemetostat. An additional combination study with a novel B-cell signaling agent (undisclosed) in DLBCL has been proposed and is similarly substantiated by strong pre-clinical evidence.
Ace in the Hole: activity in solid tumors. Oncology Discovery has previously expounded on the rationale behind targeting EZH2 in a variety of solid tumor settings here. Keeping with the theme of ‘improved responses with continued therapy,’ a INI1-negative Malignant Rhabdoid Tumor (MRT) patient achieved a CR on study, evolving from a PR at the time of the 2014 EORTC presentation (Figure 3). Tazemetostat may yet have activity in other solid tumor indications where patients exhibit SWI/SNF mutations similar to INI1-deficient MRT. The proliferation of large-scale exome sequencing has recently uncovered mutations in SWI/SNF subunits in approximately 20% of human tumors. If even a fraction of these mutations (e.g. ARID1A mutations in Ovarian Clear Cell Carcinoma) impart a dependence on EZH2 this could unlock significant value for Epizyme.
The tazemetostat phase 2 plans include the following:
– A study in relapsed/refractory NHL, stratefied by cell of origin and EZH2 mutation status (currently enrolling)
– A study in INI-deficient solid tumors (enrolling in late 2015)
– A combination study with R-CHOP in DLBCL (no timeline mentioned)
– A combination study with a B-cell signaling agent (e.g. PI3K, BTK, etc) or other emerging targeted therapies (no timeline mentioned)
It will be interesting to see whether Epizyme is capable of inking a deal to allow for a combination study with a premier BCR signaling antagonist, such as ibrutinib. Another candidate agent for combination studies would be a PI3K inhibitor, for which there are several potential partners. A IRAK4 inhibitor would similarly be a logical candidate for a combination trial, but given the early development and scarcity of agents in this space, this is probably something to consider in the long term. You can catch the ICML recap call tomorrow morning at 8:00 AM EST here.
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