First-in-Class Oral EZH2 Inhibitor Effective in Two Cancers

M. Alexander Otto, MMS, PA

October 19, 2020

Tazemetostat (Tazverik) showed potential for improving outcomes for patients with advanced or metastatic epithelioid sarcoma and also yielded clinically meaningful responses in heavily pretreated patients with follicular lymphoma. The findings come from two open-label, single-arm, phase 2 trials that led to the US Food and Drug Administration's (FDA's) recent accelerated approval for the indications.

Tazemetostat is a first-in-class oral inhibitor of EZH2 methyltransferase, an enzyme that is overexpressed in multiple cancers and that may have an important role in carcinogenesis. Tazemetostat is under investigation either alone or in combination for treating a number of other malignancies, including prostate, endometrial, and urothelial cancers.

The FDA approved tazemetostat in January for locally advanced or metastatic epithelioid sarcoma for patients who were ineligible for complete resection. In June, the FDA approved it for adults with relapsed or refractory follicular lymphoma who had undergone at least two systemic therapies and whose disease tested positive for an activating EZH2 mutation, as well as for adults for whom there were no satisfactory alternatives.

Patients in both phase 2 trials took tazemetostat 800 mg orally twice daily in continuous 28-day cycles as monotherapy; 15% of patients with epithelioid sarcoma responded per RECIST version 1.1 criteria. Response rates for patients with follicular lymphoma were 69% in the presence of an EZH2 mutation and 35% with wild-type enzyme.

"Before tazemetostat, there was no drug specifically FDA approved for epithelioid sarcoma. Now that [it's] approved, oncologists should consider prescribing this drug. In the case of follicular lymphoma where there are more options for therapy, this drug should be considered as an option" when patients meet the indications, said Vivek Subbiah, MD, an associate professor in the Department of Investigational Cancer Therapeutics at the University of Texas MD Anderson Cancer Center, Houston, Texas, when asked for comment.

In an editorial, he and colleague Roman Groisberg, MD, a medical oncologist at the Rutgers Cancer Institute of New Jersey, in New Brunswick, New Jersey, noted that the low response rate in epithelioid sarcoma and the modest response in follicular lymphoma, coupled with the finite duration of response in both trials, highlight that "tumors will naturally find ways to bypass epigenetic inhibition, and therefore a specific targeted combination therapy approach will be needed...."

The pair added that "clinically, the short-term solution would be to combine an EZH2 inhibitor with chemotherapy or immunotherapy in an attempt to increase the proportion of patients who respond."

Strategies already under investigation include tazemetostat with lenalidomide and rituximab for relapsed or refractory follicular lymphoma and tazemetostat plus doxorubicin in first-line treatment of epithelioid sarcoma.

The studies also "show that an epigenetic-directed therapy...can be clinically efficacious" in inherently difficult-to-treat cancers and "open up a whole area of preclinical and clinical research into therapies targeting epigenetic mechanisms" that regulate gene expression, the editorialists write. "Future genomic efforts should focus on the transcriptome and furthering our understanding of cancer epigenetics."

Sarcoma Benefits in Line With Cytotoxics, Without the Side Effects

Patients in the sarcoma study were aged 16 years or older and had a confirmed loss of integrase interactor 1 (INI1) expression, either because of a mutation in the SMARCB1 gene that codes for it or epigenetic silencing. INI1 regulates EZH2; it's loss and subsequent oncogenic activation of EZH2 are hallmarks of epithelioid sarcoma.

There was one complete and eight partial responses in the 62-patient trial at a median of 13.8 months' follow-up, as determined by both investigator and independent radiology review. For sixteen patients (26%), disease control was seen at 32 weeks, and 13 (21%) were progression-free at 1 year.

Median progression-free survival was 5.5 months, and median overall survival was 19 months. Response and progression-free survival were more likely among treatment-naive patients.

Median time to response was 3.9 months. The gradual onset "has been observed with other epigenetic therapies" and "could indicate gradual epigenetic reprogramming of tumor cells," say the investigators, led by Mrinal Gounder, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, New York City.

Treatment-related adverse events of grade 3 or worse included anemia, in four patients (6%), and weight loss, in two (3%). Two patients had serious, treatment-related adverse events ― one had seizure, and one, hemoptysis. There were few dose reductions or discontinuations because of adverse events.

Overall, the outcomes are similar to those with cytotoxic chemotherapy with doxorubicin or gemcitabine and docetaxel, but with "substantially less toxicity," the editorialists say.

Higher Response Rate in Follicular Lymphoma

The follicular lymphoma study included 99 patients who had stage 1-3b disease and who had previously undergone treatment with two or more systemic therapies, including anti-CD20 antibodies and alkylating agents.

Forty-five patients had EZH2 mutations (EZH2mut) that give the enzyme extra strength in suppressing antiproliferative genes, and 54 had wild-type enzyme (EZH2wt).

Responses in the EZH2mut group ― including six complete responses (13%) by radiologic review ― came at a median follow-up of 22 months. Median duration of response was 10.9 months, and median progression-free survival was 13.8 months.

Response in the EZH2wt cohort ― including two complete responses (4%) by radiology ― came at a median follow-up of 35.9 months. The median duration of response was 13 months, and median progression-free survival was 11.1 months. Similar to the sarcoma trial, the median time to first response was 3.7 months in both cohorts.

"Despite a higher proportion of poor risk features in patients in the EZH2wt cohort, we believe that the nearly doubled objective response rate for the EZH2mut cohort was mainly driven by the EZH2 mutation." EXH2mut tumors "have an increased dependency on this protein, explaining their greater responsiveness to EZH2 inhibitors," say the authors, led by Franck Morschhauser, MD, PhD, a professor of hematology at the Centre Hospitalier Universitaire de Lille, France.

Treatment-related adverse events of grade 3 or worse included thrombocytopenia in three patients (3%), neutropenia in three (3%), and anemia in two (2%). Four (4%) patients had a serious treatment-related adverse event: neutropenia, pancytopenia, and transient global amnesia in one patient each, and arrhythmia and myelodysplastic syndrome in one patient.

"With its ability to produce clinically meaningful and durable responses, favourable safety profile, and unique mechanism of action, tazemetostat represents a new therapeutic option," the investigators say.

Both studies were funded and conducted by tazemetostat maker Epizyme. Authors had numerous ties to the company. Gounder reported personal fees and a travel grant from Epizyme, and Morschhauser is a consultant. Groisberg reported receiving advisory board fees from Regeneron, and Subbiah reported receiving research funding, advisory board fees, and/or travel funding from numerous companies, including Novartis, Eli Lilly, and Amgen, and AbbVie.

Lancet Oncol. Published online October 6, 2020. Gounder et al, Abstract; Morschhauser et al, Abstract; Comment

M. Alexander Otto is a physician assistant with a master's degree in medical science. He is an award-winning medical journalist who has worked for several major news outlets before joining Medscape, including McClatchy and Bloomberg. He is an MIT Knight Science Journalism fellow. Email: aotto@mdedge.com.

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