(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.”