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Tazemetostat provides objective responses in follicular lymphoma, epithelioid sarcoma

Lancet Oncology
Reuters Health - 26/10/2020 - Tazemetostat, an oral inhibitor of the EZH2 protein, provides objective responses in patients with relapsed or refractory follicular lymphoma and advanced epithelioid sarcoma.

That's according to findings from two open-label, single-arm phase-2 trials published in The Lancet Oncology.

Activating mutations of EZH2, an epigenetic regulator of B-cell proliferation, are present in approximately 20% of patients with follicular lymphoma. And over 90% of epithelioid sarcomas have lost expression of INI1, which leads to unopposed oncogenic activation of EZH2.

In the first trial, Dr. Franck Morschhauser of Universite de Lille, in France, and colleagues at 38 clinics or hospitals in Europe and North America investigated the activity and safety of tazemetostat in 99 patients with relapsed or refractory follicular lymphoma with wild-type or mutated EZH2.

The objective response rate, defined as the proportion of patients with a best overall response of a complete or partial response, was 69% in patients with mutated EZH2 and 35% in patients with wild-type EZH2, a significant difference.

There were six complete responses in the mutated-EZH2 group and two in the wild-type group.

The median duration of response was 10.9 months in the mutated EZH2 group and 13.0 months in the wild-type EZH2 group.

Treatment-related adverse events occurred in 80 patients. Four patients had serious treatment-related adverse events and eight discontinued tazemetostat because of a treatment-emergent adverse event. There were no treatment-related deaths.

"The drug was well tolerated and showed a higher overall response rate in patients with EZH2 activating mutations but durable responses in both the EZH2-wild-type and EZH2-mutant cohorts," Dr. Morschhauser told Reuters Health by email. "Tazemetostat warrants further trials in combination in non-Hodgkin lymphoma (not only follicular lymphoma, but also other histologies)."

"A phase-3 randomized trial is ongoing, and a phase-2 trial of tazemetostat plus R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) is ongoing in first-line follicular lymphoma," he said.

"With its ability to produce clinically meaningful and durable responses, favorable safety profile, and unique mechanism of action, tazemetostat represents a new therapeutic option for patients with follicular lymphoma," the authors conclude.

In the second trial, Dr. Mrinal Gounder of Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, in New York City, and colleagues from 32 hospitals and clinics in Australia, Europe, Taiwan, and North America investigated the clinical activity and safety of tazemetostat in 62 patients with advanced or metastatic epithelioid sarcoma.

Nine of these patients (15%) had an objective response, the median duration of which had not been reached at a median follow-up of 13.8 months.

Median progression-free survival was 5.5 months, and median overall survival was 19.0 months.

At data cutoff, eight patients remained on tazemetostat, and 45 patients had discontinued tazemetostat due to disease progression.

Grade-3-4 treatment-related adverse events included anemia in four patients and weight loss in two patients, and treatment-related serious adverse events occurred in two patients. There were no treatment-related deaths.

"Given the favorable tolerability of this drug, there is potential for combining tazemetostat with other anticancer agents," the research team concludes. "A randomized, phase 1b/3 clinical trial of tazemetostat plus doxorubicin in the first-line setting is currently underway."

Dr. Vivek Subbiah of the University of Texas MD Anderson Cancer Center, in Houston, who coauthored an accompanied editorial, told Reuters Health by email, "Before tazemetostat, there was no drug specifically (approved by the U.S. Food and Drug Administration, FDA) for epithelioid sarcoma. Now that tazemetostat (TAZVERIK) is approved, oncologists should definitely consider prescribing this drug for adults and pediatric patients aged 16 years and older with metastatic or locally advanced epithelioid sarcoma who not eligible for complete surgical resection."

"In the case of follicular lymphoma, where there are more options for therapy, this drug should be considered as an option for adult patients with relapsed or refractory (R/R) follicular lymphoma (FL) whose tumors are positive for an EZH2 mutation as detected by an FDA-approved test and who have received at least two prior systemic therapies," he said. "In addition, for adult patients with R/R FL who do not harbor the EZH2 mutation, this may be considered as an option for those who have no other satisfactory alternative treatment options."

Dr. Subbiah added, "These two studies impart lessons, raise important questions, and open up a whole area of preclinical and clinical research into therapies targeting epigenetic mechanisms. This is just the beginning, and future rationally designed combination studies are warranted."

Dr. Matthew Matasar of Memorial Sloan Kettering Cancer Center, who recently reviewed emerging therapies for follicular lymphoma but was not involved in these trials, told Reuters Health by email, "Tazemetostat represents a major advancement for the treatment of relapsed/refractory follicular lymphoma harboring EZH2 mutation and could be considered a standard of care in the second line or beyond for this subset of patients. For wild-type patients, the low overall response rate limits its clinical applicability to those patients with wild-type disease who lack other clinically relevant therapeutic options."

"Future investigations evaluating tazemetostat in combination with other active agents may broaden the potential impact tazemetostat can have for patients with follicular lymphoma," he said.

Dr. Gounder did not respond to a request for comments.

Epizyme, which markets the drug, funded both trials and employed or had other financial ties to several of the authors.

By Will Boggs MD

SOURCE: https://bit.ly/3j1GMqi, https://bit.ly/3dup79p and https://bit.ly/2H7npPq Lancet Oncology, online October 6, 2020.

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