On June 18, 2020, the EZH2 inhibitor tazemetostat was granted accelerated approval for the treatment of adults with relapsed or refractory follicular lymphoma (FL) whose tumors are positive for an EZH2 mutation, as detected by a U.S. Food and Drug Administration (FDA)-approved test, and who have received at least two prior systemic therapies. The agent was also approved for treatment of adults with relapsed or refractory FL who have no satisfactory alternative treatment options.^1,2

The FDA simultaneously approved the cobas EZH2 Mutation Test as a companion diagnostic for tazemetostat.

Supporting Efficacy Data

Approval was based on findings from two open-label, single-arm cohorts (cohorts 4 and 5) of the multicenter Study E7438-G000-101 (ClinicalTrials.gov identifier NCT01897571).² Study participants had histologically confirmed FL after at least two prior systemic therapies. EZH2 mutations were identified prospectively with the use of formalin-fixed, paraffin-embedded tumor samples, which were centrally tested using the cobas EZH2 Mutation Test. Cohort 4 consisted of 42 patients with EZH2-mutated FL, and cohort 5 included 53 patients with EZH2 wild-type FL.

Patients received oral tazemetostat at 800 mg twice daily until disease progression or unacceptable toxicity. They were required to have creatinine clearance of at least 40 mL/min. Efficacy was based on overall response rate and duration of response, according to the International Working Group Non-Hodgkin Lymphoma criteria, as assessed by an independent review committee.

Among the 42 patients with EZH2-mutant disease, the overall response rate was 69% (95% confidence interval [CI] = 53%–82%), with a complete response in 12%. The median duration of response was 10.9 months (95% CI = 7.2 months to not estimable; range = 0.0+ to 22.1+ months).

Among the 53 patients with EZH2 wild-type disease, the overall response rate was 34% (95% CI = 22%–48%), with a complete response in 4%. The median duration of response was 13 months (95% CI = 5.6 months to not estimable; range = 1 to 22.5+ months).

How It Works

Tazemetostat is an inhibitor of the methyltransferase EZH2 and some EZH2 gain-of-function mutations, including Y646X and A687V. Tazemetostat also inhibits EZH1. The best characterized function of EZH2 is as the catalytic subunit of the polycomb repressive complex 2 (PRC2), catalyzing monomethylation, dimethylation, and trimethylation of lysine 27 of histone H3. Trimethylation of histone H3 leads to transcriptional repression.

Switch/sucrose nonfermentable (SWI/SNF) complexes can antagonize PRC2 function in the regulation of the expression of certain genes of patients with epithelioid sarcoma. Preclinical and in vivo models with loss or dysfunction of certain SWI/SNF complex members—eg, integrase interactor 1 (INI1/SNF5/SMARCB1/BAF47) and SMARCA4 and SMARCA2—can lead to aberrant EZH2 activity or expression and a resulting oncogenic dependence on EZH2.

Tazemetostat suppressed proliferation of B-cell lymphoma cell lines in vitro and demonstrated antitumor activity in a mouse xenograft model of B-cell lymphoma with or without EZH2 gain-of-function mutations. Tazemetostat demonstrated greater effects on the inhibition of proliferation of lymphoma cell lines with mutant EZH2.

How It Is Used

Patients with relapsed or refractory FL should be selected for treatment based on the presence of EZH2 mutation of codons Y646, A682, or A692 in tumor specimens, as detected by an FDA-approved test. The recommended dosage of tazemetostat in the current indication is 800 mg orally, twice daily, until disease progression or unacceptable toxicity. For adverse reactions, the dose may be reduced stepwise to 600 mg twice daily and then to 400 mg twice daily. The drug should be discontinued if 400 mg twice daily cannot be tolerated.

Product labeling provides instructions on dose modification, including dose reduction and treatment interruption and discontinuation for adverse reactions including neutropenia, thrombocytopenia, anemia, and other grade 3 and 4 adverse reactions.

Coadministration of tazemetostat with strong or moderate CYP3A inhibitors (eg, ketoconazole, conivaptan, clarithromycin) should be avoided. If concomitant use with a moderate CYP3A inhibitor cannot be avoided, the tazemetostat dose should be reduced from 800 mg twice daily to 400 mg twice daily, from 600 mg twice daily to 400 mg once daily plus 200 mg once daily, or from 400 mg twice daily to 200 mg twice daily. Concomitant use of tazemetostat with strong or moderate CYP3A inducers (eg, phenytoin, rifampin, carbamazepine, St. John’s wort) should be avoided.

Safety Profile

Among the 99 patients in cohorts 4 and 5 in Study E7438-G000-101 who received tazemetostat, 68% were exposed to treatment for at least 6 months, 39% for at least 12 months, and 21% for at least 18 months. The most common adverse events of any grade (≥ 20%) were fatigue (36%), upper respiratory tract infection (30%), nausea (24%), musculoskeletal pain (22%), and abdominal pain (20%). The most common grade 3 or 4 adverse events included fatigue (5%) and abdominal pain (3%). The most common grade 3 or 4 laboratory abnormalities were decreased lymphocytes (18%), increased glucose (10%), decreased white blood cells (9%), and decreased hemoglobin (8%).

Serious adverse events occurred in 30% of patients. Adverse events led to dose reduction in 9% of patients and to treatment interruption in 28%. Permanent treatment discontinuation due to adverse events occurred in 8% of patients.

Tazemetostat has warnings/precautions for secondary malignancies and embryofetal toxicity. Tazemetostat increases the risk of developing secondary malignancies, including T-cell lymphoblastic lymphoma, myelodysplastic syndrome, and acute myeloid leukemia. Patients should receive long-term monitoring for the development of secondary malignancies. Patients should be advised not to breastfeed while taking tazemetostat. 

References

1. U.S. Food and Drug Administration: FDA granted accelerated approval to tazemetostat for follicular lymphoma. Available at https://www.fda.gov/drugs/fda-granted-accelerated-approval-tazemetostat-follicular-lymphoma. Accessed July 6, 2020.

2. Tazverik (tazemetostat) tablets prescribing information, Epizyme, Inc, June 2020. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213400s000lbl.pdf. Accessed July 6, 2020.