FDA Approves Tazemetostat in Relapsed/Refractory Follicular Lymphoma

The FDA has approved the tazemetostat for the treatment of patients with relapsed/refractory follicular lymphoma whose tumors are EZH2 positive as detected by an FDA-approved test and who have received at least 2 prior systemic therapies, as well as those with relapsed/refractory disease who have no other available satisfactory treatment options.¹

The regulatory agency also approved the cobas EZH2 Mutation Test, developed by Roche Molecular Systems, Inc, as a companion diagnostic for the EZH2 inhibitor.

The decision was based on data from 2 open-label, single-arm cohorts (cohort 4, EZH2-mutated follicular lymphoma and cohort 5, EZH2 wild-type follicular lymphoma) for the multicenter Study E7438-G000-101 (NCT01897571) in patients with histologically confirmed follicular lymphoma who had received at least 2 prior systemic therapies. The mutations were prospectively detected using the cobas EZH2 Mutation Test.

Updated results from the trial showed that the first-in-class EZH2 inhibitor elicited an objective response rate (ORR), assessed by an independent review committee (IRC), of 69% in patients with EZH2-mutant disease (95% CI, 53%-82%), with 12% complete responses (CRs) and 57% partial responses (PRs). The median duration of response (DOR) in these patients was 10.9 months (95% CI, 7.2-nonevaluable [NE]). In 53 patients with EZH2 wild-type disease, the response rate was 34% (95% CI, 22%-48%), with 4% CRs and 30% PRs. The median DOR in this group with tazemetostat was 13 months (95% CI, 5.6-NE).

In the ongoing, 2-cohort, phase 2 trial, investigators are evaluating tazemetostat as a single agent for patients with follicular lymphoma who had EZH2 activating mutations (n = 45) or EZH2 wild-type (n = 54) who had received ≥2 prior lines of systemic therapy. To be eligible for enrollment, patients had to be ≥18 years old, have an ECOG performance status of 0 to 2, and measurable disease per 2007 International Working Group–Non-Hodgkin Lymphoma criteria.² All patients received oral tazemetostat at 800 mg twice daily.

Activity was reported by IRC and investigator assessment. The primary end point is investigator-assessed ORR; secondary end points include duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.

As of the data cutoff date of August 9, 2019, the investigator-assessed ORR was 78% in patients with EZH2 mutations, which included a 9% CR rate and a 69% PR rate.³ The investigator-assessed ORR was 33% in patients with EZH2 wild-type, which included a 6% CR rate and a 28% PR rate.

Results also showed that the median DOR was 10.9 months for the EZH2-mutant cohort and 13 months for those with EZH2 wild-type disease by IRC assessment.

In the EZH2-mutant cohort, the stable disease (SD) rate was 22% via investigator assessment and 29% by IRC; these rates were 30% and 33% in the EZH2 wild-type  group, respectively. No EZH2-mutant patients experienced progressive disease (PD) via investigator review but it occurred in 1 patient via IRC review. In the EZH2 wild-type cohort, this occurred in 30% and 22% by investigator and IRC, respectively.

When stratified by EZH2 status, the median PFS was 13.8 months by both investigator and IRC assessment in patients with EZH2 mutations. In the EZH2 wild-type group, the median PFS was 5.6 months by investigator review and 11.1 months by IRC review. The median overall survival has not yet been reached in either population.

With regard to safety, most common adverse events (AEs) with tazemetostat reported in patients with follicular lymphoma were fatigue, upper-respiratory tract infection, musculoskeletal pain, nausea, and abdominal pain. Serious AEs were reported in 30% of patients, and most of them were due to infection. Second primary malignancy was the most common reason for treatment discontinuation, which was reported in 2% of patients.

An international, adaptive trial will evaluate the combination of tazemetostat with lenalidomide (Revlimid) in combination with rituximab (Rituxan) for patients with follicular lymphoma in the second- or later-line setting. The study, which will be used to support a full approval for tazemetostat in this indication, is expected to enroll approximately 500 patients with follicular lymphoma that is stratified based on EZH2 mutation status. The safety run-in portion of the trial has started.

In January 2020, the FDA granted an accelerated approval to tazemetostat for the treatment of adult and pediatric patients aged ≥16 years old with metastatic or locally advanced epithelioid sarcoma that is not eligible for complete resection.

References

1. FDA granted accelerated approval to tazemetostat for follicular lymphoma. News release. FDA. June 18, 2020. Accessed June 18, 2020. bit.ly/310qcSe.
2. Morschhauser F, Tilly H, Chaidos A, et al. Phase 2 multicenter study of tazemetostat, an EZH2 Inhibitor, in patients with relapsed or refractory follicular lymphoma. Blood. 2019;134(suppl 1):123. doi:10.1182/blood-2019-128096
3. Epizyme submits new drug application to the U.S. FDA for tazemetostat for the treatment of patients with follicular lymphoma. News release. Epizyme. December 18, 2019. Accessed December 18, 2019. bit.ly/2S3SBm2.