FDA Grants Priority Review to Tazemetostat in Follicular Lymphoma

Shefali Agarwal, MD

The FDA has granted a priority review designation to a supplemental new drug application (sNDA) for tazemetostat (Tazverik) for the treatment of patients with relapsed/refractory follicular lymphoma who have received at least 2 prior lines of systemic therapy.¹

UPDATE 6/18/20: FDA Approves Tazemetostat in Relapsed/Refractory Follicular Lymphoma

The sNDA is mostly based on updated results of an ongoing phase II trial, which showed that the first-in-class EZH2 inhibitor elicited an objective response rate (ORR), assessed by an independent review committee (IRC), of 69% for patients with EZH2-mutant disease and a 35% ORR for those with wild-type EZH2  follicular lymphoma.² The IRC-assessed complete response (CR) and partial response (PR) rates were 13% and 56% in those with EZH2 mutations and 4% and 31% for patients with wild-type EZH2, respectively.

Under the Prescription Drug User Fee Act, the FDA is scheduled to decide on the sNDA on or before June 18, 2020.

“Follicular lymphoma is an incurable disease for which patients are in need of a safe, durable treatment option,” Shefali Agarwal, MD, chief medical officer of Epizyme, the developer of tazemetostat, stated in a press release. “If approved, we believe Tazverik could become an important new option for these patients and their physicians. We are thrilled with FDA’s acceptance of our application as an sNDA with priority review, for Tazverik for patients with relapsed or refractory follicular lymphoma. We look forward to working with the Agency during their review and would like to thank the many patients, caregivers and physicians whose contributions have been invaluable in bringing us to this point.”

In the ongoing, 2-cohort, phase II trial, investigators evaluated tazemetostat as a single agent for patients with follicular lymphoma who had EZH2  activating mutations (n = 45) or wild-type EZH2  (n = 54) and 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.^3  All patients received oral tazemetostat at 800 mg twice daily.

Activity was reported by IRC and investigator assessment. The primary endpoint is investigator-assessed ORR; secondary endpoints 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. The investigator-assessed ORR was 33% in patients with wild-type EZH2, 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 wild-type EZH2  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 wild-type EZH2  group, respectively. No EZH2-mutant patients experienced progressive disease (PD) via investigator review but it occurred in 1 patient via IRC review. In the wild-type EZH2  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 wild-type EZH2  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.

Regarding safety, the most frequently reported grade ≥3 treatment-emergent adverse events (TEAEs) included thrombocytopenia (3%), anemia (2%), asthenia (1%), and fatigue (1%). TEAEs that led to tazemetostat discontinuation occurred in 8% of patients; 9% of patients required dose reductions. No treatment-related deaths occurred while on study.

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. Epizyme Announces FDA Acceptance of New Drug Application for Filing with Priority Review for TAZVERIK™ (tazemetostat) for the Treatment of Follicular Lymphoma. Published Feb 14, 2020. https://bit.ly/39DlCuu. Accessed Feb 14, 2020.
2. Epizyme presents updated phase 2 data at the 2019 ASH Annual Meeting supporting planned tazemetostat NDA submission for follicular lymphoma [news release]. Epizyme. Published December 7, 2019. https://bit.ly/35GrEJc. Accessed December 7, 2019.
3. 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. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 123.