FDA Approves Tazemetostat for Relapsed/Refractory Follicular Lymphoma

The FDA has approved the use of tazemetostat (Tazverik) for 2 follicular lymphoma indications: for the treatment of adult patients with relapsed or refractory follicular lymphoma whose tumors harbor EZH2 mutations, as detected by an FDA-approved test, and who have received at least 2 prior lines of systemic therapy, and for the treatment of adult patients with relapsed or refractory follicular lymphoma who have no satisfactory alternative treatment options.¹

“Although follicular lymphoma has an indolent course, its relapsing nature requires repeated courses of treatment. The current toolbox of options includes chemotherapy, immunomodulatory agents, and PI3K inhibitors all with or without an anti-CD20 monoclonal antibody. None of the approved therapies to date are targeted, and we do not know how to sequence them. Tazemetostat, an oral EZH2 inhibitor, is the first non-antibody targeted therapy in this disease. Although the ongoing studies do not inform the treating physician on sequencing, the favorable toxicity profile and efficacy in both mutated and unmutated EZH2 follicular lymphomas makes this a promising agent in this disease,” Sonali M. Smith, MD, FASCO, told Targeted Oncology about the impact of the approval. Smith is the Elwood V. Jensen Professor of Medicine, interim chief of the Section of Hematology/Oncology, and director of the Lymphoma Program at The University of Chicago.

Approval for tazemetostat is supported by findings from a subgroup of patients with follicular lymphoma treated with the EZH2 inhibitor in a phase 2 trial. Data from the study were presented at the 2019 American Society of Hematology Annual Meeting showing that the patients with an EZH2 mutation had an objective response rate (ORR) of 69% and patients with wild-type EZH2 had an ORR of 35%.² 

The overall open-label, multicenter study explored the use of tazemetostat as a single agent in patients with advanced solid tumors or B-cell lymphomas as well as in combination with prednisolone in patients with diffuse large B-cell lymphoma (NCT01897571). The follicular lymphoma cohort included patients with grade 1 to 3b relapsed/refractory disease who had EZH2 activating mutations (n = 45) or wild-type EZH2 (n = 54). 

All patients had an ECOG performance status of 0 to 2, had measurable disease, and had received at least 2 prior therapies.

Patients were treated with 800 mg of oral tazemetostat given twice a day.

The primary end point was objective response rate (ORR) and secondary end points were progression-free survival (PFS) and safety. 

Among patients with an EZH2 mutation, the ORR was 69% by independent review and 78% by investigator assessment. The median duration of response was 10.9 months by independent review and 8.3 months by investigator review. The median PFS was 13.8 months by both independent and investigator review and the median overall survival had not yet been reached. 

In patients with wild-type EZH2, the ORR was 35% by independent review and 33% by investigator assessment. The median duration of response was 13 months by independent review and 14.7 months by investigator review. The median PFS was 11.1 months by independent review and 5.6 months by investigator assessment; the median overall survival had not yet been reached. 

The agent demonstrated a favorable safety and tolerability profile. The most common grade ≥3 treatment-related treatment-emergent adverse events were thrombocytopenia (3%), anemia (2%), asthenia (1%), and fatigue (1%). Only 9% of patients required a dose reduction and 8% discontinued treatment due to an adverse event. No treatment-related deaths were reported on the study. 

Continued approval for tazemetostat for these 2 indications may be contingent upon verification of clinical benefit in a confirmatory trial, has been initiated by the developer. The confirmatory global, randomized, adaptive trial will evaluate the use of tazemetostat plus lenalidomide (Revlimid) and rituximab (Rituxan) for patients with follicular lymphoma in the second-line setting or beyond. A total of 500 patients are expected to be enrolled in the trial and the safety run-in portion of the trial has already begun.

“Follicular lymphoma remains an incurable disease, and even with the availability of new drugs in recent years, there have remained important unmet needs in the treatment of follicular lymphoma,” said John P. Leonard, MD, the Richard T. Silver Distinguished Professor of Hematology and Medical Oncology at Weill Cornell Medicine, an oncologist at New York-Presbyterian/Weill Cornell Medical Center, and an investigator in the phase 1b/3 confirmatory trial for Tazverik for follicular lymphoma, in a statement. “The durable responses observed with this drug are notable in the context of the safety profile and route of oral, at-home administration, and will offer an important new option for physicians as we care for patients with relapsed/refractory follicular lymphoma.”

Tazemetostat is also FDA approved for the treatment of adult and pediatric patients aged 16 and above with metastatic or locally advanced epithelioid sarcoma who are not eligible for complete resection.

_References:

_{1. Epizyme Announces U.S. FDA Accelerated Approval of TAZVERIK™ (tazemetostat) for Relapsed/Refractory Follicular Lymphoma. News release. Epizyme. June 18, 2020. Accessed June 18, 2020. https://bwnews.pr/3dfzZXc}

_{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.}