Tazemetostat Monotherapy Generates Durable Responses in Heavily Pretreated Follicular Lymphoma

Tazemetostat (Tazverik) as a single agent demonstrated clinically meaningful durable responses as treatment of patients with heavily pretreated relapsed/refractory follicular lymphoma (FL), according to findings from a phase 2 study.¹

The EZH2 inhibitor received approval from the FDA in June 2020 for the treatment of adult patients with relapsed/refractory FL who harbored an EZH2 mutation and have received at least 2 prior lines of systemic therapy, as well as for the treatment of those with no satisfactory alternative therapeutic options.² Through inhibition of the EZH2 mutation, this therapy reprograms cell differentiation, reduces B-cell proliferation, promotes anti-tumor immunity, and allows expression of tumor suppressor genes.

This open-label, single-arm study was conducted across 38 sites in the United States, France, the United Kingdom, Australia, Canada, Poland, Italy, Ukraine, and Germany, in order to evaluate the activity and safety of this patient population. Overall, 45 patients with EZH2-mutant FL and 54 with EZH2 wild-type FL were included in the study.¹

The objective response rate (ORR) assessed by the independent radiology committee was 69% (95% CI, 53-82) in the EZH2-mutant cohort and 35% (95% CI, 23-49) in the EZH2 wild-type cohort, which included complete responses in 6 and 2 patients, respectively. Among the 42 patients who had partial responses (PRs), 8 (19%) in the mutational cohort and 4 in wild-type cohort had ¹⁸F-FDG PET scans, and all 8 PRs were confirmed.

Among the 50 patients who had a response overall, 3 in the mutational cohort and 7 in the wild-type cohort had a hematopoietic stem cell transplant. There was evidence of a reduction in the tumor volume in 44 patients (98%) in the mutational cohort and 35 (65%) in the wild-type cohort.

The median duration of response was 10.9 months (95% CI, 7.2-not estimable [NE]) in the mutational cohort and 13.0 months (95% CI, 5.6-NE) in the wild-type cohort. Among the 31 patients in the mutational arm who had an objective response, 19 patients (61%) had a response that lasted 6 months or longer, 7 (23%) for 12 months or longer, and 6 (19%) for 18 months or longer. Among the 19 patients with an objective response in the wild-type cohort, 10 (53%) had a response lasting for 6 months or longer, 7 (37%) for 12 months or longer, and 4 (21%) for 18 months or longer.

Eleven patients in the mutational and 8 from the wild-type cohorts completed 2 years of therapy and were entered into the roll-over trial, the TRuST study (NCT02875548). Among these patients, 2 (1 from each cohort) had relapsed, 4 had CRs (2 from each cohort), 5 had PRs (4 from the EZH2 wild-type cohort), and 2 had stable disease (both from the wild-type cohort).

Twenty-five patients in the mutational cohort and 32 patients in the wild-type cohort had progression-free survival (PFS) events. The median PFS was 13.8 months (95% CI, 10.7-22.0) in the mutational arm and 11.1 months (95% CI, 3.7-14.6) in the wild-type cohort.

The median time to first response was 2.7 months (interquartile range [IQR], 1.9-5.5) in the mutational cohort, and 3.7 (IQR, 2.2-8.3) in the wild-type cohort. Eight deaths were reported in the mutational cohort and 21 in the wild-type. The median overall survival had not been reached in the mutational cohort (95% CI, NE-NE), nor the wild-type cohort (95% CI, 24.9-NE).

All 3 patients who had grade 3b or transformed FL in the mutational cohort had a response, as well as 2 of the 6 patients with grade 3b or transformed disease in the wild-type cohort. All of these responses in both cohorts were PRs. One patient in the mutational cohort and 6 from the wild-type cohort who had relapsed after a PI3K inhibitor or immunomodulatory drug had an objective response. According to post-hoc exploratory analysis, responses deepened over time with continued treatment, and of those patients who had a best response of a CR, 5 (86%) of 6 in the mutational cohort and 1 (50%) of 2 in the wild-type cohort had a PR before the CR.

Treatment-emergent adverse events (AEs) of any grade occurred in 98 (99%) of 99 patients, and treatment-related AEs occurred in 80 (81%) in any grade. Overall, serious treatment-emergent AEs were observed in 27 (27%) of patients, of which the most common included sepsis, general physical health deterioration, and anemia. Serious treatment-related AEs occurred in 4 patients (4%), which included neutropenia, pancytopenia, and transient global amnesia in 1 patient each, and arrythmia and myelodysplastic syndrome (MDS) in 1 patient.

Treatment-related AEs of grade 3 or higher included thrombocytopenia (3%), neutropenia (3%), and anemia (2%). Treatment-emergent AEs that led to dose reductions were observed in 9 patients (9%), while treatment-emergent AEs that led to dose interruptions occurred in 27 patients (27%). Discontinuation of tazemetostat occurred in 8 patients (8%) due to treatment-emergent AEs, of which 5 (5%) were treatment-related.

At 15.3 months, MDS was reported in 1 patient after initiating treatment, and at 25.8 months after starting therapy, acute myeloid leukemia was reported in 1 patient.

Overall, tazemetostat demonstrated anti-tumor activity as treatment of patients with relapsed/refractory FL, and the high ORR observed in the mutational cohort underscores the importance of the EZH2 mutation in the pathogenesis of FL. Due to the low prevalence of treatment-related AEs in the study, as well as the low proportion of patients who required either dose reductions or discontinuations due to these AEs, allowed for patients to remain on treatment longer.

“Furthermore, the objective response rate for patients with double-refractory disease was high, suggesting the potential of EZH2 inhibition in managing difficult-to-treat follicular lymphomas,” the study authors wrote. “The responses in both EZH2 cohorts were durable.”

_References

_{1. Morschhauser F, Tilly H, Chaidos A, et al. Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicenter, phase 2 trial [Published Online October 6, 2020]. Lancet Oncol. doi: 10.1016/S1470-2045(20)30441-1}

_{2. Epizyme Announces U.S. FDA Accelerated Approval of TAZVERIK™ (tazemetostat) for Relapsed/Refractory Follicular Lymphoma. News release. Epizyme. June 18, 2020. Accessed October 13, 2020. https://bwnews.pr/3dfzZXc}