Lancet Oncology Data Reinforce Regulatory Approvals of Tazemetostat in Sarcoma, Follicular Lymphoma

Tazemetostat (Tazverik) demonstrated durable responses and sustained safety in patients with epithelioid sarcoma and relapsed/refractory follicular lymphoma, according to findings from 2 pivotal phase 2 trials that were published in The Lancet Oncology.¹

The data that were included in these publications support the accelerated approvals of the first-in-class EZH2 inhibitor by the FDA for the treatment of patients with epithelioid sarcoma in January 2020 and relapsed/refractory follicular lymphoma in June 2020.

“The two publications in such a highly regarded, peer-reviewed journal as the Lancet are the culmination of years of hard work by our team, and the significant contributions by the patients and physicians who participated in our clinical trials,” said Shefali Agarwal, MD, chief medical officer of Epizyme.

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

The approval was predominantly based on findings from cohort 5 of the single-arm, phase 2 Study EZH-202 trial. Among 62 patients with patients with epithelioid sarcoma, treatment with tazemetostat led to an objective response rate (ORR) of 15% (n = 9; 95% CI, 7%-26%), a complete response (CR) rate of 1.6%, and a partial response (PR) rate of 13%. The duration of response (DOR) was at least 6 months among responders.²

At a median follow-up of 13.8 months, the median DOR was not reached (95% CI 9.2–not estimable [NE]). Twenty-six percent of patients (n = 16; 95% CI, 16%–39%) had disease control at 32 weeks. The median time to response was 3.9 months (range, 1.9-7.4). The median progression-free survival (PFS) was 5.5 months (95% CI, 3.4-5.9), and the median overall survival (OS) was 19.0 months (95% CI, 11.0–NE).³

With regard to safety, grade 3 or worse treatment-related adverse effects (AEs) included anemia (n = 4; 6%) and weight loss (n = 2; 3%). Serious treatment-related AEs were reported in 2 patients (n = 1 seizure; n = 1 hemoptysis). No treatment-related deaths occurred.

In June 2020, the FDA granted an accelerated approval to tazemetostat for the treatment of patients with relapsed/refractory follicular lymphoma whose tumors are EZH2 positive as detected by the cobas EZH2 Mutation 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.

The approval was based on data from cohorts 4 and 5 of the multicenter, single-arm Study E7438-G000-101 trial in patients with EZH2-mutated follicular lymphoma and EZH2 wild-type follicular lymphoma, respectively. All patients had received at least 2 prior systemic therapies. The ORR, CR rate, and PR rates in patients with EZH2-mutant disease were 69% (95% CI, 53%-82%), 12%, and 57%, respectively. The median DOR in these patients was 10.9 months (95% CI, 7.2–NE). Among 53 patients with EZH2 wild-type disease, the ORR was 34% (95% CI, 22%-48%); the CR and PR rates were 4% and 30%, respectively. The median DOR in these patients was 13 months (95% CI, 5.6–NE).⁴

At a median follow-up of 22.0 months for the EZH2-mutant cohort and 35.9 months for the EZH2 wild-type cohort, the ORR was 69% (95% CI, 53%-82%; n = 31/45) and 35% (95% CI, 23%-49%; n = 19/54), respectively. The median DOR was 10.9 months (95% CI, 7.2–NE) in the EZH2-mutant cohort and 13.0 months (95% CI, 5.6–NE) in the EZH2 wild-type cohort. The median PFS was 13.8 months (95% CI, 10.7-22.0) and 11.1 months (95% CI, 3.7-14.6), respectively.⁵

Among all 99 patients, treatment-related grade 3 or higher AEs included thrombocytopenia (n = 3; 3%), neutropenia (n = 3; 3%), and anemia (n = 2; 2%). Serious treatment-related AEs occurred in 4 (4%) of 99 patients. No treatment-related deaths were reported.

“In our phase 2 trials, Tazverik demonstrated durable clinical responses in both patient populations, including in patients with advanced disease who had previously received multiple therapeutic regimens. In addition, we observed consistently favorable safety with Tazverik, which we view as one of its most attractive features,” said Agarwal. “These publications provide important support for Tazverik’s novel epigenetic approach, and I am very proud that we are able to offer it as an approved therapy for both patient populations.”

To that end, investigators have launched a phase 1b/3 trial, which will evaluate tazemetostat plus doxorubicin as frontline therapy in patients with advanced epithelioid sarcoma (NCT04204941).

“Based on its compelling clinical data and first-in-class mechanism, we believe Tazverik has a pipeline in-a-product opportunity that we hope may offer benefit to patients with a wide range of cancers,” added Robert Bazemore, president and chief executive officer of Epizyme. “The two FDA accelerated approvals this year highlight the therapeutic impact TAZVERIK could have for patients, and we look forward to continuing to explore its potential in additional tumor types and combinations to reach as many patients as possible.”

References:

1. Epizyme announces two Lancet Oncology publications on TAZVERIK^® (tazemetostat) phase 2 data in epithelioid sarcoma and follicular lymphoma. News release. October 7, 2020. Accessed October 9, 2020. https://bit.ly/3jMFXTn
2. Epizyme announces U.S. FDA accelerated approval of Tazverik (tazemetostat) for the treatment of patients with epithelioid sarcoma. News release. Epizyme. January 23, 2020. Accessed October 9, 2020. https://bwnews.pr/2GkgLBw.
3. Gounder M, Schoffski P, Jones RL, et al. Tazemetostat in advanced epithelioid sarcoma with loss of INI1/SMARCB1: an international, open-label, phase 2 study. The Lancet Oncol. 2020. doi:10.1016/S1470-2045(20)30451-4
4. FDA granted accelerated approval to tazemetostat for follicular lymphoma. News release. FDA. June 18, 2020. Accessed October 9, 2020. bit.ly/310qcSe.
5. Morschhauser F, Tilly H, Chaidos A, et al. Tazemetostat for patients with relapsed/refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial. The Lancet Oncol. 2020. doi:10.1016/S1470-2045(20)30441-1