The FDA has 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.
The FDA has granted an accelerated approval to tazemetostat (Tazverik) 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.1
The approval is primarily based on findings from a cohort of patients with epithelioid sarcoma (cohort 5; n = 62) in the ongoing, single-arm, phase II Study EZH-202 trial, which showed that treatment with tazemetostat elicited an objective response rate (ORR) of 15% (n = 9); this included a 1.6% complete response rate and a 13% partial response rate. Among responders in the trial, 67% had a duration of response (DOR) of ≥6 months.
"Despite industry advancements, there are limited therapeutic options for treating patients with epithelioid sarcoma who struggle with high rates of recurrence and toxicities associated with currently used therapies," study investigator Gary K. Schwartz, MD, chief of hematology and oncology at Columbia University and NewYork-Presbyterian Hospital, deputy director of the Herbert Irving Comprehensive Cancer Center, professor of oncology at Columbia University Vagelos College of Physicians and Surgeons, stated in a press release. “The Tazverik data from the [epithelioid sarcoma] cohort in Epizyme’s phase II trial support its potential to provide clinically meaningful and durable responses, and tolerability for [epithelioid sarcoma] patients. This approval of Tazverik represents an important advancement in the treatment of patients with [epithelioid sarcoma].”
Epizyme, the developer of the EZH2 inhibitor, stated in the press release that it will conduct post-marketing activities, such as clinical pharmacology evaluations, to assess the effect of tazemetostat on liver function as well as the effect of CYP3A inhibitors and inducers on tazemetostat; this will be used to inform aspects of prescribing information. The company will also expand enrollment of cohort 6 of Study EZH-202 for a total of ≥60 patients with epithelioid sarcoma; the cohort has enrolled 44 patients to date. This expanded enrollment is planned to provide more patient experience for potential future inclusion in the label, the company stated.
Epithelioid sarcoma is a rare and aggressive form of soft tissue sarcoma that commonly affects young adults, Epizyme, the developer of tazemetostat, stated in its briefing document to the FDA, and it is often diagnosed late in disease with a high prognosis and mortality rate.
In the multicenter, open-label phase II trial, investigators enrolled 62 patients with locally advanced or metastatic epithelioid sarcoma whose tumors lacked INI1 expression. A lack of INI1 expression enables the epigenetic modifier EZH2 to act as an oncogenic driver in tumors cells. By targeting EZH2, tazemetostat has the potential to block this process. Among the 62 patients, the median age was 34 years (range, 16-79), and 63% were male. Additionally, 76% of patients were white, and 11% were Asian; 44% had proximal disease, 92% had an ECOG performance status of 0 or 1, and 8% had an ECOG performance status of 2. Seventy-seven percent of patients had prior surgery and 61% received prior chemotherapy.
Additional data showed that serious adverse events (AEs) occurred in 37% of patients on tazemetostat; serious AEs that occurred in ≥3% of patients included hemorrhage, pleural effusion, skin infection, dyspnea, pain, and respiratory distress. One patient (2%) permanently discontinued tazemetostat due to an AE of altered mood, and AE-related dose interruptions occurred in 34% of patients. The most frequent AEs requiring dosage interruptions in ≥3% were hemorrhage, increased alanine aminotransferase (ALT), and increased aspartate aminotransferase (AST). AE-related dose reductions occurred in 1 patient due to decreased appetite. The most common (≥20%) AEs were pain, fatigue, nausea, decreased appetite, vomiting and constipation.
The approval follows a December 2019 hearing by the FDA's Oncologic Drugs Advisory Committee, in which the panel was to discuss data supporting tje new drug application (NDA) for an accelerated approval of tazemetostat in this setting, and to determine whether the ORR benefit with the EZH2 inhibitor was enough to warrant an indication and that it outweighed the risks of secondary malignancies.Although Epizyme submitted data from cohort 5 of the trial for the NDA, the FDA also assessed findings from cohort 6 (n = 44), which enrolled patients with similar eligibility criteria and baseline characteristics, and pooled data from the 2 cohorts to further assess the efficacy of tazemetostat in this patent population.2 In both cohorts, patients were treated with the same dosage regimen of tazemetostat. Additional data that were submitted to support the application were safety findings from the entire tazemetostat program in various malignancies.
Across the 2 cohorts, the median age was 37 years; 65% of patients were male, and 78% were white. Over 70% of patients had stage ≥III disease at diagnosis. The ECOG performance status was 0, 1, and 2, for 36, 21, and 5 patients, respectively. The cohort included 24 treatment-naïve patients and 38 patients who had received 1 to ≥3 prior lines of cancer treatment. Tazemetostat was administered at 800 mg twice daily.
Additionally, the FDA noted that a significant limitation of the analysis is that not all of each patient’s burden of disease was measured at baseline or followed for response.
Results in cohort 5 showed that, at a median follow-up of 13.8 months, the median DOR was 4 to 24+ months. In cohort 6, which had a median follow-up of 11.8 months, the ORR was 11%, which comprised 4 PRs and 1 CR, and a median DOR of 3.5 to 18.2+ months.
The pooled analysis showed an ORR of 13%, which had 12 PRs and 2 CRs, and a median DOR of 3.5 to 24+ months at a 12.8-month median follow-up. In its briefing document, the FDA stated its concerns that the ORR does not provide “sufficient evidence of benefit to outweigh the risks of tazemetostat in patients with epithelioid sarcoma.”
The median overall survival (OS) among all 62 patients was 82.4 weeks (95% CI, 47.4—not estimable). The median progression-free survival (PFS) was 23.7 weeks (95% CI, 14.7-25.7), and the disease control rate was 21%.
Sixty-eight percent of patients had a reduction in tumor burden, and 27% of patients with radiological progression via RECIST criteria maintained stable disease after disease progression with continued use of tazemetostat.
Regarding safety, the most common all-grade adverse events (AEs) of patients enrolled in cohort 5 included pain, fatigue, nausea, decreased appetite, vomiting and constipation. Grade ≥3 AEs occurred in 48% of patients, which most commonly included anemia (13%), pain and decreased weight (7%), and hemorrhage, decreased appetite, dyspnea, and pleural effusion (4.8% each). Serious AEs included hemorrhage (6.5%), pleural effusion (6.5%), dyspnea (5%), cellulitis (3.2%), and pain (3.2%).
Thirty-four percent of patients required dose interruptions due to AEs, and there were no deaths related to tazemetostat treatment.
In the overall tazemetostat program, 6 (0.7%) patients out of a total 822 patients developed a secondary malignancy as of May 24, 2019, Epizyme stated in their briefing document.3 In a pooled safety population of 725 adult and pediatric patients, the FDA noted that 6 (0.8%) of patients developed secondary myelodysplastic syndromes, acute myeloid leukemia, or T-cell lymphoblastic leukemia.
The randomized, confirmatory EZH-301 trial, which has opened for enrollment, is evaluating the combination of tazemetostat and doxorubicin compared with placebo and doxorubicin in patients with advanced epithelioid sarcoma who have not previously received treatment.
"Today’s accelerated approval of Tazverik is a landmark event for people with [epithelioid sarcoma] and represents our dedication to our mission of rewriting treatment for people with cancer and other serious diseases,” Robert Bazemore, president and chief executive officer of Epizyme, the developer of tazemetostat, stated in the press release. “Tazverik is now the first and only FDA-approved EZH2 inhibitor, and the first and only FDA-approved treatment specifically indicated for [epithelioid sarcoma] patients. Our commercial launch plans are underway, and we expect to make Tazverik available to [epithelioid sarcoma] patients and treating physicians across the United States within 10 business days.”
The accelerated approval of tazemetostat is contingent on the results of a confirmatory trial.