The FDA’s Oncologic Drugs Advisory Committee voted in favor of approving tazemetostat tablets as a treatment for patients with metastatic or locally advanced epithelioid sarcoma that is ineligible for curative surgery.
The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted unanimously (11-0) in favor of approving tazemetostat tablets as a treatment for patients with metastatic or locally advanced epithelioid sarcoma that is ineligible for curative surgery.
UPDATE 1/23/2020: FDA Approves Tazemetostat for Epithelioid Sarcoma
The FDA granted a priority review designation to the NDA for tazemetostat in July 2019 for the treatment of patients with metastatic or locally advanced epithelioid sarcoma that is not eligible for curative surgery. The NDA is primarily based on findings from a cohort of patients with epithelioid sarcoma (cohort 5; n = 62) in an ongoing, single-arm, phase II study (Study EZH-202), which showed that the ORR was 15% (n = 9), comprised of 8 partial responses (PRs) and 1 complete response (CR).1
“Although the response rate is low, I was impressed with the duration of some of those responses, and I’m also impressed that this does appear to be safe. While the concern for secondary malignances is out there, it seems quite rare,” meeting chairperson Philip Hoffman, MD, professor of Medicine, The University of Chicago, Section of Hematology/Oncology, said when explaining his “yes” vote.
Under the Prescription Drug User Fee Act, the FDA, which is not required to follow ODAC, is expected to make a decision on the approval by January 23, 2020.
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.
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 duration of response (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.
Regarding the randomized trial, Susan Halabi, PhD, professor of Biostatistics and Bioinformatics, Duke University Medical Center, said, “I hope a clinically meaningful endpoint [is picked] for the phase III trial because I’m not convinced progression-free survival [would be] the best endpoint.”
Also addressing the design of the randomized trial, Anthony D. Sung, MD, Duke University School of Medicine, said, “I would hope that quality-of-life studies are built into the randomized controlled trial, because I think it’s come up multiple times before ODAC where sponsors suggest that there is better quality of life or benefit, but they do not have the data to back that up.”
The purpose of the hearing was to discuss data supporting a new drug application (NDA) for an accelerated approval of tazemetostat in this setting, and to determine whether the overall response rate (ORR) benefit with the EZH2 inhibitor was enough to warrant an indication and that it outweighed the risks of secondary malignancies.