FDA News

FDA advisory committee unanimously supports approval of tazemetostat for epithelioid sarcoma

The FDA’s Oncologic Drugs Advisory Committee, or ODAC, today voted 11-0 in favor of approval of tazemetostat for the treatment of adults with metastatic or locally advanced epithelioid sarcoma who are not eligible for curative surgery.

The major discussion point regarding tazemetostat (Epizyme), an EZH2 inhibitor, focused on the low response rates observed in the EZH-202 trial, but panelists ultimately agreed these response rates represent durable benefit for a small group of patients who otherwise have few effective treatments.

“A response rate as shown in this trial of 11% to 15% is considered clinically meaningful in my opinion,” Richard Francis Riedel, MD, associate professor of medicine at Duke University School of Medicine and member of Duke Cancer Institute, said during the committee discussion.

“The response rate of pazopanib [Votrient, Novartis] is 4% across a broad range of sarcomas, and the rate for doxorubicin is 5% to 20% also across a broad range of unselected sarcomas. I can almost assure you that epithelioid sarcoma was not heavily represented in either of those studies. You are left with clinical experience of experts in the room who have conveyed that this is a relentless disease.

“This is the first prospective clinical trial in epithelioid sarcoma, and what I’m struck by is not only the responses but the durability of the responses,” Riedel added. “My mantra in clinic is that we’re more likely to get stable disease than response, and if we get a stable disease with epithelioid sarcoma I am ecstatic, because we don’t always get response.”

To inform their vote, panelists considered data on 106 patients (median age, 37 years; range, 16-79; 65% men; 78% white) with epithelioid sarcoma treated in cohorts 5 and 6 of the multicenter, global, open-label, multicohort, nonrandomized EZH-202 trial, which evaluated tazemetostat among patients with INI1-negative tumors or synovial sarcoma. Researchers used data from the patients treated in cohort 5 to evaluate the efficacy of tazemetostat in epithelioid sarcoma, and data from cohort 6 to assess the pharmacodynamic effects of tazemetostat on tumor immune priming in epithelioid sarcoma.

Patients received 800 mg tazemetostat twice daily in continuous 28-day cycles for 2 years or until disease progression or unacceptable toxicity.

Median follow-up for both cohorts was 12.8 months (range, 0.2-32).

Results showed an overall response rate of 15% (95% CI, 7-26) in cohort 5 and 11% (95% CI, 4-25) in cohort 6, for a pooled ORR of 13% (95% CI, 7-21). This included one complete response in each cohort.

Duration of response ranged from 3.5 months to more than 24 months among both cohorts. Nine of 14 patients (64%) had responses lasting for at least 6 months, and four of these patients responded for at least 1 year.

For comparison, the FDA background materials included data on doxorubicin, which was approved for soft tissue sarcoma in 1974 based on an ORR of 24% (95% CI, 19-30) among 234 patients treated at nine centers. However, the FDA acknowledged that the comparability of these data may be limited because the EZH-202 trial used different response criteria and the doxorubicin trial excluded patients who could not receive at least two doses of the study drug, which may have inflated the response rates.

Gary Schwartz
Gary K. Schwartz

“As an oncology community, we’re not convinced standard chemotherapy has any benefit in this disease,” Gary K. Schwartz, MD, division chief of hematology/oncology and deputy director of Herbert Irving Comprehensive Cancer Center at Columbia University, said on behalf of Epizyme during a presentation on the clinical benefit of tazemetostat. “Looking at the historical data, as oncologists, we don’t feel there is a role for standard chemotherapy in this disease. When we see a patient with this type of cancer, we are looking for new therapies, new trials or studies that have medical meaningful benefit. In my experience, tazemetostat achieves these goals.”

Overall, data from EZH-202 suggest tazemetostat is well-tolerated. The most common adverse events observed in cohort 5 included pain, fatigue, nausea, decrease appetite, vomiting and constipation.

Forty-eight percent of patients experienced a grade 3 or grade 4 adverse reaction, the most common of which included anemia (13%), pain and decreased weight (7%), hemorrhage (4.8%), decreased appetite (4.8%), dyspnea (4.8%) and pleural effusion (4.8%). Serious adverse events occurred among 23 patients (37%) — including hemorrhage (6.5%), pleural effusion (6.5%), dyspnea (5%), cellulitis (3.2%) and pain (3.2%) — but no fatal adverse events occurred.

Data also suggested an increased risk for secondary malignancies. Among a pooled safety population of 725 adults and children with solid tumors or hematologic malignancies treated with tazemetostat, six (0.8%) developed secondary myelodysplastic syndrome, acute myeloid leukemia or T-cell lymphoblastic lymphoma.

“This is a relentless and progressive disease, for which I haven’t seen the types of responses presented here,” Christian Frederick Meyer, MD, MS, PhD, assistant professor of oncology at Johns Hopkins Medicine, said during the committee discussion. “I have not seen this disease spontaneously regress. So, this drug is having some effect.

“When I have a patient in the room and I am counseling them on treatment, what I am able to say is that there are no data for epithelioid sarcoma,” he added. “So, I am wide open in what I would consider using for treatment. It is a balance of help and harm. The standard therapies we have mentioned here come with significant side effects. I am not discounting any of the grade 3 or grade 4 adverse events presented here but, relatively speaking, they are minor compared with the side effects that we are presented with when using pazopanib.”

Epizyme has planned Study 301, a confirmatory multicenter, double-blind, randomized phase 3 study to assess the addition of tazemetostat to doxorubicin as first-line treatment for patients with advanced epithelioid sarcoma. PFS will serve as the study’s primary endpoint. Enrollment began in November and the study is expected to be completed in 2029.

Although the FDA is not required to follow the advice of ODAC, it often does so. The agency will decide on the approval of tazemetostat, which received priority review, by Jan. 23. – by Alexandra Todak

 

The FDA’s Oncologic Drugs Advisory Committee, or ODAC, today voted 11-0 in favor of approval of tazemetostat for the treatment of adults with metastatic or locally advanced epithelioid sarcoma who are not eligible for curative surgery.

The major discussion point regarding tazemetostat (Epizyme), an EZH2 inhibitor, focused on the low response rates observed in the EZH-202 trial, but panelists ultimately agreed these response rates represent durable benefit for a small group of patients who otherwise have few effective treatments.

“A response rate as shown in this trial of 11% to 15% is considered clinically meaningful in my opinion,” Richard Francis Riedel, MD, associate professor of medicine at Duke University School of Medicine and member of Duke Cancer Institute, said during the committee discussion.

“The response rate of pazopanib [Votrient, Novartis] is 4% across a broad range of sarcomas, and the rate for doxorubicin is 5% to 20% also across a broad range of unselected sarcomas. I can almost assure you that epithelioid sarcoma was not heavily represented in either of those studies. You are left with clinical experience of experts in the room who have conveyed that this is a relentless disease.

“This is the first prospective clinical trial in epithelioid sarcoma, and what I’m struck by is not only the responses but the durability of the responses,” Riedel added. “My mantra in clinic is that we’re more likely to get stable disease than response, and if we get a stable disease with epithelioid sarcoma I am ecstatic, because we don’t always get response.”

To inform their vote, panelists considered data on 106 patients (median age, 37 years; range, 16-79; 65% men; 78% white) with epithelioid sarcoma treated in cohorts 5 and 6 of the multicenter, global, open-label, multicohort, nonrandomized EZH-202 trial, which evaluated tazemetostat among patients with INI1-negative tumors or synovial sarcoma. Researchers used data from the patients treated in cohort 5 to evaluate the efficacy of tazemetostat in epithelioid sarcoma, and data from cohort 6 to assess the pharmacodynamic effects of tazemetostat on tumor immune priming in epithelioid sarcoma.

Patients received 800 mg tazemetostat twice daily in continuous 28-day cycles for 2 years or until disease progression or unacceptable toxicity.

Median follow-up for both cohorts was 12.8 months (range, 0.2-32).

Results showed an overall response rate of 15% (95% CI, 7-26) in cohort 5 and 11% (95% CI, 4-25) in cohort 6, for a pooled ORR of 13% (95% CI, 7-21). This included one complete response in each cohort.

PAGE BREAK

Duration of response ranged from 3.5 months to more than 24 months among both cohorts. Nine of 14 patients (64%) had responses lasting for at least 6 months, and four of these patients responded for at least 1 year.

For comparison, the FDA background materials included data on doxorubicin, which was approved for soft tissue sarcoma in 1974 based on an ORR of 24% (95% CI, 19-30) among 234 patients treated at nine centers. However, the FDA acknowledged that the comparability of these data may be limited because the EZH-202 trial used different response criteria and the doxorubicin trial excluded patients who could not receive at least two doses of the study drug, which may have inflated the response rates.

Gary Schwartz
Gary K. Schwartz

“As an oncology community, we’re not convinced standard chemotherapy has any benefit in this disease,” Gary K. Schwartz, MD, division chief of hematology/oncology and deputy director of Herbert Irving Comprehensive Cancer Center at Columbia University, said on behalf of Epizyme during a presentation on the clinical benefit of tazemetostat. “Looking at the historical data, as oncologists, we don’t feel there is a role for standard chemotherapy in this disease. When we see a patient with this type of cancer, we are looking for new therapies, new trials or studies that have medical meaningful benefit. In my experience, tazemetostat achieves these goals.”

Overall, data from EZH-202 suggest tazemetostat is well-tolerated. The most common adverse events observed in cohort 5 included pain, fatigue, nausea, decrease appetite, vomiting and constipation.

Forty-eight percent of patients experienced a grade 3 or grade 4 adverse reaction, the most common of which included anemia (13%), pain and decreased weight (7%), hemorrhage (4.8%), decreased appetite (4.8%), dyspnea (4.8%) and pleural effusion (4.8%). Serious adverse events occurred among 23 patients (37%) — including hemorrhage (6.5%), pleural effusion (6.5%), dyspnea (5%), cellulitis (3.2%) and pain (3.2%) — but no fatal adverse events occurred.

Data also suggested an increased risk for secondary malignancies. Among a pooled safety population of 725 adults and children with solid tumors or hematologic malignancies treated with tazemetostat, six (0.8%) developed secondary myelodysplastic syndrome, acute myeloid leukemia or T-cell lymphoblastic lymphoma.

“This is a relentless and progressive disease, for which I haven’t seen the types of responses presented here,” Christian Frederick Meyer, MD, MS, PhD, assistant professor of oncology at Johns Hopkins Medicine, said during the committee discussion. “I have not seen this disease spontaneously regress. So, this drug is having some effect.

PAGE BREAK

“When I have a patient in the room and I am counseling them on treatment, what I am able to say is that there are no data for epithelioid sarcoma,” he added. “So, I am wide open in what I would consider using for treatment. It is a balance of help and harm. The standard therapies we have mentioned here come with significant side effects. I am not discounting any of the grade 3 or grade 4 adverse events presented here but, relatively speaking, they are minor compared with the side effects that we are presented with when using pazopanib.”

Epizyme has planned Study 301, a confirmatory multicenter, double-blind, randomized phase 3 study to assess the addition of tazemetostat to doxorubicin as first-line treatment for patients with advanced epithelioid sarcoma. PFS will serve as the study’s primary endpoint. Enrollment began in November and the study is expected to be completed in 2029.

Although the FDA is not required to follow the advice of ODAC, it often does so. The agency will decide on the approval of tazemetostat, which received priority review, by Jan. 23. – by Alexandra Todak