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The following information helps you to find FDA Alerts and Pharmacist’s Applications to Practice quickly and easily. In cooperation with the Food and Drug Administration (FDA), and as a service to our members, HOPA periodically distributes information about newly approved therapies for cancer patients from FDA’s Office of Oncology Drug Products Director, Dr. Richard Pazdur to inform oncologists and professionals in oncology-related fields in a timely manner. Links to product labels will take you to relevant clinical information on the indication, contraindications, dosing, and safety. In sending this information, HOPA does not endorse any product or therapy and does not take any position on the safety or efficacy of the product or therapy described.

Along with HOPA’s Publications Committee, members also review new drug updates and provide analysis and research on the application of these new drugs or indications. Pharmacist’s Applications to Practice, or PAP, are listed after drugs that include the additional analysis.

You can also find additional information on FDA Alerts and Updates by listening to FDA Drug Safety Podcasts.

June 18, 2020–(TAZVERIK, Epizyme, Inc.), for adult patients with relapsed or refractory (R/R) follicular lymphoma (FL) whose tumors are positive for an EZH2 mutation as detected by an FDA-approved test and who have received at least 2 prior systemic therapies, and for adult patients with R/R FL who have no satisfactory alternative treatment options.

January 23, 2018–Tazemetostat (Tazverik, Epizyme, Inc.) for the treatment of adults and pediatric patients aged 16 years and older with metastatic (when cancer cells spread to other parts of the body) or locally advanced (when cancer has grown outside the organ it started in, but has not yet spread to distant parts of the body) epithelioid sarcoma not eligible for complete resection (surgically removing all of a tissue, structure, or organ). Epithelioid sarcoma is a rare sub-type of soft tissue sarcoma that often occurs in young adults.(With Pharmacist's Applications to Practice)


June 18, 2020

http://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213400s000lbl.pdf.

On June 18, 2020, the Food and Drug Administration granted accelerated approval to tazemetostat (TAZVERIK, Epizyme, Inc.), an EZH2 inhibitor, for adult patients with relapsed or refractory (R/R) follicular lymphoma (FL) whose tumors are positive for an EZH2 mutation as detected by an FDA-approved test and who have received at least 2 prior systemic therapies, and for adult patients with R/R FL who have no satisfactory alternative treatment options.

Today, the FDA also approved the cobas EZH2 Mutation Test (Roche Molecular Systems, Inc.) as a companion diagnostic for tazemetostat.

Approval was based on two open-label, single-arm cohorts (Cohort 4 - EZH2 mutated FL and Cohort 5 - EZH2 wild-type FL) of a multi-center trial (Study E7438-G000-101, NCT01897571) in patients with histologically confirmed FL after at least 2 prior systemic therapies. EZH2 mutations were identified prospectively using formalin-fixed, paraffin-embedded tumor samples, which were centrally tested using the cobas® EZH2 Mutation Test. Patients received tazemetostat 800 mg orally twice daily until confirmed disease progression or unacceptable toxicity.

Efficacy was based on overall response rate (ORR) and duration of response (DOR) according to the International Working Group Non-Hodgkin Lymphoma criteria as assessed by an independent review committee. ORR in 42 patients with EZH2 mutant FL was 69% (95% CI: 53%, 82%), with 12% complete responses and 57% partial response. Median DOR in these patients was 10.9 months (95% CI: 7.2, NE). The ORR in 53 patients with EZH2 wild-type FL was 34% (95% CI: 22%, 48%), with 4% complete responses and 30% partial responses. Median DOR was 13 months (95% CI: 5.6, NE).

The most common (≥20%) adverse reactions in patients with follicular lymphoma included fatigue, upper respiratory tract infection, musculoskeletal pain, nausea and abdominal pain. Serious adverse reactions occurred in 30%, most often from infection. Second primary malignancy was the most common reason for treatment discontinuation (2% of patients). The prescribing information includes a warning and precaution for secondary malignancies.

The recommended tazemetostat dose is 800 mg taken orally twice daily with or without food.

View full prescribing information for TAZVERIK.

These indications are approved under accelerated approval based on overall response rate and duration of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

This application was granted priority review and Fast Track designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email This email address is being protected from spambots. You need JavaScript enabled to view it..

For information on the COVID-19 pandemic, see the following resources:

Follow the Oncology Center of Excellence on Twitter @FDAOncology


January 23, 2018 with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211723s000lbl.pdf

On January 23, 2020, the Food and Drug Administration granted accelerated approval to Tazemetostat (Tazverik, Epizyme, Inc.) for the treatment of adults and pediatric patients aged 16 years and older with metastatic (when cancer cells spread to other parts of the body) or locally advanced (when cancer has grown outside the organ it started in, but has not yet spread to distant parts of the body) epithelioid sarcoma not eligible for complete resection (surgically removing all of a tissue, structure, or organ). Epithelioid sarcoma is a rare sub-type of soft tissue sarcoma that often occurs in young adults.

“Epithelioid sarcoma accounts for less than one percent of all soft tissue sarcomas,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research. “Until today, there were no treatment options specifically for patients with epithelioid sarcoma. The approval of Tazverik provides a treatment option that specifically targets this disease. When we brought Tazverik’s application to the Oncologic Drugs Advisory Committee last month, the committee voted unanimously that the benefits of the drug outweighed the risks.”

Tazverik blocks activity of the EZH2 methyltransferase, which may help keep the cancer cells from growing. Most cases of epithelioid sarcoma begin in the soft tissue under the skin of an extremity, though it can start in other areas of the body. Surgical removal is considered the main treatment when the cancer is localized to one area of the body. Chemotherapy or radiation may also be given. However, there is a high likelihood for local and regional spread of the disease even with treatment and approximately 50% of patients have metastatic disease at the time of diagnosis. Metastatic disease is considered life-threatening to the patient.

Tazverik’s approval was based on the results of a clinical trial enrolling 62 patients with metastatic or locally advanced epithelioid sarcoma. During the clinical trial, patients received 800 milligrams (mg) of Tazverik twice a day until the disease progressed or the patient reached an unacceptable level of toxicity. Tumor response assessments were performed every eight weeks during the clinical trial. The trial measured how many patients experienced complete or partial shrinkage (by a certain amount) of their tumors during treatment (overall response rate). The overall response rate was 15%, with 1.6% of patients having a complete response and 13% having a partial response. Of the nine patients that had a response, six (67%) patients had a response lasting six months or longer.

The most common side effects for patients taking Tazverik were pain, fatigue, nausea, decreased appetite, vomiting and constipation. Patients treated with Tazverik are at increased risk of developing secondary malignancies including: T-cell lymphoblastic lymphoma (a type of blood cancer that affects the lymphatic system usually found in the lymph nodes), myelodysplastic syndrome (a disorder resulting from poorly formed or dysfunctional blood cells) and acute myeloid leukemia (a cancer of the blood and bone marrow). The FDA advises health care professionals to tell females of reproductive potential to use effective contraception during treatment with Tazverik and for six months after the final dose. Males with a female partner of reproductive potential should use effective contraception during treatment with Tazverik and for three months after the final dose. Females who are pregnant or breastfeeding should not take Tazverik because it may cause harm to a developing fetus or newborn baby. Tazverik must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks.

Tazverik was granted Accelerated Approval, which enables the FDA to approve drugs for serious conditions to fill an unmet medical need based on a result that is reasonably likely to predict a clinical benefit to patients. Further clinical trials may be required to verify and describe Tazverik’s clinical benefit. Tazverik also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Tazverik to Epizyme Inc.

View prescribing information for Tazverik https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211723s000lbl.pdf

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Pharmacist’s Applications to Practice

Tazemetostat for the Treatment of Metastatic or Locally Advanced Epithelioid Sarcoma

Author: Kristen T. Peterson, PharmD
Clinical Oncology Pharmacist
Duke University Hospital
Durham, NC

What is the potential role for tazemetostat in the treatment of metastatic or locally advanced epithelioid sarcoma?1-5

  • Epithelioid sarcoma is a rare soft tissue sarcoma that leads to metastasis in 30%–50% of cases. Complete surgical resection is the primary treatment for most patients with soft tissue sarcomas, but treatment becomes more difficult if patients are not eligible for complete resection.
  • More than 90% of epithelioid sarcoma tumors lack expression of integrase interactor 1 (INI1), which plays an integral role in epigenetic regulation. Loss of INI1 function allows another epigenetic modifier, EZH2 (enhancer of zeste homolog 2), to become an oncogenic driver in tumor cells.
  • EZH2 is overexpressed or mutated in many cancer types and plays a role in tumor proliferation. Preclinical in vitro and in vivo models with the loss or dysfunction of certain SWI/SNF complex members (e.g., INI1/SNF5/SMARCB1/BAF47, SMARCA4 and SMARCA2) can lead to aberrant EZH2 activity or expression. This can result in oncogenic dependence on EZH2 leading to proliferation of disease, which makes it a favorable target for inhibition.
  • Tazemetostat is a first-in-class selective inhibitor of the histone methyltransferase EZH2 and some of its gain-of-function mutations, including Y646X and A687V.
  • In phase 1/2 trials that included patients with metastatic or locally advanced epithelioid sarcoma, tazemetostat demonstrated tumor regression and had a favorable safety profile.
    • Accelerated U.S. Food and Drug Administration (FDA) approval was based on the results from a single-arm cohort of 62 patients (Cohort 5) of a phase 2 prospective multicenter trial (Study EZH-202, NCT02601950) in patients with histologically confirmed, metastatic, or locally advanced epithelioid sarcoma. Patients were required to have INI1 loss and an Eastern Cooperative Oncology Group performance status of 0–2.
    • Treatment with tazemetostat resulted in an overall response rate of 15% (95% confidence interval [CI]: 7%, 26%), with 1.6% having complete responses and 13% partial responses.
    • The duration of response ranged from 7.1+ weeks to 103.0+ weeks (median: not reached) with a median overall survival of 82.4 weeks (95% CI: 47.4, not estimable) for all 62 patients.
    • 67% of patients responding had responses lasting 6 months or longer.
    • It is important to note that continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
  • Tazemetostat has also been studied in relapsed or refractory B-cell non-Hodgkin lymphoma in addition to advanced solid tumors, but currently it does not have any other FDA-approved indications.
  • The National Comprehensive Cancer Network has updated its guidelines to include tazemetostat as a category 2A recommendation. At this time, it is the only medication recommendation for metastatic or locally advanced epithelioid sarcoma not eligible for complete resection.

What role can the pharmacist play in the management of patients on tazemetostat?2,3,5

  • Tazemetostat is dosed 800 mg orally twice daily and can be taken with or without food, to be continued until disease progression or unacceptable toxicity.
  • Tazemetostat is primarily metabolized by CYP3A4. Patients should be screened for concomitant use of CYP3A4 inhibitors and inducers.
    • Avoid coadministration of tazemetostat with strong or moderate CYP3A inhibitors.
    • Avoid coadministration of moderate and strong CYP3A inducers with tazemetostat, which may decrease the efficacy of tazemetostat.
  • No tazemetostat dose adjustment is required in any severity of renal impairment. No dose adjustment is required in mild hepatic impairment (Child-Pugh class A). Tazemetostat has not been studied in patients with moderate-to-severe hepatic impairment (Child-Pugh classes B and C).
  • Dose adjustments are recommended for hematologic toxicities or other grade 3/4 adverse reactions.
  • The most common treatment-related adverse events seen in trials were pain, fatigue, decreased appetite or decreased weight, mild nausea or vomiting, and constipation. Low discontinuation rates of tazemetostat were seen (1.7%).
    • Serious adverse reactions occurring in ≥3% and seen in trials included hemorrhage, pleural effusion, skin infection, dyspnea, pain, and respiratory distress.
    • Emetogenicity = minimal to low risk (emesis in 24%)
    • In addition, the risk of developing secondary malignancies was found to be increased following the use of tazemetostat. In clinical trials, myelodysplastic syndrome or acute myeloid leukemia occurred in 0.6% of patients. T-cell lymphoblastic lymphoma was observed in a pediatric case report.
  • Evaluate pregnancy status prior to use in women of reproductive potential because tazemetostat can cause fetal harm when administered to pregnant women.
    • Women of reproductive potential should be counseled to use effective nonhormonal contraception during therapy and for 6 months after the last tazemetostat dose.
    • Men with women partners of reproductive potential should use effective contraception during therapy and for at least 3 months after the last dose of tazemetostat.

Clinical Pearls2,3,5

  • Tazemetostat is supplied as 200-mg tablets. This tablet size allows for easier dose titration if needed because of toxicity or drug interactions. However, if the medication is used at the standard dose, it is important to counsel patients that they will need to take four tablets twice daily.
  • If coadministration with a moderate CYP3A inhibitor cannot be avoided, recommendations for dose reduction include the following:
    • If taking 800 mg twice daily, the dose should be reduced to 400 mg twice daily.
    • If taking 600 mg twice daily, the dose should be reduced to 400 mg for first dose and 200 mg for second dose.
    • If taking 400 mg twice daily, the dose should be reduced to 200 mg twice daily.
    • After discontinuation of the moderate CYP3A inhibitor for 3 elimination half-lives, resume the tazemetostat dose that was administered prior to initiating the inhibitor.
  • Important monitoring parameters include complete blood count with differential, renal function, electrolyte abnormalities, liver function tests, development of secondary malignancies, and adherence.
  • Financial assistance options are available through Epizyme for commercially insured, government-insured, and uninsured patients. Additional information can be found by calling 1.833.4EPINOW (437.4669) or viewing the following form: https://www.tazverik.com/patient-support-form.pdf

References

  1. U.S. Food and Drug Administration: Approved Drugs. FDA approves tazemetostat for advanced epithelioid sarcoma. January 23, 2020. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tazemetostat-advanced-epithelioid-sarcoma. Accessed April 15, 2020.
  2. Stacchiotti S, Schoffski P, Jones R, et al. Safety and efficacy of tazemetostat, a first-in-class EZH2 inhibitor, in patients (pts) with epithelioid sarcoma (ES) (NCT02601950). J Clin Oncol. 2019;37(15s: 11003).
  3. Italiano A, Soria JC, Toulmonde M, et al. Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: a first-in-human, open-label, phase 1 study. Lancet Oncol. 2018;19(5):649-659. Available at https://doi.org/10.1016/S1470-2045(18)30145-1
  4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Soft Tissue Sarcoma. Version 2.2020 (May 28, 2020). Available at https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf. Accessed June 8, 2020.
  5. Tazverik (tazemetostat) [prescribing information]. Cambridge, MA: Epizyme Inc.; January 2020.
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