Tazemetostat for tumors harboring SMARCB1/SMARCA4 or EZH2 alterations: results from NCI-COG pediatric MATCH APEC1621C

Author:

Chi Susan N1ORCID,Yi Joanna S2ORCID,Williams P Mickey3,Roy-Chowdhuri Sinchita4ORCID,Patton David R5,Coffey Brent D5,Reid Joel M6,Piao Jin7,Saguilig Lauren8,Alonzo Todd A7,Berg Stacey L2,Ramirez Nilsa C9,Jaju Alok10,Mhlanga Joyce C11,Fox Elizabeth12,Hawkins Douglas S13ORCID,Mooney Margaret M14ORCID,Takebe Naoko14,Tricoli James V15,Janeway Katherine A1,Seibel Nita L14ORCID,Parsons D Williams2

Affiliation:

1. Department of Pediatrics, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Harvard Medical School , Boston, MA, USA

2. Department of Pediatrics, Texas Children’s Cancer and Hematology Center, Baylor College of Medicine , Houston, TX, USA

3. Molecular Characterization Laboratory, Frederick National Laboratory for Cancer Research , Frederick, MD, USA

4. Department of Pathology and Laboratory Medicine, University of Texas MD Anderson Cancer Center , Houston, TX, USA

5. Center for Biomedical Informatics and Information Technology, National Cancer Institute, National Institutes of Health , Bethesda, MD, USA

6. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic , Rochester, MN, USA

7. Department of Biostatistics, Keck School of Medicine, University of Southern California , Los Angeles, CA, USA

8. Children’s Oncology Group Statistical Center , Monrovia, CA, USA

9. Biopathology Center, Research Institute at Nationwide Children’s Hospital , Columbus, OH, USA

10. Department of Radiology, Ann and Robert H. Lurie Children's Hospital , Chicago, IL, USA

11. Department of Radiology, Washington University School of Medicine , St Louis, MO, USA

12. Department of Oncology, St Jude Children’s Research Hospital , Memphis, TN, USA

13. Department of Hematology-Oncology, Seattle Children’s Hospital, University of Washington , Seattle, WA, USA

14. Division of Cancer Treatment and Diagnosis, National Cancer Institute, Cancer Therapy Evaluation Program , Bethesda, MD, USA

15. Division of Cancer Treatment and Diagnosis, National Cancer Institute , Bethesda, MD, USA

Abstract

Abstract Background National Cancer Institute-Children’s Oncology Group Pediatric Molecular Analysis for Therapy Choice assigns patients aged 1-21 years with refractory solid tumors, brain tumors, lymphomas, and histiocytic disorders to phase II trials of molecularly targeted therapies based on detection of predefined genetic alterations. Patients whose tumors harbored EZH2 mutations or loss of SMARCB1 or SMARCA4 by immunohistochemistry were treated with EZH2 inhibitor tazemetostat. Methods Patients received tazemetostat for 28-day cycles until disease progression or intolerable toxicity (max 26 cycles). The primary endpoint was objective response rate; secondary endpoints included progression-free survival and tolerability of tazemetostat. Results Twenty patients (median age = 5 years) enrolled, all evaluable for response and toxicities. The most frequent diagnoses were atypical teratoid rhabdoid tumor (n = 8) and malignant rhabdoid tumor (n = 4). Actionable alterations consisted of SMARCB1 loss (n = 16), EZH2 mutation (n = 3), and SMARCA4 loss (n = 1). One objective response was observed in a patient with non-Langerhans cell histiocytosis with SMARCA4 loss (26 cycles, 1200 mg/m2/dose twice daily). Four patients with SMARCB1 loss had a best response of stable disease: epithelioid sarcoma (n = 2), atypical teratoid rhabdoid tumor (n = 1), and renal medullary carcinoma (n = 1). Six-month progression-free survival was 35% (95% confidence interval [CI] = 15.7% to 55.2%) and 6-month overall survival was 45% (95% CI = 23.1% to 64.7%). Treatment-related adverse events were consistent with prior tazemetostat reports. Conclusions Although tazemetostat did not meet its primary efficacy endpoint in this population of refractory pediatric tumors (objective response rate = 5%, 90% CI = 1% to 20%), 25% of patients with multiple histologic diagnoses experienced prolonged stable disease of 6 months and over (range = 9-26 cycles), suggesting a potential effect of tazemetostat on disease stabilization.

Funder

NCTN Operations Center

COG Biospecimen Bank

NCTN Statistics and Data Center

St. Baldrick’s Foundation

Publisher

Oxford University Press (OUP)

Subject

Cancer Research,Oncology

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