TY - JOUR
T1 - Tazemetostat in advanced epithelioid sarcoma with loss of INI1/SMARCB1
T2 - an international, open-label, phase 2 basket study
AU - Gounder, Mrinal
AU - Schöffski, Patrick
AU - Jones, Robin L.
AU - Agulnik, Mark
AU - Cote, Gregory M.
AU - Villalobos, Victor M.
AU - Attia, Steven
AU - Chugh, Rashmi
AU - Chen, Tom Wei Wu
AU - Jahan, Thierry
AU - Loggers, Elizabeth T.
AU - Gupta, Abha
AU - Italiano, Antoine
AU - Demetri, George D.
AU - Ratan, Ravin
AU - Davis, Lara E.
AU - Mir, Olivier
AU - Dileo, Palma
AU - Van Tine, Brian A.
AU - Pressey, Joseph G.
AU - Lingaraj, Trupti
AU - Rajarethinam, Anand
AU - Sierra, Laura
AU - Agarwal, Shefali
AU - Stacchiotti, Silvia
N1 - Funding Information:
MG reports personal fees and a travel grant from Epizyme; personal fees from Springworks, Karyopharm, Daiichi, Bayer, Amgen, Tracon, Flatiron, Medscape, Physicians Education Resource, and UpToDate; and grants from the National Cancer Institute, National Institutes of Health (P30CA008748). PS reports personal fees from Deciphera; and his institution received financial support from Exelixis, Plexxikon, Eisai, Loxo, Eli Lilly, Blueprint Medicines, Ellipses Pharma, Deciphera, Merck, Servier, Genmab, Adaptimmune, Intellisphere, and Transgene. RLJ reports research grants from Merck Sharp & Dohme; and personal fees from Adaptimmune, Blueprint, Clinigen, Eisai, Epizyme, Daiichi, Deciphera, Immunedesign, Lilly, Merck, Pharmamar, Tracon, and UptoDate. MA reports personal fees from Novartis, Eli Lilly, Immune Design, Bayer, Janssen, Eisai, and Bristol Myers Squibb. GMC reports personal fees from Epizyme, PharmaMar, and Agios; non-financial support (pharmaceutical drugs for an investigator-sponsored clinical trial) from PharmaMar, Eisai, and the EMD Serono Research and Development Institute; financial support to his institution for the conduct of clinical trials from Epizyme, PharmaMar, Agios, Otsuka, Amgen, Eisai, Macrogenics, Boston Biomedical, Plexxicon, EMD Serono Research and Development Institute, CBA Pharma, SpringWorks Therapeutics, Bavarian-Nordic, Aileron Therapeutics, and Bayer. VMV reports personal fees from Epizyme, Lilly, Nanocarrier, Agios, Daiichi, Novartis, Janssen, Springworks, AbbVie, and Blueprint. SAt reports research grants from the Desmoid Tumour Research Foundation; personal fees from Immune Design; and research grants to his institution from AB Science, TRACON Pharma, CytRx Corporation, Bayer, Novartis, Daiichi Sankyo, Eli Lilly, Immune Design, Karyopharm Therapeutics, Epizyme, Blueprint Medicines, Genmab, CBA Pharma, Merck, Philogen, Gradalis, Deciphera, Takeda, Incyte, Springworks, Adaptimmune, Advenchen Laboratories, Bavarian Nordic, BTG, PTC Therapeutics, GlaxoSmithKline, and FORMA Therapeutics. RC reports grants from Epizyme, Aadi Bioscience, Novartis, Springworks, Plexxikon, Advenchen, Mundipharma, Pfizer; personal fees from Epizyme, Janssen, and Immune Design; and non-financial support from Janssen, Springworks, and GlaxoSmithKline. TW-WC reports grants from Eisai; personal fees from Eisai, Novartis, Eli Lilly, Roche, Bayer, and Pfizer; non-financial support from Epizyme, Eisai and Novartis; travel sponsorship from Eisai, Roche, and Pfizer; and manuscript preparation support from Epizyme. TJ reports grants from Aduro Pharma, AstraZeneca, Bristol Myers Squib, Eli Lilly, Epizyme, Polaris Pharma, and Trizell; and non-financial support from Atara Pharmaceuticals. AI reports personal fees from Epizyme. GDD reports grants from Epizyme, Novartis, Bayer, Pfizer, Loxo Oncology, AbbVie, Daiichi-Sankyo, Adaptimmune, GlaxoSmithKline, Janssen, PharmaMar, Roche-Genentech, and Ignyta; personal fees from Epizyme, Novartis, Bayer, Pfizer, EMD-Serono, Sanofi, Loxo Oncology, AbbVie, Mirati Therapeutics, Daiichi-Sankyo, WIRB Copernicus Group, ZioPharm, Polaris Pharmaceuticals, MJ Hennessey-OncLive, Adaptimmune, Blueprint Medicines, Merrimack Pharmaceuticals, G1 Therapeutics, CARIS Life Sciences, CHAMPIONS Oncology, Janssen, PharmaMar, Translate BIO, Roche-Genentech, and Ignyta; non-financial support from Epizyme, Novartis, AbbVie, Daiichi-Sankyo, PharmaMar, and Roche-Genentech; travel support from Epizyme, Novartis, Bayer, Pfizer, EMD-Serono, Loxo Oncology, Daiichi-Sankyo, WIRB Copernicus Group, MJ Hennessey-OncLive, Adaptimmune, Blueprint Medicines, Merrimack Pharmaceuticals, CARIS Life Sciences, PharmaMar, and Roche-Genentech; equity or equity options from Blueprint Medicines, Merrimack Pharmaceuticals, G1 Therapeutics, CARIS Life Sciences, Bessor Pharmaceuticals, ERASCA Pharmaceuticals, CHAMPIONS Oncology, and Translate BIO; and a use patent on imatinib for gastrointestinal stromal tumours through Novartis, with royalties paid to Dana-Farber. RR reports personal fees from Epizyme. LED reports personal fees and support for the conduct of clinical trials from Epizyme. OM reports personal fees from Amgen, Bristol Myers Squibb, Eli Lilly, Ipsen, Janssen, Lundbeck, Merck Sharp & Dohme, Pfizer, Roche, Servier, and Vifor Pharma; and non-financial support from Blueprint Medicines. BAVT reports research grants from Pfizer, Merck, and Tracon; and personal fees from Epizyme, Pfizer, Eli Lilly, CytRx, Janssen, CARIS Life Sciences, Bayer, Immune Design, Daiichi-Sankyo, Adaptimmune, GlaxoSmithKline, and Plexxicon. JGP reports personal fees from General Dynamics and Cellectar; and financial support to his institution for the conduct of clinical trials from Epizyme. TL, AR, LS, and SAg are employees of and own stock in Epizyme. SS reports personal fees from Epizyme and Eli Lilly; and research funding to his institution from Epizyme, Novartis, and Eli Lilly. ETL, AG, and PD declare no competing interests.
Funding Information:
This study was funded by Epizyme. We thank all of the patients, caregivers, and families who have contributed to the study. We acknowledge Neil Michaud and Scott Daigle for their contributions to the molecular pathology analysis, and Jay Yang for providing statistical assistance. The results published here on tumour mutational burden are, in part, based on data generated by The Cancer Genome Atlas Research Network. Support for third party editorial assistance was provided by Meredith Kalish of Ashfield Healthcare Communications (Lyndhurst, NJ, USA), and funded by Epizyme. A medical writer, funded by Epizyme, did the literature search. VMV was affiliated to the University of Colorado Denver (Aurora, CO, USA) at the time the study was done, but is now affiliated to Janssen Pharmaceuticals (Spring House, PA, USA). LS was affiliated to Epizyme (Cambridge, MA, USA) at the time the study was done, but is now affiliated to Bristol Myers Squibb (Cambridge, MA, USA).
PY - 2020/11
Y1 - 2020/11
N2 - Background: Epithelioid sarcoma is a rare and aggressive soft-tissue sarcoma subtype. Over 90% of tumours have lost INI1 expression, leading to oncogenic dependence on the transcriptional repressor EZH2. In this study, we report the clinical activity and safety of tazemetostat, an oral selective EZH2 inhibitor, in patients with epithelioid sarcoma. Methods: In this open-label, phase 2 basket study, patients were enrolled from 32 hospitals and clinics in Australia, Belgium, Canada, France, Germany, Italy, Taiwan, the USA, and the UK into seven cohorts of patients with different INI1-negative solid tumours or synovial sarcoma. Patients eligible for the epithelioid sarcoma cohort (cohort 5) were aged 16 years or older with histologically confirmed, locally advanced or metastatic epithelioid sarcoma; documented loss of INI1 expression by immunohistochemical analysis or biallelic SMARCB1 (the gene that encodes INI1) alterations, or both; and an Eastern Cooperative Oncology Group performance status score of 0–2. Patients received 800 mg tazemetostat orally twice per day in continuous 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed objective response rate measured according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints were duration of response, disease control rate at 32 weeks, progression-free survival, overall survival, and pharmacokinetic and pharmacodynamic analyses (primary results reported elsewhere). Time to response was also assessed as an exploratory endpoint. Activity and safety were assessed in the modified intention-to-treat population (ie, patients who received one or more doses of tazemetostat). This trial is registered with ClinicalTrials.gov, NCT02601950, and is ongoing. Findings: Between Dec 22, 2015, and July 7, 2017, 62 patients with epithelioid sarcoma were enrolled in the study and deemed eligible for inclusion in this cohort. All 62 patients were included in the modified intention-to-treat analysis. Nine (15% [95% CI 7–26]) of 62 patients had an objective response at data cutoff (Sept 17, 2018). At a median follow-up of 13·8 months (IQR 7·8–19·0), median duration of response was not reached (95% CI 9·2–not estimable). 16 (26% [95% CI 16–39]) patients had disease control at 32 weeks. Median time to response was 3·9 months (IQR 1·9–7·4). Median progression-free survival was 5·5 months (95% CI 3·4–5·9), and median overall survival was 19·0 months (11·0–not estimable). Grade 3 or worse treatment-related adverse events included anaemia (four [6%]) and weight loss (two [3%]). Treatment-related serious adverse events occurred in two patients (one seizure and one haemoptysis). There were no treatment-related deaths. Interpretation: Tazemetostat was well tolerated and showed clinical activity in this cohort of patients with advanced epithelioid sarcoma characterised by loss of INI1/SMARCB1. Tazemetostat has the potential to improve outcomes in patients with advanced epithelioid sarcoma. A phase 1b/3 trial of tazemetostat plus doxorubicin in the front-line setting is currently underway (NCT04204941). Funding: Epizyme.
AB - Background: Epithelioid sarcoma is a rare and aggressive soft-tissue sarcoma subtype. Over 90% of tumours have lost INI1 expression, leading to oncogenic dependence on the transcriptional repressor EZH2. In this study, we report the clinical activity and safety of tazemetostat, an oral selective EZH2 inhibitor, in patients with epithelioid sarcoma. Methods: In this open-label, phase 2 basket study, patients were enrolled from 32 hospitals and clinics in Australia, Belgium, Canada, France, Germany, Italy, Taiwan, the USA, and the UK into seven cohorts of patients with different INI1-negative solid tumours or synovial sarcoma. Patients eligible for the epithelioid sarcoma cohort (cohort 5) were aged 16 years or older with histologically confirmed, locally advanced or metastatic epithelioid sarcoma; documented loss of INI1 expression by immunohistochemical analysis or biallelic SMARCB1 (the gene that encodes INI1) alterations, or both; and an Eastern Cooperative Oncology Group performance status score of 0–2. Patients received 800 mg tazemetostat orally twice per day in continuous 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed objective response rate measured according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints were duration of response, disease control rate at 32 weeks, progression-free survival, overall survival, and pharmacokinetic and pharmacodynamic analyses (primary results reported elsewhere). Time to response was also assessed as an exploratory endpoint. Activity and safety were assessed in the modified intention-to-treat population (ie, patients who received one or more doses of tazemetostat). This trial is registered with ClinicalTrials.gov, NCT02601950, and is ongoing. Findings: Between Dec 22, 2015, and July 7, 2017, 62 patients with epithelioid sarcoma were enrolled in the study and deemed eligible for inclusion in this cohort. All 62 patients were included in the modified intention-to-treat analysis. Nine (15% [95% CI 7–26]) of 62 patients had an objective response at data cutoff (Sept 17, 2018). At a median follow-up of 13·8 months (IQR 7·8–19·0), median duration of response was not reached (95% CI 9·2–not estimable). 16 (26% [95% CI 16–39]) patients had disease control at 32 weeks. Median time to response was 3·9 months (IQR 1·9–7·4). Median progression-free survival was 5·5 months (95% CI 3·4–5·9), and median overall survival was 19·0 months (11·0–not estimable). Grade 3 or worse treatment-related adverse events included anaemia (four [6%]) and weight loss (two [3%]). Treatment-related serious adverse events occurred in two patients (one seizure and one haemoptysis). There were no treatment-related deaths. Interpretation: Tazemetostat was well tolerated and showed clinical activity in this cohort of patients with advanced epithelioid sarcoma characterised by loss of INI1/SMARCB1. Tazemetostat has the potential to improve outcomes in patients with advanced epithelioid sarcoma. A phase 1b/3 trial of tazemetostat plus doxorubicin in the front-line setting is currently underway (NCT04204941). Funding: Epizyme.
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U2 - 10.1016/S1470-2045(20)30451-4
DO - 10.1016/S1470-2045(20)30451-4
M3 - Article
C2 - 33035459
AN - SCOPUS:85094834213
VL - 21
SP - 1423
EP - 1432
JO - The Lancet Oncology
JF - The Lancet Oncology
SN - 1470-2045
IS - 11
ER -