Phase II Study of Tazemetostat in Solid Tumors Harboring an ARID1A Mutation

Overview

The FDA approved targeted agent tazemetostat inhibits EZH2 and induces durable tumor responses in patients with B-cell non-Hodgkin's lymphoma and epithelioid sarcomas. Responses have also been demonstrated in INI1 and SMARCA4 negative solid tumors patients. Since EZH2 plays a critical role in driving the biology of ARID1A mutated malignancies, we hypothesize that inhibition of EZH2 with tazemetostat will lead to significant clinical benefit in ARID1A mutated malignancies.

AT rich interacting domain containing protein 1A (ARID1A) is a tumor suppressor gene frequently mutated in solid tumor malignancies, often loss of function mutations (frameshift or non-sense). ARID1A encodes a large nuclear protein BAF250a, a vital component of the Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex, which participates in several nuclear activities including transcription, DNA synthesis and DNA damage repair. ARID1A alterations are particularly prevalent in ovarian clear cell carcinoma (46-50%), ovarian and uterine endometrioid carcinomas (24-44%), and cholangiocarcinoma (27%); reported in up to 27% of gastric carcinoma, esophageal adenocarcinoma, Waldenstrom macroglobulinemia, pediatric Burkitt lymphoma, hepatocellular carcinoma, urothelial carcinoma, 12% of colorectal carcinoma (CRC) , 15% of invasive ductal carcinoma of breast, and 7.5% of NSCLC, as a sample representation reported in the COSMIC database. ARID1A plays a key role in regulating cell cycle and DNA damage repair, through its critical role in chromatin regulation. Loss of function of ARID1A leads to dysregulation of many gene pathways, supporting its role as a tumor suppressor gene. Loss of ARID1A mediates fulvestrant resistance, demonstrated in multiple elegant studies involving ER+ breast cancer lines, related to therapeutic pressure and selection \[1\]. Sporadic deletion of ARID1A in mice leads to de novo invasive colon adenocarcinoma. Loss of ARID1A leads to deregulation of the MEK/ERK pathway, critical in kras mutated CRC. ARID1A loss is associated with microsatellite instability in ovarian and endometrial endometrioid adenocarcinomas and gastric cancer. Preclinical data demonstrates enhanced clinical activity of check point inhibitors in ARID1A mutated tumors. EZH2, enhancer of zeste homologue 2, the enzymatically active core of PRC2 (polycomb repression complex 2/3) plays a key role in tumorigenesis. Over-expression in tumor cells leads to histone hypermethylation, tumor proliferation, cell cycle dysregulation, metastases and angiogenesis. Tazemetostat is an FDA approved selective small molecule inhibitor of the histone lysine methyltransferase enhancer of zeste homolog 2 (EZH2). Posttranslational modifications of core histone proteins of chromatin play an important role in controlling the fidelity of gene transcription patterns in cells. Paramount among these transcription-controlling modifications is methylation events at lysine and arginine residues, catalyzed by histone methyltransferases (HMTs). Genetic alterations in a number of HMTs have been identified in human cancers where they are purported to play a causal role in malignancies. Tazemetostat has been shown to produce durable tumor responses in patients with B-cell non-Hodgkin's lymphoma and epithelioid sarcomas. Responses have also been demonstrated in INI1 and SMARCA4 negative solid tumors patients. Hypothesis: EZH2 plays a critical role in driving the biology of ARID1A mutated malignancies. Inhibition of EZH2 with tazemetostat will lead to significant clinical benefit in ARID1A mutated malignancies. Cell homeostasis requires a balance in ARID1A and EZH2 through chromatin mediated gene expression. Loss of ARID1A expression leads to imbalance, with enhanced EZH2 activity in malignancies. Targeted EZH2 inhibition in ARID1A mutated tumors leads to synthetic lethality in several malignancies, with upregulation of PI3K interacting protein 1 gene (PI3K1P1) and associated growth suppression. EZH2 plays a key role in ovarian carcinoma. Benjamin Bitler et al \[2\] demonstrated PIK3IP1 as a direct target of ARID1A and EZH2, upregulated by EZH2 inhibition and contributing to synthetic lethality by inhibiting PI3K-AKT signaling. EZH2 inhibition caused in vivo regression of ARID1A-mutated ovarian tumors. A recent published study suggests the synthetic lethality of targeting EZH2 in ARID1A mutated gastric cancer. Leo Yamada et al \[3\] demonstrated selective sensitivity of EZH2 inhibitors against ARID1A-deficient GC supporting the potential efficacy of targeted therapy using EZH2 inhibitors in this patient population. Targeting EZH2 has also demonstrated potential synthetical lethality in kras mutated CRC in ARID1A mutated tumors \[4\]. The Prisma Health Cancer Institute reviewed molecular profiling of current patients and identified 124 cancer patients with an ARID1A mutation in a spectrum of malignancies including breast, non-small cell lung cancer, pancreas, uterine, ovarian, cholangiocarcinoma, hepatocellular, and multiple rare solid tumors. A high frequency of concurrent PTEN and PI3K pathways mutations along with ARID1A mutations was also seen, suggesting a potentially significant role of EZH2. There are no clinical trials addressing therapy in ARID1A mutated malignancies. A current clinical trial, NCT03348631, is evaluating tazemetostat in patients with recurrent ovarian, peritoneal, and endometrial cancer, not selected by ARID1A mutation status \[5\]. These data support the need for further clinical investigation of tazemetostat as monotherapy and in combination with other agents in solid tumors harboring an ARID1A mutation.

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