Tazemetostat, an EZH2 inhibitor, in solid tumors harboring SWI/SNF alterations: a phase II basket study

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Advanced tumors with SWI/SNF mutations are rare, aggressive, and present limited treatment options, often in young patients.
• EZH2 (enhancer of zeste homolog 2) is a key epigenetic regulator implicated in various cancers.

Purpose of the Study:

• To assess the efficacy and safety of oral tazemetostat, a potent EZH2 inhibitor, in patients with advanced SWI/SNF-mutated cancers.
• To evaluate tazemetostat's activity across distinct rare cancer types, including malignant rhabdoid tumors, synovial sarcoma, and INI1-negative tumors.

Main Methods:

• A phase II basket study (NCT02601950) enrolled 129 patients across multiple cancer cohorts.
• Efficacy was assessed using a 2-stage Green-Dahlberg design, with predefined futility criteria based on objective response rate (ORR) and progression-free survival (PFS).
• Primary endpoints included complete/partial responses (CR/PR) and stable disease (SD) in specific cohorts.

Main Results:

• Tazemetostat demonstrated preliminary antitumor activity in malignant rhabdoid tumors (9% ORR), INI1-negative tumors (9% ORR), and poorly differentiated chordoma (6% ORR).
• Synovial sarcoma cohort showed a 16-week PFS of 15.2%, meeting the primary endpoint criteria.
• No responses were observed in renal medullary carcinoma or other cohorts; Grade ≥3 treatment-related adverse events occurred in 10% of patients.

Conclusions:

• Tazemetostat exhibits preliminary antitumor activity in a subset of poor-prognosis cancers driven by SWI/SNF mutations.
• The findings highlight the importance of EZH2 inhibition but underscore the need for combination strategies when EZH2 signaling is not the sole driver of disease.
• Further research should explore combination therapies to enhance treatment efficacy in these challenging malignancies.