Tazemetostat produced an overall response rate of 15% and median overall survival of 19.0 months.
Major Finding: Tazemetostat produced an overall response rate of 15% and median overall survival of 19.0 months.
Concept: Mutations affecting the SWI/SNF-complex component INI1 drive EZH2 dependency in this rare cancer.
Impact: The results of this trial led to a phase Ib/III trial of first-line tazemetostat plus doxorubicin.
The rare soft-tissue malignancy epithelioid sarcoma is commonly characterized by loss of SMARCB1, encoding INI1, a component of the ATP-dependent chromatin-remodeling SWI/SNF complexes. Loss of INI1 causes constitutive activation of the PRC2 component EZH2, a methyltransferase responsible for trimethylating histone 3 lysine residue 27 to silence target genes. Gounder and colleagues conducted an open-label, phase II basket trial of the first-in-class oral EZH2 inhibitor tazemetostat in SMARCB1-mutant cancers and are currently reporting on results from the epithelioid sarcoma cohort. This cohort included 62 patients with stage I (3%), stage II (11%), stage III (11%), stage IV (60%), or unknown-stage (15%) disease, 61% of whom had received prior systemic anticancer therapy. The overall response rate was 15%, and one patient exhibited a complete response that was ongoing at the time of data cutoff, lasting 24.4 months. The median overall survival was 19.0 months. Notably, as has been observed with some other epigenetic inhibitors, the median time to response was relatively long (3.9 months), which may result from slow epigenetic remodeling of cancer cells. The most common treatment-emergent adverse events were grade 1 or 2 fatigue, nausea, cancer pain, and gastrointestinal disturbances; serious treatment-emergent adverse events were more rare, and those that affected more than one patient included pleural effusion, hemoptysis, death, dyspnea, cellulitis, and cancer pain. Although the small sample size due to the rarity of this malignancy indicates that caution is required in interpreting these results, the promising early signs of efficacy have led to the initiation of a phase Ib/III trial of tazemetostat plus doxorubicin as a first-line treatment for epithelioid sarcoma.
Gounder M, Schöffski P, Jones RL, Agulnik M, Cote GM, Villalobos VM, et al. Tazemetostat in advanced epithelioid sarcoma with loss of INI1/SMARCB1: an international, open-label, phase 2 basket study. Lancet Oncol 2020 Oct 6 [Epub ahead of print].
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