CDER-Approved NDA for TAZVERIK™ (tazemetostat)
On January 23, 2020, the FDA approved Epizyme’s TAZVERIK™ (tazemetostat) for patients “16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection.” Key findings from the FDA’s Multi-Discipline Review, Administrative and Correspondence Documents, and the Sponsor Briefing Document for NDA 211723: Safety and efficacy for TAZVERIK are based on an open label, single-arm cohort (Cohort 5) of a multi-center study, EZH-202 (NCT02601950, n=62). Cohort 5 demonstrated an objective response rate (ORR) of 15% (95% CI: 7, 26); according to the Multi-Discipline Review, ORR is defined as “confirmed complete response (CR) or partial response (PR) from the start of treatment until disease progression or the start of subsequent anti-cancer therapy as per RECIST 1.1 criteria.” The sponsor also submitted a natural history study, Study EZH-1001 (NCT03837678; n=69) among patients with epitheliloid sarcoma (ES) who had not received tazemetostat. Intent of the RWE study The applicant shared a proposal with the FDA to submit an ES natural history study as a control arm to support full approval. The specific study goals were to determine safety and efficacy in the real world for patients with ES who require systemic therapy, and to improve understanding of the natural history of ES. However, the agency provided feedback during an end-of-phase 2 meeting on March 3, 2017: It did not agree that the proposed study could provide a control arm to Cohort 5 of EZH-202 to support regular approval. Instead, the agency stated that the natural study could “provide a better understanding of the natural history and outcomes of patients with ES.” In the same document, the FDA later writes “while these comments are intended to enhance the interpretability of the data from the Natural History study, the FDA considers [real-world overall response rate (rwORR)] not comparable to ORR as assessed on a clinical trial, and considers cross-trial comparisons of time-to-event endpoints not valid. It is thus unlikely that a response to these comments will result in FDA agreement that the ES Natural History Study can be used as a ‘control arm’ for the purposes of regular approval.” Protocol for RWE generation Study EZH-1001, a multi-center, non-interventional retrospective medical chart review, involved ES patients who were initiated on systemic chemotherapy between 2000 and 2017. Data were abstracted from medical charts at five U.S. academic cancer centers; specifically:
- demographic characteristics;
- disease history;
- prior treatments for ES; and
- tumor response information, which were then categorized and referred to as rwORR.
- years studied;
- INI-1 status;
- cancer therapy(ies) prior to enrollment; and
- the minimum length of the pre-index period for assessing patient characteristics.
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