FDA Maintains ‘High Bar’ for P13K Inhibitors
MEI Pharma and Kyowa Kirin have decided to abandon developing PI3K inhibitor zandelisib outside of Japan for B-cell malignancies following FDA input that raised the bar on clinical trial data needed for such an approval. At a meeting with FDA last month, the agency reiterated its recent stance that a Phase 3 randomized trial should be used to support an initial zandelisib registration in patients with indolent non-Hodgkin lymphoma, the companies say, adding that “data generated from single arm studies such as the Phase 2 TIDAL trial are insufficient to adequately assess the risk/benefit of PI3K inhibitors evaluating indolent non-Hodgkin lymphoma.”
MEI and Kyowa Kirin say they no longer “believe clinical development can be completed within a time period that would support further investment, or with sufficient certainty of the regulatory requirements to justify continued global development efforts.”
FDA’s position on P13K inhibitors is consistent with advice it received in April from its Oncologic Drugs Advisory Committee, which voted unanimously 16-0 (one abstention) to recommend that the agency require future approvals of PI3K inhibitors be supported by randomized clinical trial data. Panel members agreed with FDA reviewers’ concerns about toxicity and using overall response rates in single-arm trials to support approvals, particularly in hematological malignancies.
Most of FDA’s concerns were outlined in a recent online Lancet Oncology article by FDA Oncology Center of Excellence director Richard Pazdur and other FDA officials (see earlier story). A briefing document released in advance of the meeting also criticized current PI3K inhibitor development programs that did not perform adequate dose exploration which in some cases was further complicated by selecting a single-arm study design for initial registration. “The safety analysis of data from single-arm trials,” it said, “is confounded by the absence of a control, which can pose challenges in accurately attributing AEs [adverse events] to either drug or the underlying disease. Because sponsors may select a dose to achieve the highest ORR [objective response rate] without carefully considering a benefit-risk analysis, toxicities are compounded and may contribute to the worrisome OS [overall survival] results seen repeatedly in multiple RCTs [randomized control trials] of these agents.”
Additionally, the briefing document endorsed randomized trials as the “most effective method to control for confounding factors” and because they allow for assessing progression-free survival, overall survival (OS), and patient reported outcomes. It says that “OS data should be fully collected and analyzed, as OS is an important metric in the benefit-risk determination, especially for products with significant toxicity.”
During the panel discussion, some members were concerned that raising the approval bar on the drug class could stifle innovation and delay important products for patients. Pazdur weighed in to offer reassurance that if the agency saw early data from a PI3K inhibitor that had phenomenal response rates and was very non-toxic, “then that’s a different story here and we always would demonstrate the appropriate degree of flexibility” to move the product through development.