Pazdur et al Weigh Challenges with PI3K Inhibitors
FDA oncology officials have outlined challenges with current PI3K inhibitors that have the agency reconsidering how the drugs can demonstrate safety and efficacy for their use in treating hematological malignancies. Writing in the 4/14 online Lancet Oncology, FDA Oncology Center of Excellence director Richard Pazdur and other FDA officials dismiss the “current paradigm of using overall response rates in single-arm trials to support accelerated approvals.”
In the case of PI3K inhibitors, the officials note that “limited dose-exploration studies were conducted before choosing maximum or near-maximum tolerated doses for subsequent single-arm trials for accelerated approval. Although an exposure–response association exists for adverse events associated with drugs in this class, such an association for efficacy has not necessarily been observed.”
The Lancet article comes on the heels of a 4/21 Oncologic Drugs Advisory Committee meeting that is set to discuss FDA’s PI3K inhibitor safety concerns (see earlier story). TG Therapeutics has also now withdrawn its accelerated approval of PI3K inhibitor Ukoniq (umbralisib) for treating adults with relapsed or refractory marginal zone lymphoma, and with relapsed or refractory follicular lymphoma. It also withdrew two pending submissions for the drug due to the ongoing safety concerns.
Late late last month, FDA discouraged MEI Pharma and Kyowa Kirin from seeking accelerated approval of a BLA for zandelisib, a PI3K inhibitor drug candidate for treating patients with B-cell malignancies, based on data from their single-arm Phase 2 TIDAL study. In a recent meeting, FDA told the companies that its position now requires a randomized trial to adequately assess drug efficacy and safety of PI3K inhibitor drug candidates, including zandelisib, according to an MEI release.
In the Lancet article, the safety concerns have led the officials to recommend a new “framework to re-examine drug development for hematological malignancies, especially those with long natural histories. First, careful dose selection through robust dose exploration should be advocated, preferentially via early randomized trials examining doses and the irrelative safety and efficacy. Patient-reported outcomes should be incorporated into this assessment. Further development of the four currently approved PI3K inhibitors should identify optimal doses as single agents or in combination.”
Additionally, the FDA officials say that “single-arm trials should be avoided as regulatory strategies in favor of randomized trials. Single-arm trials allow for the assessment of overall response rates, but cannot accurately assess progression-free survival and overall survival. The assessment of safety is also hampered by the absence of a control group. Finally, data on overall survival should be fully collected and analyzed, especially when substantial differences in safety profiles exist between trial groups, to assess the drug’s effect on this ultimate safety endpoint.”