PI3K inhibitors in haematological malignancies

Richard Pazdur, director of the US Food and Drug Administration's (FDA's) Oncology Center of Excellence (Silver Spring, MD, USA), stated in July, 2014, that idelalisib's approval “reflects the promise of the breakthrough therapy designation program and represents the FDA's commitment to working cooperatively with companies to expedite a drug's development, review and approval”.2 However, since then, growing scrutiny regarding the safety of these drugs led the US FDA to meet virtually on April 21, 2022, to discuss the appropriate approach for PI3K inhibitors. The FDA discussed PI3K inhibitors that are under development and whether randomised data should be mandated to judge the net balance of benefit in the intended population.3 In a Comment published in April, 2022, Nicholas Richardson and colleagues presented several considerations of the FDA in the development of future clinical trials, including dose exploration, avoidance of single-arm trials, and allowing for maturation of overall survival data before analysis.4 We consider these proposed solutions and address several issues related to the development and approval of PI3K inhibitors. [...]the FDA granted regular approval, after initial accelerated approval, for two PI3K inhibitors on the basis of surrogate endpoints.4 Idelalisib received regular approval in 2014 for treatment of patients with relapsed chronic lymphocytic leukaemia in combination with rituximab, and duvelisib received regular approval in 2018 for relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic leukaemia after two or more therapies.