Safety and Tolerability of Phosphatidylinositol-3-Kinase (PI3K) Inhibitors in Oncology.

Activation of phosphatidylinositol-3-kinase (PI3K) and downstream signalling by AKT/mammalian target of rapamycin (mTOR) modulates cellular processes such as increased cell growth, cell proliferation and increased cell migration as well as deregulated apoptosis and oncogenesis. The PI3K/AKT/mTOR pathway (particularly Class I PI3K isoforms) is frequently activated in a variety of solid tumours and haematological malignancies, making PI3K an attractive therapeutic target in oncology. Inhibitors of PI3K also have the potential to restore sensitivity to other modalities of treatments when administered as part of combination regimens. Although many PI3K inhibitors have reached different stages of clinical development, only two (idelalisib and copanlisib) have been currently approved for use in the treatment of B cell lymphoma and leukaemias. While these two agents are effective clinically, their use is associated with a number of serious class-related as well as drug-specific adverse effects. Some of these are immune-mediated and include cutaneous reactions, severe diarrhoea with or without colitis, hepatotoxicity and pneumonitis. They also induce various metabolic abnormalities such as hyperglycaemia and hypertriglyceridaemia. Not surprisingly, therefore, many new PI3K inhibitors with a varying degree of target selectivity have been synthesised in expectations of improved safety and efficacy, and are currently under clinical investigations for use in a variety of solid tumours as well as haematological malignancies. However, evidence from early clinical trials, reviewed herein, suggests that these newer agents are also associated not only with class-related but also other serious and unexpected adverse effects. Their risk/benefit evaluations have resulted in a number of them being discontinued from further development. Cumulative experience with the use of PI3K inhibitors under development suggests that, compared with their use as monotherapy, combining them with other anticancer therapies may be a more effective strategy in improving current standard-of-care and clinical outcomes in cancers beyond haematological cancers. For example, combination of alpelisib with fulvestrant has recently demonstrated unexpectedly superior efficacy compared to fulvestrant alone. Furthermore, the immunomodulatory activity of PI3Kδ and PI3Kγ inhibitors also provides unexpected opportunities for their use in cancer immunotherapy, as is currently being tested in several clinical trials.