Introduction

Excessive activation of the phosphatidylinositol 3-kinase (PI3K) signalling pathway is considered to be one of the hallmarks of human malignancies (Fruman et al. 2017). The pathway is activated through diverse genomic alterations, including the oncogenes phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1), the tumour suppressor gene phosphatase and tensin homolog (PTEN), and other crucial genes, which hold promise as effective therapeutic targets (Janku et al. 2018). In addition, the PI3K axis plays a fundamental role in the survival, cell proliferation, metabolism and inflammation of several cellular processes (De Santis et al. 2019). Hence, it follows that the significance of the PI3K pathway has facilitated pharmacological intervention targeting PI3K.

PI3K is a family of lipid kinases that have been divided into three classes (I, II, III) based on sequence homology and substrate specificity (Miller et al. 2019). There are few reports on the specific functions of class II and class III PI3Ks relative to class I PI3Ks. Class II PI3Ks consist of the p110-like catalytic subunit and are capable of regulating the internalization of receptors. Class III PI3Ks are key proteins for vesicle transport from the Golgi to the vacuole in budding yeast (Aksoy et al. 2018). Class I PI3Ks are closely related to cancer and have been studied in-depth. Focus is on the class I PI3Ks, a heterodimer composed of a regulatory subunit and a catalytic subunit, which are divided into class IA and class IB due to different coupled receptors. Class IA is activated by growth factor receptor tyrosine kinase (RTK) and class IB is activated by G-protein-coupled receptor (GPCR) (Fig. 1). Class IA PI3Ks are further subdivided into p110α, p110β, p110δ with regulatory subunit p85, and class IB only includes p110γ with regulatory subunit p87 or p101 (Bilanges et al. 2019). Isoform-specific functions are related to the expression levels in different tissues. p110α and p110β are widely distributed throughout tissues, while p110δ is highly expressed in haematopoietic cells, and p110γ is mainly expressed in leukocytes (Thorpe et al. 2015). Using gene targeting studies, p110α was identified as the crucial isoform involved in vascular remodelling (Vantler et al. 2015), and p110β was considered to play a major role in platelet physiology (Moore et al. 2019); p110δ and p110γ regulate diverse aspects of the function of T and B lymphocytes (De Henau et al. 2016; Horwitz et al. 2018). Therefore, the drug’s effectiveness may be increased by specific PI3K subtype inhibition, but this could also result in more severe adverse events. (Esposito et al. 2019).

Fig. 1
figure 1

Overview of the phosphatidylinositol 3-kinase (PI3K) signalling pathway. The PI3K signalling pathway is activated by G protein-coupled receptor (GPCR) or receptor tyrosine kinase (RTK). Class I PI3Ks activate phosphatidylinositol 4,5‑bisphosphate (PIP2) to generate phosphatidylinositol 3,4,5‑trisphosphate (PIP3), and PIP3 can be dephosphorylated by phosphatase and tensin homolog (PTEN) to form PIP2. PIP3 further induces the activation of the downstream protein kinases phosphoinositide-dependent kinase 1 (PDK1), protein kinase B (Akt), and mammalian target of rapamycin (mTOR) to regulate cell survival and proliferation. Class I PI3Ks are divided into class A and class B. The class A PI3Ks are further subdivided into catalytic subunit p110α, p110β, p110δ with p85 regulatory subunit, and class IB include p110γ with p87 or p101 regulatory subunit

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PI3K inhibitors have shown desired therapeutic effects in various cancer treatments. Among these PI3K inhibitors, copanlisib, alpelisib, idelalisib, duvelisib and umbralisib have been approved by the Food and Drug Administration (FDA), although approvals/accelerated application indications of partial inhibitors (idelalisib, duvelisib and umbralisib) have been withdrawn (Meng et al. 2021). In addition, several PI3K inhibitors are undergoing clinical trials. Despite ongoing research on this target, unintended side effects such as hyperglycaemia, rash, diarrhoea/colitis, hepatotoxicity and hypertension continue to be a major barrier to the development of PI3K inhibitors (Hanker et al. 2019).

In this review, we provide a comprehensive summary of the PI3K inhibitors that have been approved or in clinical trials (Table 1). Representative adverse effects associated with PI3K inhibitors, management guidelines and the conceivable mechanisms that have been reported are also discussed.

Table 1 The typical and clinically developed PI3K inhibitors.
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The typical PI3K inhibitors approved or in clinical trials

Pan-PI3K inhibitors

Due to the lack of a thorough understanding of the structure of the PI3K protein and isoforms in the early stage, PI3K inhibitors targeting the four isoforms of class I PI3K were mainly developed. In addition to playing different roles in tumour proliferation, various isoforms are often associated with multiple physiological functions, such as glucose metabolism, inflammation and immunity. Thus, pan-PI3K inhibitors have inevitably increased safety risks. In particular, the high incidence of metabolic-related adverse events, such as hyperglycaemia, has led to limited clinical doses (De Santis et al. 2019; Janku et al. 2018).

Copanlisib

Copanlisib (Aliqopa™; BAY 80–6946; Bayer AG) is an intravenous pan-class I PI3K inhibitor with potent activity against all four isoforms (Markham 2017) and was approved by the FDA in May 2017 for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies. In addition, copanlisib shows greater efficacy and safety both as monotherapy and in combination in various clinical trials. In a phase II study, copanlisib as a single agent also demonstrated significant efficacy with relapsed or refractory indolent lymphoma (NCT01660451) (Dreyling et al. 2017b) and relapsed or refractory diffuse large B cell lymphoma (NCT02391116) (Lenz et al. 2020), and the median progression-free survival (PFS) was 11.2 months and 2.4 months, respectively. Copanlisib plus gemcitabine act synergistically when treating peripheral T cell lymphomas (NCT03052933); PFS was 6.9 months, and median overall survival (OS) was not reached (Yhim et al. 2021). In addition, copanlisib combined with rituximab improved PFS (21.5 months versus 13.8 months in the placebo plus rituximab group) in patients with relapsed indolent non-Hodgkin lymphoma in the CHRONOS-3 study (NCT02367040) (Matasar et al. 2021). Hyperglycaemia, diarrhoea and hypertension are the most frequent adverse events with copanlisib, but all of them are minor (Dreyling et al. 2020). Notably, although other PI3K inhibitors have remarkable safety concerns, copanlisib has a low incidence of severe toxicities may be due to the intravenous route of administration and intermittent dosing schedule (Killock 2021; Munoz et al. 2021).

Buparlisib

Buparlisib (NVP-BKM120; Novartis) is an oral pan-PI3K inhibitor that selectively inhibits all isoforms of class I PI3K (Maira et al. 2012). On one hand, buparlisib has shown improved PFS in the clinical development of combined treatment, but on the other hand, it is limited by extensive toxicities (van Dam 2019). The BELLE-2 (NCT01610284) and BELLE-3 (NCT01633060) trials reported that buparlisib plus fulvestrant was effective in hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, advanced breast cancer, with a median PFS of 6.9 months and 3.9 months, respectively. However, the toxicities associated with this combination, such as increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST), hyperglycaemia and rash, led to clinical trial discontinuation (Baselga et al. 2017; Di Leo et al. 2018). Other studies have shown that buparlisib failed to have sufficient antitumour activity as a single agent or even plus carboplatin/lomustine in patients with recurrent glioblastoma (Rosenthal et al. 2020; Wen et al. 2019). Although some clinical trials suggest that buparlisib showed modest activity in solid tumours, this may be due to the different tissue distributions and functions of the various subunits. To increase efficacy while reducing the toxicity of PI3K inhibitors, future development of PI3K inhibitors should concentrate on isoform-selective PI3K inhibitors (McPherson et al. 2020; Soulieres et al. 2017).

Isoform-specific PI3K inhibitors

The four isoforms of class I PI3Ks (α, β, δ, γ) have different tissue distributions and physiological functions, which affect the inhibitory effect of isoform-specific inhibitors on various tumours and the incidence of adverse effects (Table 2).

Table 2 Catalytic subunit ty** of class I PI3K and their main physiological functions
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PI3Kα inhibitors

The PIK3CA gene encodes the p110α catalytic subunit of PI3K, and its mutation occurs at a high rate in endometrial, breast, bladder, cervical and colorectal cancers (Arafeh and Samuels 2019). The PIK3CA activation mutation is among the most common oncogenic mutations described in breast cancer to date (Arafeh and Samuels 2019).

p110α is a widely expressed PI3K isoform in vivo and a key intermediate in insulin-like growth factor-1 (IGF-1), insulin and leptin signalling, where it plays a key role in growth factor and metabolic signalling through highly selective recruitment and activation of the insulin receptor substrate (IRS) signalling complex (Hopkins et al. 2018). p110α is significantly expressed in endothelial cells and its activity is necessary for vascular development. Severe defects in angiogenic sprouting and vascular remodelling caused by generalized or endothelial cell-specific inactivation of p110α lead to embryo death in the second trimester (Araiz et al. 2019).

Alpelisib

Alpelisib (Piqray™; BYL719; Novartis) is an oral, highly selective inhibitor of PI3Kα, that received approval on May 2019 by the FDA and is indicated in combination with fulvestrant for the treatment of postmenopausal women, and men, with HR-positive, HER2-negative, PIK3CA-mutated, advanced or metastatic breast cancer (Markham 2019). The SOLAR-1 trial (NCT02437318) showed that the PFS of breast cancer patients treated with alpelisib plus fulvestrant was significantly longer than that of patients treated with placebo-fulvestrant (11 months versus 5.7 months), and the overall response rate was greater (26.6% versus 12.8%) (Andre et al. 2019). Furthermore, in a phase Ib clinical trial (NCT01623349), alpelisib in combination with olaparib was also tolerable and effective in patients with triple-negative breast cancer. The median OS of the enrolled patients was 11.8 months (Batalini et al. 2019). Currently, FDA-approved inhibitors include the pan-PI3K inhibitor copanlisib, PI3Kα inhibitor alpelisib, PI3Kγ/δ inhibitor duvelisib, PI3Kδ inhibitor idelalisib and umbralisib. In addition to alpelisib for the treatment of breast cancer, the approved indications for other inhibitors are haematological malignancies. Meanwhile, exploring the application of PI3K inhibitors in solid tumours has become a new hotspot.

However, with the launch of PI3K inhibitors, serious safety issues related to p110δ are increasingly exposed (Curigliano and Shah 2019). p110δ is preferentially expressed mainly in the haematopoietic system and affects immune cell development and function (Braun et al. 2021). On one hand, PI3Kδ inhibitors, thus, show significant efficacy in the treatment of haematological malignancies due to the regulation of immune cells (Xenou and Papakonstanti 2020). On the other hand, the immune-activating effects of PI3Kδ inhibitors have resulted in severe and lethal immune-related adverse reactions, such as hepatotoxicity, pneumonia, colitis and even intestinal perforation (Roskoski 2021). Furthermore, regulation of insulin signalling by p110α also contributes to PI3Kα inhibitor-related hyperglycaemia (Molinaro et al. 2019).

The PI3K inhibitors approved by the FDA based on single-arm trials have basically failed to show their due advantages. Although single-arm trials allow the evaluation of ORRs, they cannot accurately assess PFS and OS, and it is difficult to accurately characterize the efficacy and toxicity observed in patients. Approval of PI3K inhibitors will be significantly more difficult in the future due to serious safety issues. There are three recommendations made by ODAC: first, advocate careful dose selection through robust dose exploration in early randomized trials; second, avoid single-arm trials as a regulatory strategy in favour of randomized trials; third, comprehensively collect and analyse OS data to assess the effect of the drug on this “ultimate safety endpoint”. In brief, the above three points are achieved to determine a real and credible safety window of PI3K inhibitors, thereby ensuring the efficacy and safety of treatment.

Overall, first, on-target toxicities severely limit the development of PI3K inhibitors, and understanding the physiological functions of different isoforms of PI3K and their distribution in tissues is helpful for the clinical prediction of adverse effects. In addition to the need for corresponding adverse event management guidelines, it is also necessary to further clarify the mechanism of toxicities and find targeted intervention strategies. In addition, the side effects of PI3K inhibitors are closely related to their high-dose clinical application. Therefore, a large number of clinical studies are needed to determine the balance point of immunoregulation with PI3K inhibitors and to reduce side effects by optimizing low-dose and multiple administration. Future development of PI3K inhibitors requires exploring new intermittent delivery modalities or combination regimens to reduce the clinical dose of PI3K inhibitors while ensuring antitumour efficacy. Second, the lack of biomarkers also limits the clinical application of PI3K inhibitors. For example, stratification of breast tumours according to single and multiple copies of PIK3CA mutations resulted in distinct distributions of scores for PI3K signalling and cellular stemness (Madsen et al. 2021). This suggests that more genomic studies are still needed to accurately assess patient stratification for PI3K-targeted therapy and to identify a biomarker that can effectively predict patient susceptibility to PI3K inhibitors.