The phosphatidylinositol 3-kinase (PI3K) pathway has attracted immense interest as a therapeutic target for cancer treatment. Idelalisib was the first PI3K inhibitor approved by the US Food and Drug Administration and is utilized in the treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma. Copanlisib has subsequently been approved for relapsed follicular lymphoma in patients who have received at least two prior systemic therapies. There are multiple other PI3K agents currently in development; these target various combinations of PI3K isoforms. Despite the therapeutic benefit, there have been concerns about the severe and sometimes fatal adverse effects of this class of drug. Several side effects are unusual and have poorly understood mechanisms; these include autoimmune dysfunction, opportunistic infections, skin toxicity, hypertension, and hyperglycemia. An understanding of these unusual toxicities, as well as a good grasp of management principles, will be important as more PI3K inhibitors are approved and become incorporated into routine practice.
The phosphatidylinositol 3-kinase (PI3K) family consists of highly conserved enzymes that are a part of the intracellular PI3K/Akt/mammalian target of rapamycin (mTOR) signaling axis. This axis transmits cell surface receptor signals and affects a variety of tissue-dependent cellular functions. The PI3K/Akt/mTOR axis has been implicated in a variety of cancers, and the pathway is found to be constitutively activated in many B-cell malignancies.[2,3] Importantly, in both normal and malignant B cells, PI3K lies downstream of the B-cell receptor, leading to proliferation via the nuclear factor kappa B pathway (Figure 1). The activation of this pathway provides an attractive target for therapeutic intervention in B-cell malignancies.
In mammals, the PI3K family is divided into three different classes (I, II, and III), and class I PI3K is further subdivided into IA (activated by receptor tyrosine kinases) and IB (activated by G protein–coupled receptors) (Figure 2). Class IA is the subfamily most implicated in human cancer.[1,2,5] Within the PI3K family are four tissue-specific isoforms (α, β, δ, and γ) that are associated with various tissue pathways (see Figure 1). The α, β, and δ isoforms are all associated with class IA and have a p85 regulatory subunit, while the γ isoform is associated with class IB and has a p101 regulatory subunit.[1,6]
The tissue distribution of the different isoforms informs the expected activity and toxicity seen with pharmacologic inhibition of these different PI3K isoforms. PI3K α and β isoforms are expressed in multiple tissues, while the δ isoform is preferentially expressed on leukocytes.[7,8] PI3Kα isoforms are expressed ubiquitously and play a critical role in insulin signaling, facts that have relevance for agents currently in development. PI3Kγ has been shown to be expressed in many cells of the cardiovascular system.
The δ isoform–specific PI3K inhibitor idelalisib has been the most extensively described; however, there are multiple other agents in development targeting various isoforms. Here, we briefly describe the clinical efficacy of these PI3K inhibitors, then discuss the mechanisms and management of the more common unusual toxicities seen with these agents.
Clinical Efficacy and Toxicity to Date
Idelalisib was the first US Food and Drug Administration (FDA)-approved PI3K inhibitor; its use is indicated in relapsed/refractory chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and small lymphocytic lymphoma (SLL). In the phase II study that led to registration, the overall response rate (ORR) for single-agent idelalisib was 54% in FL and 61% in SLL. A phase III study evaluated idelalisib in combination with rituximab in relapsed CLL, with an ORR of 81% that subsequently resulted in combination idelalisib/rituximab being approved for relapsed CLL. In September 2017, the FDA granted copanlisib accelerated approval for use in relapsed FL after two previous lines of therapy. Approval was based on a phase II study of 104 heavily pretreated patients with FL, in which the ORR was 58.7%, with a 14.4% complete response (CR) rate.
While idelalisib has proven to be efficacious for patients with relapsed FL, CLL, and SLL, unexpected autoimmune and infectious toxicities have demonstrated the need for careful development and monitoring of new agents, both alone and in combination with other agents. In a trial in which idelalisib was combined with lenalidomide and rituximab, the Alliance reported unexpected toxicities, including grade 3 or higher transaminitis, hypotension, rash, sepsis syndrome, and pulmonary infiltrates. Of the 8 patients enrolled prior to trial suspension, care in the intensive care unit was required for 3 of them; most toxicities occurred within 3 weeks of initiation of idelalisib. Other studies have also revealed high rates of autoimmune toxicities such as pneumonitis, hepatitis, and noninfectious colitis.[17-21] Increased rates of infection, including opportunistic infections such as Pneumocystis jirovecii pneumonia (PJP) and cytomegalovirus (CMV) infection, have also been seen, with deaths noted from PJP as well as from fungal sinusitis in trials.[13,22] Based on these encountered toxicities, idelalisib now carries a black-box warning regarding hepatotoxicity, diarrhea/colitis, pneumonitis, and intestinal perforation. Use of idelalisib in nonapproved settings is not recommended outside of a clinical trial.[11,23,24]
Phase III testing is currently ongoing for several experimental PI3K inhibitors, including duvelisib (ClinicalTrials.gov identifiers: NCT02049515, NCT02004522) and umbralisib (TGR-1202; NCT02612311, NCT02793583), as well as FDA-approved copanlisib (NCT02367040, NCT02369016, NCT02626455). RP6530, buparlisib (BKM120), and INCB050465 are undergoing earlier-phase testing. A review of current trials and preliminary results has recently been published.
Mechanisms of Immune-Related Toxicity
PI3K inhibition is generally well tolerated when used in a clinically approved setting. However, unusual and unexpected toxicities have been seen with use of PI3K inhibitors during development that are important to keep in mind when considering these agents and when treating patients. These unusual toxicities are best understood in the context of the normal physiology of the PI3K/Akt/mTOR pathway and the tissue distribution of the different PI3K isoforms.
Many of the autoimmune toxicities encountered are likely mediated through the effects of PI3K inhibition on different lymphocyte subsets, with the PI3Kδ isoform classically implicated. T-regulatory lymphocytes (Tregs), classically identified by expression of CD4/CD25 and more specifically by expression of FOXP3, are critical in the maintenance of immune self-tolerance and downregulation; they also appear to be instrumental in the mechanism of PI3K-associated autoimmune toxicities. In multiple series, colonic biopsy specimens of patients experiencing idelalisib-associated diarrhea demonstrated intraepithelial lymphocytosis, crypt cell apoptosis, and neutrophilic infiltration.[20,27] In a phase II trial of idelalisib in combination with rituximab, 64% of the enrolled patients experienced diarrhea, and of the 14 patients with diarrhea who underwent colonoscopy, in most a T-cell infiltrate was identified. In addition to the importance of PI3Kδ to Treg function, the δ isoform plays a role in the differentiation of peripheral T-helper cells into the Th1 and Th2 lineages. Accordingly, in a separate phase II study of the combination of idelalisib and the spleen tyrosine kinase inhibitor entospletinib, high rates of autoimmune pneumonitis were seen, with accompanying increases in the Th1-associated cytokines interferon γ, interleukin (IL)-6, IL-7, and IL-8 identified in the peripheral blood of affected patients.
Interestingly, younger age and previously untreated disease may be associated with increased risk of autoimmune toxicity. In a phase II trial involving idelalisib in which 79% of subjects experienced transaminase elevation, those who experienced hepatotoxicity had a median age of 61 years, compared with 72 years in those who did not experience hepatotoxicity (P = .02). In patients receiving idelalisib who experienced hepatotoxicity, an increase in proinflammatory cytokines CCL-3 and CCL-4, in addition to a decrease in peripheral blood Tregs, was seen. Liver biopsy samples from affected patients demonstrated an increased infiltrate of activated CD8+ cytotoxic T cells.
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