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The data from emerging PI3K inhibitors is impressive, based on both efficacy and importantly on more favorable safety profile compared to the predecessors such as idelalisib7 (adverse events) or duvelisib8 (modest outcomes).

Will the PI3K inhibitor class pull out of the looming safety concerns and remain relegated to only salvage therapy options in the treatment guidelines of lymphomas and leukemia or will this class move up the frontline treatment options? The next generation of isoform-specific PI3K inhibitors appear very promising, nevertheless.

PI3K is a major player in the B-cell receptor (BCR) signaling axis, which is critical for the survival and maintenance of B-cells. The Phosphoinositide 3-kinase (PI3K)/AKT/mTOR is one of the pivotal pathways that has most frequently dysregulated signaling cascades in human malignancies and is implicated in a wide variety of different neoplasms such as lymphoma and leukemia9-15. PI3Ks are a family of lipid kinases that catalyze the phosphorylation of plasma membrane phosphoinositides resulting in phosphatidylinositol 3, 4, 5-trisphosphate (PI(3,4,5)P3/PIP3) that causes AKT activation. PI3Ks transmit extracellular signals from transmembrane receptors like G-protein coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) to the cytoplasm to regulate the key cellular processes9-13. Though PTEN negatively regulates the PI3K/AKT/mTOR pathway, the PTEN activity is frequently lost in cancer, leading to constitutive pathway activation and tumorigenesis9. PI3K is the central junction for pathways that control multiple crucial physiological functions and cellular processes, including cell proliferation, differentiation, growth, survival, motility and metabolism9. In many hematologic malignancies, PI3K activation is seen, providing a promising targeted therapy option9-14.

PI3Ks are divided into three classes (I-III). Class I is most frequently implicated in cancers9,16-18. Class I has two subtypes IA and IB based on cell surface receptors each with a regulatory and a catalytic subunit. Class IA has catalytic isoforms p110α, p110β and p110δ, while class IB has isoform p110γ. The PI3K-δ isoform is highly expressed in hematopoietic cells such as lymphatic tissues, PI3K-γ is differentially expressed in leucocytes and PI3K-α has ubiquitous expression. Blood cancers usually express p110δ and/or p110γ that lends responsiveness to isoform selective PI3K inhibition. Multiple in vitro and in vivo studies support the association of impaired immune response and B-cell development with lack of p110δ and p110γ isoforms9. Most PI3K inhibitors are not specific for mutant isoforms, therefore, also affect the wild type PI3K and physiologic PI3K activity. Uniquely hematologic cancers are in constant contact with immune system that allows the sensitivity to immune modifying effects of PI3K inhibitors9, 16-18

Potential role of PI3K pathway in hematologic malignancies

Currently, the PI3K inhibitors have the most advanced data in lymphomas and CLL, with potential for an important role in other leukemias, and B-cell and also in T-cell lymphomas9,11,12.

Acute myeloid leukemia (AML)

For nearly three decades, AML management has heavily depended on poly-cytotoxic treatment regimens, until the recent approval of the targeted therapies midostaurin (in combination with chemotherapy) for patients with FMS-like tyrosine kinase 3 (FLT3) mutation positive for both internal tandem duplication and tyrosine kinase domain and enasidenib for IDH2 mutated patients. Several oncogenic mutations are well established and reported in AML such as FLT3 mutations, KIT receptor tyrosine kinase and Ras mutations that can potentially activate the PI3K signaling pathway11. PI3K-δ is known to be expressed in AML blast cells. Preclinical data suggests that PI3K inhibitors can block downstream signaling pathway and suppress the growth of AML cells making it a worthy target for further exploration.

Chronic myelogenous leukemia (CML)

Tyrosine kinase inhibitors (TKI) are the mainstay of CML treatment. Resistance to TKIs resulting in disease progression and relapse is common. The oncogenic driver BCR-ABL1 tyrosine kinase is most frequently activated that further activates PI3K signaling that is found to be associated with imatinib resistance and MRD positive CML. Preclinical data indicates that PI3K inhibition potentiates the activity of imatinib in CML cell lines11. The combination of TKIs and PI3K inhibitors may have the potential to eliminate the residual disease.

Acute lymphoblastic leukemia (ALL)

Like other leukemias, ALL management also harnesses the efficacy of poly-cytotoxic chemotherapies and stem cell transplants, though relapsed or refractory ALL has a poor prognosis. The elimination of minimal residual longer and durable remissions. A quarter of ALL patients harbor Philadelphia chromosome (Ph +ve) and express BCR-ABL1 that also activates downstream PI3K pathway. PI3K is hyper-activated in majority of T-cell ALL patients11, 13. In mouse models of Ph +ve pre-B cell ALL PI3K inhibition inhibited BCR-ABL induced leukogenesis. Hence, PI3K inhibition could serve as a beneficial therapy option for B and T-cell ALL patients.

Chronic lymphocytic leukemia (CLL)

So far, CLL is the only leukemia to have an approved PI3K inhibitor idelalisib. In recent times, CLL has been an area of intense drug development and there are multiple targeted therapies recently approved across lines of therapy and subtypes of CLL in a very short period of time. High-risk patients with 17p deletion/TP53 mutations, now have multiple choices of effective chemo-free targeted therapies such as ibrutinib, idelalisib16 and venetoclax that have constantly improved the outcomes in this poor prognosis group. It is known that PI3K is constitutively activated in CLL via p110δ isoform and this activation in CLL cells is associated with increased expression of anti-apoptotic proteins such as Bcl-xL, Mcl-1 and XIAP11. Dual PI3Kδ, γ inhibitor Duvelisib is also being explored in relapsed or refractory CLL including patients who have failed BTK inhibitors such as ibrutinib. However, idelalisib’s frontline trials have been terminated in CLL due to safety concerns

Indolent Non-Hodgkin’s lymphoma (iNHL): Follicular lymphoma, Marginal zone lymphoma, Small lymphocytic lymphoma and lymphoplasmacytic lymphoma/ Walden-strom’s macroglobulinemia

iNHL is perhaps the home ground for PI3K inhibitor drug development. The PI3K pathway is an important target in FL because of the constitutive phosphorylation of AKT and mTOR substrates p70S6K and 4E-BP1 in FL cells and patient samples. Idelalisib, the first-in-class PI3K-δ inhibitor is already approved in FL in relapsed and refractory (aka double refractory) setting establishing the role of this pathway in disease control11, 16. Many other molecules are in late stage development including duvelisib, umbralisib, and copanlisib in relapsed or refractory iNHL. Recent data at AACR and EHA meetings has shown impressive data of copanlisib1 and umbralisib3, however, duvelisib failed to impress in iNHL with modest data (Table. 1).

Diffuse large B-cell lymphoma (DLBCL)

Preclinical studies indicate the activation of PI3K pathway in DLBCL cell lines and also the downstream activation of AKT, FOXO1 and GSK-3 that can be blocked by PI3K inhibition to induce apoptosis11. Clinical studies indicate that PTEN deletions and mutations result in the activation of the PI3K pathway in DLBCL associated with shorter survival. The phase II Copanlisib single arm trial is ongoing in relapsed or refractory DLBCL for both cell of origin subtypes (GCB and ABC patient populations). Idelalisib in combination with entospletinib is in a phase II trial evaluating relapsed or refractory DLBCL patients. Multiple trials of buparlisib are ongoing in relapsed or refractory DLBCL.

Mantle cell lymphoma (MCL)

Multiple PI3K inhibitors including idelalisib, copanlisib and buparlisib are being tested in MCL. Preclinical studies have reported the activation of PI3K pathway via B-cell receptor leading to deregulated cell-cycle progression in MCL cells11,13. PI3K constitutive activation via the BCR results in deregulation of cell cycle progression. The phosphorylation of PTEN is common in MCL that causes PTEN inactivation resulting in the activation of PI3K pathway. However, PI3K-δ inhibitors have shown modest responses, possibly because of PIK3CA amplifications observed in MCL cell lines rendering resistance.

Peripheral T-cell lymphoma (PTCL)

PTCL is classified into many rare and distinct subtypes such as PTCL NOS, anaplastic large-cell lymphoma, angioimmunoblastic T-cell lymphoma. PI3K-δ and PI3K-γ isoforms are preferentially expressed in leukocytes with distinct roles in T-cell function, therefore, are important for the growth and survival of T-cell malignancies. Cell cycle arrest and apoptosis were observed in PTCL cell lines treated with PI3K inhibitors27. PTCL patients with high p-AKT expression showed aggressive clinical courses with significantly worse OS and PFS and a poor chemotherapy response rate. Frontline treatment in PTCL relies on multi-drug chemotherapy regimens such as CHOP, EPOCH or HyperCVAD with or without stem cell transplant achieving less frequent durable remissions, hence, most patients eventually relapse. Despite multiple approved therapies such as belionostat, romidepsin, pralatrexate and brentuximab vedotin (for ALCL) in the relapsed or refractory setting of PTCL with ORR range of 25-35%, many novel molecules are under evaluation20. In a phase I study, duvelisib showed an impressive ORR of 47% heavily pretreated PTCL patients (Table. 1). PI3K inhibitors warrant further research especially as combination strategy in T-cell lymphomas.

Clinical data of key assets in lymphomas and leukemia: Successes and misses

PI3K pathway has a critical role in lymphoma. Many pan and isoform-specific inhibitors are in various stages of clinical development both as monotherapy and in combinations. Here we discuss about the approved and the key emerging PI3K inhibitors in development.

Table 1: Key PI3K inhibitors in development for hematologic malignancies

Click Here to Enlarge

iNHL: Indolent Non-Hodgkin’s lymphoma, ORR: Objective response rate, CR: Complete response, PR: Partial response, mPFS: Median progression-free survival, mOS: Median overall survival, mos: Months

Idelalisib (Gilead)

This first-in-class PI3K-δ isoform inhibitor gained both FDA and EMA approval based on improved outcomes in relapsed or refractory CLL (in combination with rituximab) and as monotherapy in indolent lymphoma. The registrational trial of idelalisib in combination with rituximab in prognostically unfavorable relapsed or refractory CLL patients showed an impressive ORR of 81% against placebo (13%)10,13. Despite the lack of appropriate comparator and the FDA-issued black box warning, it finds use in the relapsed or refractory CLL settings including 17p del/TP53 mutations. The accelerated approval of Idelalisib in iNHL came through the pivotal phase II trial in relapsed or refractory (double refractory to rituximab and an alkylator) that showed an impressive ORR (57%). However, overwhelming safety issues post approval led to the recent termination of multiple frontline and later line trials in both CLL and iNHL7. The FDA label is not recommended for first-line treatment currently.

The future strategy for idelalisib development and administration would require very stringent patient selection criteria. Hepatotoxicity was a major issue in younger and fit CLL patients treated with frontline idelalisib probably as a result of autoimmune reaction as T-cell infiltrates were found in the liver biopsies and a decrease in T regulatory cells28. Therefore, upfront use of idelalisib in younger, immunocompetent and less pretreated patients must be carefully planned. Evaluating idelalisib in treatment naïve older CLL patients with lower tumor burden might be a better strategy. Patients on concomitant steroids fare better, hence better prophylactic protocols for pneumocystis and frequent monitoring for CMV could help ameliorate or mitigate the adverse events for idelalisib administration. Also alternative combination strategies must be explored beyond rituximab such as ofatumumab combination which showed relatively lower pneumonitis rates than rituximab. 

Duvelisib (IPI-145) (Infinity Pharmaceuticals, Verastem Inc.)

A dual PI3K-δ and γ inhibitor in mid-late stage development has few ongoing trials in CLL/SLL and indolent lymphomas. These two isoforms of enzymes support the growth and survival of malignant B-cells and T-cells. The randomized phase III DUO monotherapy study against ofatumumab is evaluating relapsed or refractory CLL that is likely to lead to the commercial launch. However, SYNCHRONY study in BTKi experienced CLL patients has been withdrawn.

In iNHL, the latest follow up data of the single arm phase II DYNAMO study (monotherapy) at EHA in refractory iNHL (double refractory to both rituximab and chemotherapy) demonstrated a modest response rate of 41% (all PRs) in double refractory FL as seen in Table.1

Pneumonitis and colitis remained relatively uncommon22. However, the modest efficacy outcomes led to the cessation of several planned trials including duvelisib and venetoclax combination study8.

In SLL, the IRC assessed ORR was 68% and the safety profile was generally manageable with grade 3-4 adverse events for both FL and SLL. Duvelisib is also under early evaluation for the treatment of heavily pretreated relapsed or refractory T-cell lymphoma.

Copanlisib (BAY 80-6946) (Bayer Pharma AG)

Copanlisib is a novel, intravenous, highly selective, pan-class I PI3K inhibitor with preferential activity against the p110α and p110δ isoforms. Based on recent CHRONOS-1 data, copanlisib has been granted Fast Track and Orphan Drug Designation for FL and more recently FDA has also granted priority review designation for the treatment of relapsed or refractory FL patients who have received at least two prior therapies. An earlier phase I study, showed promising activity in NHL patients, and favorable safety.

In the single-arm phase II CHORNOS-1 study in relapsed or refractory iNHL patients with ≥2 prior lines of treatment, copanlisib demonstrated impressive 59% ORR as shown in Table 1. The most common adverse events were transient hyperglycemia and hypertension besides neutropenia, diarrhea, lung infection and pneumonitis. Transient elevation of blood glucose is an on-target class effect via disruption of insulin signaling. In contrast to continuously dosed oral PI3K inhibitors, the efficacy of copanlisib (i.v.) was impressive and safety profile was manageable and unique. Dr. Dreyling, the investigator of the study, attributes it to intermittent administration schedule and intravenous route of administration. Copanlisib has demonstrated a distinct safety profile with low rate of severe gastrointestinal toxicities, hepatotoxicities, pneumonitis, and opportunistic infections in reduced discontinuation. The lower incidence and severity of toxicities observed with copanlisib is likely due to the route of administration that induces reduced gastrointestinal toxicity, while higher concentration in the gut and possible first-pass metabolism is dose limiting for oral agents for both isoform selective or pan class I PI3K inhibitors24. It is also argued that intravenous route of administration might help in fixed dosing, higher patient compliance and reduced cumulative toxicity. 

TGR-1202 (Umbralisib) (TG Therapeutics Inc.)

This next generation oral PI3K-δ inhibitor TGR-1202, is an attempt to mitigate the hepatotoxicity associated with delta class of agents and has shown promising activity in preclinical studies. Multiple studies are ongoing in various phases and settings in NHL and CLL with impressive data. The FDA has granted two orphan drug designations covering the chemo-free combinations of ublituximab (TG-1101) and oral umbralisib (TGR-1202) for the treatment of DLBCL and CLL in UNITY-DLBCL and UNITY-CLL respectively. The ongoing phase II study, assessing the role of umbralisib in CLL patients who are intolerant to prior BTK or PI3K-δ has also shown a favorable safety profile5. The data from multiple key trials was presented in ASCO and EHA 2017 this year Table 1.

In majority of studies, a favorable safety profile was observed compared to prior PI3K inhibitors with limited and fewer grade 3-4 transaminitis, pneumonitis, diarrhea, and colitis. 

TG-1202 is considered to be the best in class with much lower toxicities which may allow to avoid a safety warning label and provide a competitive advantage over other similar inhibitors. (Table. 1) 

Buparlisib (BKM120) (Novartis)

A pan-class I PI3K inhibitor is being evaluated in a phase II trial in relapsed DLBCL, MCL and FL. In a phase I study, buparlisib in combination with rituximab has shown ORR of 64% , all PRs, estimated 1-year PFS of 74%  in heavily pretreated NHL including FL, MZL, MCL and WM patients26. 

Pilaralisib (SAR245408) (Sanofi, Exelixis)

Another pan-class I PI3K inhibitor that has relatively less off-target effects and is well tolerated in early studies. Phase I trial in relapsed lymphomas and CLL showed fewer adverse events such as diarrhea, hyperglycemia, and headache. Preliminary results have previously shown activity in NHL subtypes with ORR of 50% in FL and SLL11 (Table.1).

Challenges and future strategies for successful PI3K drug development in hematologic malignancies

Several PI3K inhibitors are in development including pan-class I PI3K inhibitors that target all four Class I isoforms with the notion that the cancer cells express various PI3K isoforms in the signaling pathway10. The main challenges with pan-PI3K inhibitors are that the doses required to block all the isoforms for longer duration might not be tolerable and safe. Another issue is that pan-PI3K inhibitors are likely to have relatively higher off-target effects compared to isoform specific inhibitors. The isoform specific inhibitors on the other hand can block the relevant target more efficiently with limited toxicities. The first-in-class p110δ inhibitor idelalisib is selective and targets not only the cancer cell but also the tumor microenvironment in both leukemia and lymphoma10, 18.

The emergence of new patient segments such as prior BTK inhibitor experienced patients who develop acquired resistance due to mutations in BTK and/or PLCG2 highlights the need for more effective therapies that allow for a precision therapy approach. PI3K is known to be upregulated in ibrutinib resistant lymphoma, suggesting idelalisib therapy may be beneficial in ibrutinib-refractory population primarily because of the no- overlapping mechanism of action26. Real world evidence has shown an ORR of 28% and median PFS of 8 months in ibrutinib-resistant patient treated with idelalisib29. Also in preclinical study, duvelisib might be active in CLL patients with BTK mutations (C481S)30. The preliminary clinical evidence in ibrutinib-refractory CLL patients demonstrated one PR and five stable disease. Ibrutinib resistant patients with BTK mutations showed reductions of pAKT31. Further studies are warranted to establish the role of PI3K inhibitors in this population.31

Pre-clinical studies also show activity of PI3K inhibitors in drug-resistant cell lines that warrant further research of the potential of PI3K inhibitors to overcome limitations of conventional therapies and restore sensitivity to prior treatment. Restoring sensitivity to therapy could be particularly important for patients with relapsed or refractory disease. In CLL and lymphomas, PI3K inhibitors exhibit action through the microenvironment and via blockade of BCR signaling than merely affecting the tumor cells.

Most PI3K inhibitors currently are targeting the relapsed or refractory setting and remains to be proven for frontline therapies. The expansion to upfront therapy option would require cautious and rational combination approach with favorable safety profile. The combinatorial strategy of rational combinations of PI3K inhibitors with immunotherapies, cancer vaccines that can overcome the immune tolerance and exhaustion would be ideal. The combination with other approved targeted standards of care are likely to return clinically meaningful benefits10. Though combination therapies might be more cost intensive and face reimbursement and market access challenges, but proven benefits in a specific patient population will justify the higher cost.  A phase II trial of pembrolizumab in combination with idelalisib is ongoing in relapsed or refractory CLL and low grade B-cell lymphomas (NCT02332980). Ideal combination partners need to be identified to potentiate the PI3K inhibitor activity. 

Tumor microenvironment modulation is another powerful strategy of creating an optimal environment for effective tumor killing. Since, the hematopoietic cancer cells are in constant contact with immune cells, they are potentially more sensitive to immune microenvironment affecting PI3K inhibitors. Hence, modulating the immune microenvironment for tumor killing is another potentially effective approach. PI3K signaling pathway is active in both cancer cells as well as in tumor microenvironment10,18. For example, the white blood cell-selective PI3K-δ and PI3K-γ isoforms are known to have an important role in regulating the immune-suppressive, tumor-associated myeloid cell and regulatory T-cell subsets, respectively, and are crucial in solid tumor growth18. Future strategies can include rationale combination approaches that can maximize the effectiveness of PI3K pathways.

Lastly but importantly, there is a lack of validated prognostic and predictive biomarkers for patient selection in PI3K/AKT/mTOR pathway, and are not in prime time yet for lymphoma. The strategies directed at therapeutic response prediction would allow for personalized medicine for patients with PI3K –driven cancers including lymphoma, by identifying oncogenic driving mutations or modifying microenvironment. Identification of genetic biomarkers to aid patient selection is important in targeted therapy approach. The sophisticated methods such as next generation sequencing could help in the understanding of responders versus non responders. 

Conclusion

In the current era of precision medicine, it is important to identify and classify patients that are more likely to benefit from a particular therapy for not only effective therapies, but also to overcome reimbursement and market access challenges. There is an unmet need for potent PI3K inhibitors with specificity for isoforms and effective strategies for rational combinations may help overcome the toxicity and enhance efficacy. Future research must explore the merits of inhibiting all 4 isoforms of class I PI3K versus inhibiting specific isoforms. The optimized use of next generation PI3K inhibitors in development as monotherapy or in a combination strategy are likely to provide additional treatment options for lymphoma and leukemia patients. Novel strategies are required that incorporate learnings from the failures as well as the successes while targeting this important pathway in hematologic malignancies, especially in B-cell malignancies.

With novel immunotherapies, antibody-drug conjugates and CAR-T therapies ready to disrupt the lymphoma and leukemia management, small molecule inhibitors such as PI3K kinase inhibitors must have a well thought out strategy to stay relevant. The PI3K kinase pathway is an important target that provides an effective targeted therapeutic option for the management of hematologic malignancies. PI3K inhibitors currently exhibits a strong pipeline with approximately 37 drug candidates and is likely to see increased R&D efforts in near future.   Cautious patient selection and managing adverse effects is needed in order to determine the appropriateness of PI3K inhibitor therapy. PI3K inhibitors remain a viable and useful treatment option in patients who fail other lines of therapy. Safety issues may have stymied the development of this important class of inhibitors, but it is not written off yet.

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