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
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
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
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
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
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.
1: Key PI3K inhibitors in development for hematologic
Click Here to Enlarge
Non-Hodgkin’s lymphoma, ORR: Objective response rate, CR:
Complete response, PR: Partial response, mPFS: Median
progression-free survival, mOS: Median overall survival, mos:
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
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,
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.
80-6946) (Bayer Pharma AG)
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
earlier phase I study, showed promising activity in NHL
patients, and favorable safety.
single-arm phase II CHORNOS-1 study in relapsed or
refractory iNHL patients with ≥2 prior lines of
copanlisib demonstrated impressive 59% ORR as shown in Table
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
(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
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
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)
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.
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
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.
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
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