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The PI3K pathway: clinical inhibition in chronic lymphocytic leukemia
Author's Accepted Manuscript
The PI3K Pathway: Clinical Inhibition in CLL Jennifer R. Brown MD PhD
PII: DOI: Reference:
www.elsevier.de/endend S0093-7754(16)00010-5 http://dx.doi.org/10.1053/j.seminoncol.2016.02.004 YSONC51908
To appear in:
Semin Oncol
Cite this article as: Jennifer R. Brown MD PhD, The PI3K Pathway: Clinical Inhibition in CLL, Semin Oncol, http://dx.doi.org/10.1053/j.seminoncol.2016.02.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
The PI3K Pathway: Clinical Inhibition in CLL Jennifer R Brown MD PhD
Director, CLL Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Department of Medicine, Harvard Medical School, Boston, MA
Correspondence should be addressed to Jennifer R Brown, MD, PhD, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215; telephone 617-632-4564; fax 617-5827890; email [email protected]
Abstract Constitutive or mutational activation of the phosphatidylinositol 3 kinase, or PI3K, has been implicated in many cancers, including CLL. The delta isoform of the p110 catalytic subunit of PI3K has its primary physiologic function in B cells and appears to be the predominant mediator of most PI3K signals in CLL cells. Idelalisib is a first-in-class inhibitor of the PI3K delta isoform which shows near complete inhibition of AKT phosphorylation in CLL cells in vitro and in vivo. Idelalisib shows the classic pattern of response to BCR inhibition in CLL, with rapid nodal response and transient increase in lymphocytosis. The phase 1 study established the recommended dose as 150 mg twice per day. Subsequent registration trials have
focused predominantly on antibody combinations, leading to the FDA approval of idelalisib with rituximab for relapsed CLL patients for whom rituximab is appropriate therapy in summer 2014. The median PFS of idelalisib-rituximab in this heavily pretreated CLL population with multiple comorbidities and frequent 17p deletion was an impressive 19.4 months. The success of idelalisib has paved the way for the development of other PI3K inhibitors in CLL, including duvelisib and TGR-1202, which are in or moving toward registration trials.
Introduction Chronic lymphocytic leukemia (CLL) is the most common leukemia of adults and remains an incurable disease at present.
Although a subset of patients have indolent disease and
may not require therapy for years or ever, approximately half of patients experience steadily progressive disease and another quarter will progress to therapy eventually. Once patients do require therapy, historically outcomes are poor, with progressively shorter remissions over time, and frequent infections and cytopenias1. The last five years have seen a revolution in CLL therapy, however, with two improved anti-CD20 antibodies (ofatumumab and obinutuzumab), as well as new targeted kinase inhibitor therapies that affect signaling downstream of the B cell receptor and other cell surface receptors2. This review focuses on one of the two best validated new targets, the PI3 kinase, and particularly the delta isoform, which is expressed predominantly in hematopoietic cells and has its primary physiologic function in B cells3.
PI3 Kinase PI3K is a heterodimeric lipid kinase comprised of a regulatory and catalytic subunit. The catalytic subunit has four different class 1 isoforms that show different cell type specificity which is well illustrated by their knockout mouse phenotypes.
The p110
isoenzymes are ubiquitously expressed4 and knockout mice created for p110
and p110
and p110
are
embryonic lethal at E10.5 and E3.5, respectively5. The alpha isoform is also important for insulin signaling, such that pan-PI3K inhibitors or alpha-specific inhibitors often cause hyperglycemia. In contrast, the p110
and p110
isoenzymes are thought to be predominantly
expressed in hematopoietic cell types3,6. The knockout mice for p110
are viable and fertile
with a phenotype primarily affecting the B cell compartment5. Interestingly, however, a recent study has identified that the delta knockout mouse also has impaired T cell function, which impacts on T regulatory cells more than T effector cells. In this study the authors showed that this phenotype was relatively protective against solid tumor xenografts in mice7. The gamma isoform also has expression limited predominantly to hematopoietic cells, with the knockout mouse phenotype leading to impaired T-cell migration, inhibition of T-cell activation and proliferation and defects in macrophage function8,9. Although pan PI3K inhibitors and alpha inhibitors have been extensively studied in solid tumors, most of the effort in CLL and lymphoid malignancies has focused on specific delta inhibition, even though other isoforms including alpha and gamma are expressed in CLL.
Interestingly, inhibition of delta alone does
substantially reduce phosphorylation of the downstream target AKT in CLL in vitro and in vivo10-12. PI3K functions to transduce signals downstream of the B cell receptor in CLL but also integrates signals from a variety of other cell surface receptors including CD40, CXCR4, and
integrins11,13. As such PI3K also has a profound influence on B cell trafficking by promoting B cell chemotaxis towards CXCL12/13, migration beneath stromal cells, and upregulation of CLL cell chemokine secretion. It is likely that the prosurvival and proliferative signals stimulated by both BCR activation and stromal cell interaction are amplified by the convergence of these pathways on common downstream kinases that include PI3K. These pathways are constitutively activated in CLL, likely due to this continual stimulation from the microenvironment. Unlike in solid tumors, mutational activation of this pathway is rare in CLL, although the alpha isoform has been found to be amplified in 5.5% of CLLs14. Whether this confers resistance to delta inhibition is not yet known.
Idelalisib: the first PI3K inhibitor in CLL Idelalisib, formerly known as CAL-101 or GS-1101, is a potent specific inhibitor of the delta isoform of PI3 kinase, with an EC50 of 8 nM in isoform specific cell-based assays12. In vitro, idelalisib can induce apoptosis and suppress AKT phosphorylation nearly completely at baseline and in response to CD40L or IgM stimulation11. The phase 1 study of idelalisib included all hematologic malignancies and ultimately enrolled approximately 190 patients10,15,16. During initial dose escalation no dose limiting toxicities were seen, but at the highest dose the investigators noticed that grade 3-4 transaminitis was seen more frequently, albeit often after the official observation period for dose limiting toxicities. This observation led to expansion cohorts at a variety of different dose levels in both CLL and NHL, and ultimately, the dose selected was 150 mg BID because of a plateau in exposure and nodal response as well as concern about more frequent LFT abnormalities at higher doses10.
An early observation from this study was that some CLL patients were showing an increase in lymphocyte count even while their nodes were rapidly decreasing and they were clinically improved. This type of response was reported very early on from this study17 but soon thereafter was seen also with the BTK inhibitor ibrutinib18 and led to a revision of the response criteria such that this increase in lymphocyte count was not considered progressive disease. A new category of response called PR-L, for partial response with lymphocytosis, was created for patients who met all criteria for PR except a persistently elevated lymphocyte count19. In the CLL portion of this phase 1 study, a subset of patients showed persistent elevation of their lymphocyte count even at one year, and long-term follow-up shows that some patients may continue to have this persistent lymphocytosis even while remaining in good response, for years10. In total in this study, 54 heavily pretreated CLL patients with a median of 5 prior regimens showed a nodal response rate of 81%, IWCLL20 PR rate of 39%, and PR-L rate of 33%. No difference was seen in PFS between patients with PR and PR-L, and PFS was 32 months for those patients treated at doses of at least 150 mg BID10. A number of small phase 1b combination studies were then performed, which established the safety of combining idelalisib with rituximab, ofatumumab, bendamustine, and bendamustine–rituximab. A recent update of the 40 patients treated with idelalisib plus either rituximab or ofatumumab showed a 83% ORR, with 2 CRs, and a median PFS of 24 months21. A similar update on the combination of idelalisib with chemoimmunotherapy reported on 114 patients, and found a 82.5% ORR, including 70% in those with del 17p CLL, and median PFS 26 mos in the overall population and 20 mos in those with del 17p CLL22.
Idelalisib Registration Trials Because of the persistence of lymphocytosis over time in many patients in the phase 1 study, and the fact that the response criteria were still in evolution at the time the trials were designed, the registration trials for idelalisib in CLL were all based on combination therapy designed to abrogate the lymphocytosis, such that all patients with nodal response would likely meet traditional IWCLL response criteria. The first study compared idelalisib-rituximab to placebo-rituximab in CLL patients who had relapsed within 24 months of their most recent prior therapy, and who had significant comorbidities. The second study compared idelalisib-BR to BR alone in relapsed fit CLL patients, and the third study compared idelalisib-ofatumumab to ofatumumab alone in relapsed CLL patients. The first study was closed early in mid-2013 by its data monitoring committee, because of the very high efficacy in the experimental arm. On the basis of this study, the idelalisib rituximab regimen was approved by the FDA in July 2014 for relapsed CLL patients for whom rituximab therapy would be an appropriate regimen23. Looking at the data, the patient population in this study was high-risk, with a median of 3 prior therapies and 44% of patients carrying high risk 17p deletion23. All had progressed within 24 months of their most recent prior regimen, and had significant comorbidity, reduced renal function or cytopenias.
In the initial publication, the idelalisib-rituximab arm showed an ORR
of 81% (as compared to 13% for placebo-rituximab), and the hazard ratio for PFS was 0.15 (p<0.0001)23. The 44% of patients with high risk 17p deletion, as well as other high risk disease groups like those with unmutated IGHV and 11q deletion, had high response rates similar to the patients without the high risk marker. Both progression-free (PFS) and overall (OS) survival were significantly improved (PFS HR 0.15, 95% CI 0.08-0.28, p<0.0001) although the OS data
were immature, with 3 deaths on the idelalisib arm vs 9 on the placebo arm (HR 0.28, p=0.018)23. Follow-up at the time of this report was extremely short for both arms of the study, and even now is fairly short at approximately 18 months. Following the first interim analysis all patients crossed over to idelalisib-rituximab, but the PFS difference remains quite large (median 19.4 vs 7.3 mos, HR 0.25, p< 0.0001)24. The median PFS estimated at about 19 months is impressive in this refractory patient population with multiple comorbidities and high rates of 17p deletion24. The first results of the ofatumumab-idelalisib vs ofatumumab alone study were reported recently in abstract form at the 2015 meeting of the American Society of Clinical Oncology25. In this study CLL patients with relapsed or refractory disease were randomized 2:1 to idelalisibofatumumab vs ofatumumab alone. ORR was 75% in the combination arm vs. 18% in the single agent arm (p<0.001), and median PFS was 16.3 mos in the combination arm vs 8 mos in the single agent arm (p<0.0001). In CLL patients with del 17p, the median PFS was 13.7 mos25. These results will likely be submitted to the FDA for registration.
Idelalisib for Initial CLL Therapy: Effective but Toxic The primary upfront study to date with idelalisib was done in combination with rituximab and enrolled CLL patients over 65 in need of therapy by IWCLL criteria. 64 patients were enrolled, including nine patients with 17p deletion26. ORR was 97% with 19% complete remissions, similar in the 17p patients, and PFS 93% at 24 months. This regimen did have impressive activity, but about 40% of patients did discontinue therapy before the 24 month mark,
due to a number of toxicities that are now well-recognized but were less clear at the time of this study. Early discontinuations tended to be due to rash or grade 3-4 transaminitis, which was seen in 23% of patients. The latter was similar to what was seen in the initial phase 1 study, but was more common in the untreated patients. The transaminitis was generally asymptomatic, occurred 5-8 weeks from initiation of therapy, typically resolved with drug hold and then might not recur upon restart, but if it did would usually respond again to drug hold and subsequent dose reduction. Another side effect seen in the phase 1 study but probably more common in this upfront study was a drug-related pneumonitis which likely occurs in up to a few percent of patients at both relatively early and later times. Once pulmonary infection has been ruled out, this pneumonitis responds to corticosteroids. Later discontinuations are more commonly due to diarrhea and colitis, which was grade 3-4 in 23% of patients. Idelalisib can cause two types of diarrhea, an early generally self-limited grade 1-low grade 2 diarrhea that responds to antidiarrheal medication, and a later potentially severe and fulminant diarrhea usually associated with colitis. This later colitis has a median time to onset of 7 months27 but can also occur at very late times. Findings on colonoscopy vary, with some essentially normal, some showing microscopic lymphocytic colitis, and some showing greater inflammation. This more severe delayed diarrhea is typically seen in 10-15% of relapsed patients28 but was seen in 23% of these upfront patients.
The colitis will respond to
corticosteroids and oral budesonide is a good option that allows a slow taper with restart of idelalisib27. For sicker patients oral or intravenous systemic steroids can be used. About half of patients can ultimately continue on idelalisib. The mechanism of this colitis is not known but is
speculated to be autoimmune. Interestingly, the PI3K delta knockout mouse gets an inflammatory colitis5, suggesting a possible immunologically mediated on-target effect.
Other PI3K Inhibitors: Duvelisib The other PI3K inhibitor most advanced in clinical trials in CLL is duvelisib (IPI-145), a potent inhibitor of both the PI3K delta and gamma isoforms. The gamma isoform has a primary physiologic effect on neutrophils and T cells but is also present in CLL cells. The expected impact of adding gamma inhibition to delta inhibition on efficacy and toxicity in CLL is not clear. Duvelisib is a very potent inhibitor with an IC50 in whole blood of 96 nM against the delta isoform, and 1.0
M against the gamma isoform.
In the initial phase 1 study, which enrolled a range of hematologic malignancies, the maximum tolerated dose of IPI-145 was found to be 75 mg BID29. Significant infectious toxicity including opportunistic infections were seen early in this study, leading to a recommendation for Pneumocystis prophylaxis and antiviral prophylaxis with IPI-145. Because high efficacy was seen in CLL at lower doses, 25 mg BID was explored in CLL and ultimately selected as the recommended phase 2 dose in CLL. This dose completely inhibits the delta isoform but inhibits the gamma isoform only about 50%30. The data with IPI-145 in relapsed refractory CLL were just updated at the American Society of Hematology meeting in 2014, in which 55 patients were reported, including 31 treated at 25 mg BID31. The patients had 4-5 prior regimens and 52% had 17p deletion. The ORR was 58%, and lymphocytosis returned to baseline by 12 weeks. Fiftynine percent were progression free at 24 months, although 78% had discontinued therapy, including 33% for adverse events31.
Although concerns had been raised about infectious
toxicities given inhibition of the gamma isoform and some of the early higher dose data, the
more recent safety data in a population treated with planned infection prophylaxis look similar to other studies in this relapsed CLL patient population. Recently, data were reported on 18 treatment-naïve CLL patients treated with duvelisib, which showed a 80% ORR and 18 month PFS of 92%32. A registration trial comparing IPI-145 to ofatumumab in relapsed refractory CLL is ongoing.
Second Generation PI3K Delta Inhibition: TGR-1202 TGR-1202 is a PI3K delta inhibitor in phase 1 clinical trials in CLL. It is considered second generation as its structure has been modified in a way that is proposed to reduce the incidence of transaminitis. At the 2014 American Society of Hematology meeting, updated data from the ongoing single agent phase 1 study were presented33. Fifty-five patients were evaluable for safety, and 43 for efficacy. Patients had received a median of three prior regimens, and included CLL patients and a range of lymphoma patients. Median time on study is now greater than six months, and no cases of drug-related hepatotoxicity or pneumonitis have been reported, and no cases of colitis. Thirteen of fourteen patients had achieved nodal partial response, and concomitant lymphocytosis was seen33. Dose escalation is ongoing, and combination phase 1 studies, including with ibrutinib, have been initiated.
Pan-PI3K Inhibitors Experience with other PI3K inhibitors, in particular pan PI3K inhibitors that inhibit all class I isoforms, is currently quite limited in CLL and B cell malignancies. Our group led a phase 1b expansion cohort study of a pan-PI3K inhibitor, SAR245408, in CLL and lymphoma. This multicenter study enrolled 25 relapsed patients, 10 with CLL and 15 with lymphoma, and
treated them with the dose established for solid tumors, a 600 mg daily capsule34. In CLL, the expected pattern of response with lymphocytosis was observed. The nodal response rate was 60%, and the PR rate was 50%, with four patients showing PFS greater than 15 months. Thus this agent showed meaningful activity, although likely was not as efficacious as the delta inhibitors studied to date. Toxicities were also similar and included rash and diarrhea sometimes severe with colitis34. The other relevant study is ARD12130, which looked at SAR245409 (XL765), a panPI3K and mTOR inhibitor, in four cohorts of B cell malignancies, namely CLL, follicular lymphoma, mantle cell lymphoma and diffuse large B cell lymphoma. SAR245409 is a potent pan-class I PI3K inhibitor (IC50 for
39 nM,
43 nM,
9 nM, and
113 nM), that also
inhibits mTORC1 (IC50 190 nM) and mTORC2 (IC50 908 nM). Each cohort except DLBCL had a two stage design based on a targeted ORR, and unfortunately the ORR in the CLL cohort was not sufficient to move to stage 2, which required at least a 17% ORR35. Both the follicular and mantle cell lymphoma cohorts went forward to stage 2, but the results have not yet been reported. The limited results to date with pan-PI3K isoform inhibition in CLL do not suggest that these drugs will have greater activity than the delta inhibitors, and, with the caveat of small studies, appear to suggest less activity. The latter may not be an entirely fair conclusion, however, since it is likely that neither of the two drugs discussed above has the same level of bioavailability and effective drug-like properties that the delta inhibitors tested thus far have. Thus any conclusions about the relative efficacy of pan-PI3K inhibition in CLL may need to await a molecule that has better drug-like properties in vivo.
Summary PI3K inhibitors specific for the delta isoform have shown profound activity in CLL, yet also have an interesting and characteristic pattern of likely autoimmune toxicity in a subset of patients. Understanding the basis of this toxicity to better manage it and/or select the most appropriate patients for PI3K inhibitor therapy will be critical moving forward. In addition, the design of the most rational and effective combination or sequential therapies will depend on understanding the molecular basis of primary and acquired resistance, which at present is still in its infancy.
REFERENCES 1.
Brown, J.R. The treatment of relapsed refractory chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program 2011, 110-8 (2011).
2.
Davids, M.S. & Brown, J.R. Targeting the B Cell Receptor Pathway in Chronic Lymphocytic Leukemia. Leuk Lymphoma (2012).
3.
Chantry, D. et al. p110delta, a novel phosphatidylinositol 3-kinase catalytic subunit that associates with p85 and is expressed predominantly in leukocytes. J Biol Chem 272, 19236-41 (1997).
4.
Vanhaesebroeck, B., Leevers, S.J., Panayotou, G. & Waterfield, M.D. Phosphoinositide 3-kinases: a conserved family of signal transducers. Trends Biochem Sci 22, 267-72 (1997).
5.
Vanhaesebroeck, B., Ali, K., Bilancio, A., Geering, B. & Foukas, L.C. Signalling by PI3K isoforms: insights from gene-targeted mice. . Trends Biochem Sci 30, 194-204 (2005).
6.
Vanhaesebroeck, B. et al. P110delta, a novel phosphoinositide 3-kinase in leukocytes. Proc Natl Acad Sci U S A 94, 4330-5 (1997).
7.
Ali, K. et al. Inactivation of PI(3)K p110delta breaks regulatory T-cell-mediated immune tolerance to cancer. Nature 510, 407-11 (2014).
8.
Hirsch, E. et al. Central role for G protein-coupled phosphoinositide 3-kinase gamma in inflammation. Science 287, 1049-53 (2000).
9.
Reif, K. et al. Cutting edge: differential roles for phosphoinositide 3-kinases, p110gamma and p110delta, in lymphocyte chemotaxis and homing. J Immunol 173, 2236-40 (2004).
10.
Brown, J.R. et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia. Blood 123, 3390-7 (2014).
11.
Herman, S.E. et al. Phosphatidylinositol 3-kinase-delta inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood 116, 2078-88 (2010).
12.
Lannutti, B.J. et al. CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood 117, 591-4 (2011).
13.
Hoellenriegel, J. et al. The phosphoinositide 3'-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood 118, 3603-12 (2011).
14.
Brown, J.R. et al. Integrative genomic analysis implicates gain of PIK3CA at 3q26 and MYC at 8q24 in chronic lymphocytic leukemia. Clin Cancer Res 18, 3791-802 (2012).
15.
Flinn, I.W. et al. Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase-delta, as therapy for previously treated indolent non-Hodgkin lymphoma. Blood 123, 3406-13 (2014).
16.
Kahl, B.S. et al. A phase 1 study of the PI3Kdelta inhibitor idelalisib in patients with relapsed/refractory mantle cell lymphoma (MCL). Blood 123, 3398-405 (2014).
17.
Brown, J.R. et al. Preliminary Evidence of Clinical Activity in a Phase I Study of CAL101, a Potent Selective Inhibitor of the p110 Delta Isoform of Phosphatidylinositol-3Kinase, in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia. Haematologica 94, S88 (2009).
18.
Advani, R.H. et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol 31, 88-94 (2013).
19.
Cheson, B.D. et al. Novel targeted agents and the need to refine clinical end points in chronic lymphocytic leukemia. J Clin Oncol 30, 2820-2 (2012).
20.
Hallek, M. et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 111, 5446-56 (2008).
21.
Furman, R.R. et al. A Phase 1 Study Of The Selective PI3Kδ Inhibitor Idelalisib (GS1101) In Combination With Therapeutic Anti-CD20 Antibodies (Rituximab or Ofatumumab) In Patients With Relapsed Or Refractory Chronic Lymphocytic Leukemia, 4180-4180 (2013).
22.
Barrientos, J. et al. Long-term follow-up of a phase 1b trial of idelalisib (IDELA) in combination with chemoimmunotherapy (CIT) in patients with relapsed/refractory (R/R) CLL including pts with del17p/TP53 mutation. ASCO Meeting Abstracts 33, abstr 7011 (2015).
23.
Furman, R.R. et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 370, 997-1007 (2014).
24.
Sharman, J.P. et al. Second Interim Analysis of a Phase 3 Study of Idelalisib (ZYDELIG®) Plus Rituximab (R) for Relapsed Chronic Lymphocytic Leukemia (CLL): Efficacy Analysis in Patient Subpopulations with Del(17p) and Other Adverse Prognostic Factors, 330-330 (2014).
25.
Jones, J. et al. Results of a Phase 3 Randomized, Controlled Study Evaluating the Efficacy and Safety of Idelalisib (IDELA) in Combination with Ofatumumab (OFA) for Previously Treated Chronic Lymphocytic Leukemia (CLL). ASCO Meeting Abstracts 33, abstr 7023 (2015).
26.
O'Brien, S.M. et al. A phase II study of the selective phosphatidylinositol 3-kinase delta (PI3K{delta}) inhibitor idelalisib (GS-1101) in combination with rituximab (R) in treatment-naive patients (pts) ≥65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Journal of Clinical Oncology, 2013 ASCO Annual Meeting Abstracts 31, 7005 (2013).
27.
Coutre, S.E. et al. Management of adverse events associated with idelalisib treatment: expert panel opinion. Leuk Lymphoma, 1-8 (2015).
28.
Coutre, S. et al. Safety of idelalisib in B-cell malignancies: Integrated analysis of eight clinical trials. ASCO Meeting Abstracts 33, abstr e18030 (2015).
29.
Horwitz, S.M. et al. Preliminary safety and efficacy of IPI-145, a potent inhibitor of phosphoinositide-3-kinase-{delta},{gamma}, in patients with relapsed/refractory lymphoma. Journal of Clinical Oncology, 2013 ASCO Annual Meeting Abstracts 31, 8518 (2013).
30.
Flinn, I. et al. Preliminary Safety and Efficacy Of IPI-145, a Potent Inhibitor Of Phosphoinositide-3-Kinase-δ,γ, In Patients With Chronic Lymphocytic Leukemia. Blood 122, 677 (2013).
31.
O'Brien, S.M. et al. Duvelisib (IPI-145), a PI3K-d,g Inhibitor, Is Clinically Active in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia. Blood 124, 3334 (2014).
32.
Patel, M.R. et al. Early Clinical Activity and Pharmacodynamic Effects of Duvelisib, a PI3K-d,g Inhibitor, in Patients with Treatment-Naive CLL. ASCO Meeting Abstracts 33, 7074 (2014).
33.
Burris, H.A. et al. TGR-1202, a Novel Once Daily PI3Kd Inhibitor, Demonstrates Clinical Activity with a Favorable Safety Profile, Lacking Hepatotoxicity, in Patients with Chronic Lymphocytic Leukemia and B-Cell Lymphoma. Blood 124, 1984 (2014).
34.
Brown, J.R. et al. Phase I trial of the pan-PI3K inhibitor pilaralisib (SAR245408/XL147) in patients with chronic lymphocytic leukemia (CLL) or relapsed/refractory lymphoma. Clinical Cancer Research epub ahead of print (2015).
35.
Brown, J.R. et al. SAR245409 Monotherapy In Relapsed/Refractory Follicular Lymphoma: Preliminary Results From The Phase II ARD12130 Study. Blood 122, 86 (2013).
Table 1: CLL Trials with PI3K Inhibitors Drug Idelalisib
IPI-145
TGR-1202
Target PI3Kδ δ
PI3Kδ δγ
PI3Kδ δ
SAR245408 PanPI3K SAR245409 PanPI3K + mTOR35
Study Type Phase 1 Single Agent10
Patients Rel/refr CLL (n=54)
ORR 72% (39% PR + 33% PR-L)
+ anti-CD2021 + CIT22
Rel/refr CLL (n=40) Rel/refr CLL (n=114)
Phase III Idela- R vs Placebo-R24 Phase III Idela Ofa vs Ofa25
Rel/refr CLL (n=110 per arm)
83% 82.5% (70% in 17p pts) 81% ORR vs 13% (p<0.001)
Rel/refr CLL (n=174 idela ofa, 87 ofa)
75% ORR vs 18% (p<0.001)
Phase II, + R26
Untreated, >65 yo (n= 64) Rel / refr CLL (n=55)
97%, with 19% CRs 58% ORR
Untreated (n=18) Rel / refr CLL and NHL (n= 55) Rel / refr CLL (n=10) and lymphoma (n=15) Rel / refr CLL
88% ORR 93% PR-L (13/14 CLL pts) 50%
Phase 1 single agent31 Phase 1b32 Phase 1 single agent33 Phase 1b expansion cohort34 Phase II
Cohort stopped at first stage due to inadequate response
PFS 29 mos median at RPD2 >= 150 mg BID 24 mos median 26.1 mos median 19.4 mo median vs 7.3 mo (p<0.0001) 16.3 mos median vs 8 mos (p<0.0001) 93% at 24 mos 59% at 24 mos 92% at 18 mos Too early N.R.
The PI3K Pathway: Clinical Inhibition in CLL Jennifer R. Brown MD PhD
PII: DOI: Reference:
www.elsevier.de/endend S0093-7754(16)00010-5 http://dx.doi.org/10.1053/j.seminoncol.2016.02.004 YSONC51908
To appear in:
Semin Oncol
Cite this article as: Jennifer R. Brown MD PhD, The PI3K Pathway: Clinical Inhibition in CLL, Semin Oncol, http://dx.doi.org/10.1053/j.seminoncol.2016.02.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
The PI3K Pathway: Clinical Inhibition in CLL Jennifer R Brown MD PhD
Director, CLL Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Department of Medicine, Harvard Medical School, Boston, MA
Correspondence should be addressed to Jennifer R Brown, MD, PhD, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215; telephone 617-632-4564; fax 617-5827890; email [email protected]
Abstract Constitutive or mutational activation of the phosphatidylinositol 3 kinase, or PI3K, has been implicated in many cancers, including CLL. The delta isoform of the p110 catalytic subunit of PI3K has its primary physiologic function in B cells and appears to be the predominant mediator of most PI3K signals in CLL cells. Idelalisib is a first-in-class inhibitor of the PI3K delta isoform which shows near complete inhibition of AKT phosphorylation in CLL cells in vitro and in vivo. Idelalisib shows the classic pattern of response to BCR inhibition in CLL, with rapid nodal response and transient increase in lymphocytosis. The phase 1 study established the recommended dose as 150 mg twice per day. Subsequent registration trials have
focused predominantly on antibody combinations, leading to the FDA approval of idelalisib with rituximab for relapsed CLL patients for whom rituximab is appropriate therapy in summer 2014. The median PFS of idelalisib-rituximab in this heavily pretreated CLL population with multiple comorbidities and frequent 17p deletion was an impressive 19.4 months. The success of idelalisib has paved the way for the development of other PI3K inhibitors in CLL, including duvelisib and TGR-1202, which are in or moving toward registration trials.
Introduction Chronic lymphocytic leukemia (CLL) is the most common leukemia of adults and remains an incurable disease at present.
Although a subset of patients have indolent disease and
may not require therapy for years or ever, approximately half of patients experience steadily progressive disease and another quarter will progress to therapy eventually. Once patients do require therapy, historically outcomes are poor, with progressively shorter remissions over time, and frequent infections and cytopenias1. The last five years have seen a revolution in CLL therapy, however, with two improved anti-CD20 antibodies (ofatumumab and obinutuzumab), as well as new targeted kinase inhibitor therapies that affect signaling downstream of the B cell receptor and other cell surface receptors2. This review focuses on one of the two best validated new targets, the PI3 kinase, and particularly the delta isoform, which is expressed predominantly in hematopoietic cells and has its primary physiologic function in B cells3.
PI3 Kinase PI3K is a heterodimeric lipid kinase comprised of a regulatory and catalytic subunit. The catalytic subunit has four different class 1 isoforms that show different cell type specificity which is well illustrated by their knockout mouse phenotypes.
The p110
isoenzymes are ubiquitously expressed4 and knockout mice created for p110
and p110
and p110
are
embryonic lethal at E10.5 and E3.5, respectively5. The alpha isoform is also important for insulin signaling, such that pan-PI3K inhibitors or alpha-specific inhibitors often cause hyperglycemia. In contrast, the p110
and p110
isoenzymes are thought to be predominantly
expressed in hematopoietic cell types3,6. The knockout mice for p110
are viable and fertile
with a phenotype primarily affecting the B cell compartment5. Interestingly, however, a recent study has identified that the delta knockout mouse also has impaired T cell function, which impacts on T regulatory cells more than T effector cells. In this study the authors showed that this phenotype was relatively protective against solid tumor xenografts in mice7. The gamma isoform also has expression limited predominantly to hematopoietic cells, with the knockout mouse phenotype leading to impaired T-cell migration, inhibition of T-cell activation and proliferation and defects in macrophage function8,9. Although pan PI3K inhibitors and alpha inhibitors have been extensively studied in solid tumors, most of the effort in CLL and lymphoid malignancies has focused on specific delta inhibition, even though other isoforms including alpha and gamma are expressed in CLL.
Interestingly, inhibition of delta alone does
substantially reduce phosphorylation of the downstream target AKT in CLL in vitro and in vivo10-12. PI3K functions to transduce signals downstream of the B cell receptor in CLL but also integrates signals from a variety of other cell surface receptors including CD40, CXCR4, and
integrins11,13. As such PI3K also has a profound influence on B cell trafficking by promoting B cell chemotaxis towards CXCL12/13, migration beneath stromal cells, and upregulation of CLL cell chemokine secretion. It is likely that the prosurvival and proliferative signals stimulated by both BCR activation and stromal cell interaction are amplified by the convergence of these pathways on common downstream kinases that include PI3K. These pathways are constitutively activated in CLL, likely due to this continual stimulation from the microenvironment. Unlike in solid tumors, mutational activation of this pathway is rare in CLL, although the alpha isoform has been found to be amplified in 5.5% of CLLs14. Whether this confers resistance to delta inhibition is not yet known.
Idelalisib: the first PI3K inhibitor in CLL Idelalisib, formerly known as CAL-101 or GS-1101, is a potent specific inhibitor of the delta isoform of PI3 kinase, with an EC50 of 8 nM in isoform specific cell-based assays12. In vitro, idelalisib can induce apoptosis and suppress AKT phosphorylation nearly completely at baseline and in response to CD40L or IgM stimulation11. The phase 1 study of idelalisib included all hematologic malignancies and ultimately enrolled approximately 190 patients10,15,16. During initial dose escalation no dose limiting toxicities were seen, but at the highest dose the investigators noticed that grade 3-4 transaminitis was seen more frequently, albeit often after the official observation period for dose limiting toxicities. This observation led to expansion cohorts at a variety of different dose levels in both CLL and NHL, and ultimately, the dose selected was 150 mg BID because of a plateau in exposure and nodal response as well as concern about more frequent LFT abnormalities at higher doses10.
An early observation from this study was that some CLL patients were showing an increase in lymphocyte count even while their nodes were rapidly decreasing and they were clinically improved. This type of response was reported very early on from this study17 but soon thereafter was seen also with the BTK inhibitor ibrutinib18 and led to a revision of the response criteria such that this increase in lymphocyte count was not considered progressive disease. A new category of response called PR-L, for partial response with lymphocytosis, was created for patients who met all criteria for PR except a persistently elevated lymphocyte count19. In the CLL portion of this phase 1 study, a subset of patients showed persistent elevation of their lymphocyte count even at one year, and long-term follow-up shows that some patients may continue to have this persistent lymphocytosis even while remaining in good response, for years10. In total in this study, 54 heavily pretreated CLL patients with a median of 5 prior regimens showed a nodal response rate of 81%, IWCLL20 PR rate of 39%, and PR-L rate of 33%. No difference was seen in PFS between patients with PR and PR-L, and PFS was 32 months for those patients treated at doses of at least 150 mg BID10. A number of small phase 1b combination studies were then performed, which established the safety of combining idelalisib with rituximab, ofatumumab, bendamustine, and bendamustine–rituximab. A recent update of the 40 patients treated with idelalisib plus either rituximab or ofatumumab showed a 83% ORR, with 2 CRs, and a median PFS of 24 months21. A similar update on the combination of idelalisib with chemoimmunotherapy reported on 114 patients, and found a 82.5% ORR, including 70% in those with del 17p CLL, and median PFS 26 mos in the overall population and 20 mos in those with del 17p CLL22.
Idelalisib Registration Trials Because of the persistence of lymphocytosis over time in many patients in the phase 1 study, and the fact that the response criteria were still in evolution at the time the trials were designed, the registration trials for idelalisib in CLL were all based on combination therapy designed to abrogate the lymphocytosis, such that all patients with nodal response would likely meet traditional IWCLL response criteria. The first study compared idelalisib-rituximab to placebo-rituximab in CLL patients who had relapsed within 24 months of their most recent prior therapy, and who had significant comorbidities. The second study compared idelalisib-BR to BR alone in relapsed fit CLL patients, and the third study compared idelalisib-ofatumumab to ofatumumab alone in relapsed CLL patients. The first study was closed early in mid-2013 by its data monitoring committee, because of the very high efficacy in the experimental arm. On the basis of this study, the idelalisib rituximab regimen was approved by the FDA in July 2014 for relapsed CLL patients for whom rituximab therapy would be an appropriate regimen23. Looking at the data, the patient population in this study was high-risk, with a median of 3 prior therapies and 44% of patients carrying high risk 17p deletion23. All had progressed within 24 months of their most recent prior regimen, and had significant comorbidity, reduced renal function or cytopenias.
In the initial publication, the idelalisib-rituximab arm showed an ORR
of 81% (as compared to 13% for placebo-rituximab), and the hazard ratio for PFS was 0.15 (p<0.0001)23. The 44% of patients with high risk 17p deletion, as well as other high risk disease groups like those with unmutated IGHV and 11q deletion, had high response rates similar to the patients without the high risk marker. Both progression-free (PFS) and overall (OS) survival were significantly improved (PFS HR 0.15, 95% CI 0.08-0.28, p<0.0001) although the OS data
were immature, with 3 deaths on the idelalisib arm vs 9 on the placebo arm (HR 0.28, p=0.018)23. Follow-up at the time of this report was extremely short for both arms of the study, and even now is fairly short at approximately 18 months. Following the first interim analysis all patients crossed over to idelalisib-rituximab, but the PFS difference remains quite large (median 19.4 vs 7.3 mos, HR 0.25, p< 0.0001)24. The median PFS estimated at about 19 months is impressive in this refractory patient population with multiple comorbidities and high rates of 17p deletion24. The first results of the ofatumumab-idelalisib vs ofatumumab alone study were reported recently in abstract form at the 2015 meeting of the American Society of Clinical Oncology25. In this study CLL patients with relapsed or refractory disease were randomized 2:1 to idelalisibofatumumab vs ofatumumab alone. ORR was 75% in the combination arm vs. 18% in the single agent arm (p<0.001), and median PFS was 16.3 mos in the combination arm vs 8 mos in the single agent arm (p<0.0001). In CLL patients with del 17p, the median PFS was 13.7 mos25. These results will likely be submitted to the FDA for registration.
Idelalisib for Initial CLL Therapy: Effective but Toxic The primary upfront study to date with idelalisib was done in combination with rituximab and enrolled CLL patients over 65 in need of therapy by IWCLL criteria. 64 patients were enrolled, including nine patients with 17p deletion26. ORR was 97% with 19% complete remissions, similar in the 17p patients, and PFS 93% at 24 months. This regimen did have impressive activity, but about 40% of patients did discontinue therapy before the 24 month mark,
due to a number of toxicities that are now well-recognized but were less clear at the time of this study. Early discontinuations tended to be due to rash or grade 3-4 transaminitis, which was seen in 23% of patients. The latter was similar to what was seen in the initial phase 1 study, but was more common in the untreated patients. The transaminitis was generally asymptomatic, occurred 5-8 weeks from initiation of therapy, typically resolved with drug hold and then might not recur upon restart, but if it did would usually respond again to drug hold and subsequent dose reduction. Another side effect seen in the phase 1 study but probably more common in this upfront study was a drug-related pneumonitis which likely occurs in up to a few percent of patients at both relatively early and later times. Once pulmonary infection has been ruled out, this pneumonitis responds to corticosteroids. Later discontinuations are more commonly due to diarrhea and colitis, which was grade 3-4 in 23% of patients. Idelalisib can cause two types of diarrhea, an early generally self-limited grade 1-low grade 2 diarrhea that responds to antidiarrheal medication, and a later potentially severe and fulminant diarrhea usually associated with colitis. This later colitis has a median time to onset of 7 months27 but can also occur at very late times. Findings on colonoscopy vary, with some essentially normal, some showing microscopic lymphocytic colitis, and some showing greater inflammation. This more severe delayed diarrhea is typically seen in 10-15% of relapsed patients28 but was seen in 23% of these upfront patients.
The colitis will respond to
corticosteroids and oral budesonide is a good option that allows a slow taper with restart of idelalisib27. For sicker patients oral or intravenous systemic steroids can be used. About half of patients can ultimately continue on idelalisib. The mechanism of this colitis is not known but is
speculated to be autoimmune. Interestingly, the PI3K delta knockout mouse gets an inflammatory colitis5, suggesting a possible immunologically mediated on-target effect.
Other PI3K Inhibitors: Duvelisib The other PI3K inhibitor most advanced in clinical trials in CLL is duvelisib (IPI-145), a potent inhibitor of both the PI3K delta and gamma isoforms. The gamma isoform has a primary physiologic effect on neutrophils and T cells but is also present in CLL cells. The expected impact of adding gamma inhibition to delta inhibition on efficacy and toxicity in CLL is not clear. Duvelisib is a very potent inhibitor with an IC50 in whole blood of 96 nM against the delta isoform, and 1.0
M against the gamma isoform.
In the initial phase 1 study, which enrolled a range of hematologic malignancies, the maximum tolerated dose of IPI-145 was found to be 75 mg BID29. Significant infectious toxicity including opportunistic infections were seen early in this study, leading to a recommendation for Pneumocystis prophylaxis and antiviral prophylaxis with IPI-145. Because high efficacy was seen in CLL at lower doses, 25 mg BID was explored in CLL and ultimately selected as the recommended phase 2 dose in CLL. This dose completely inhibits the delta isoform but inhibits the gamma isoform only about 50%30. The data with IPI-145 in relapsed refractory CLL were just updated at the American Society of Hematology meeting in 2014, in which 55 patients were reported, including 31 treated at 25 mg BID31. The patients had 4-5 prior regimens and 52% had 17p deletion. The ORR was 58%, and lymphocytosis returned to baseline by 12 weeks. Fiftynine percent were progression free at 24 months, although 78% had discontinued therapy, including 33% for adverse events31.
Although concerns had been raised about infectious
toxicities given inhibition of the gamma isoform and some of the early higher dose data, the
more recent safety data in a population treated with planned infection prophylaxis look similar to other studies in this relapsed CLL patient population. Recently, data were reported on 18 treatment-naïve CLL patients treated with duvelisib, which showed a 80% ORR and 18 month PFS of 92%32. A registration trial comparing IPI-145 to ofatumumab in relapsed refractory CLL is ongoing.
Second Generation PI3K Delta Inhibition: TGR-1202 TGR-1202 is a PI3K delta inhibitor in phase 1 clinical trials in CLL. It is considered second generation as its structure has been modified in a way that is proposed to reduce the incidence of transaminitis. At the 2014 American Society of Hematology meeting, updated data from the ongoing single agent phase 1 study were presented33. Fifty-five patients were evaluable for safety, and 43 for efficacy. Patients had received a median of three prior regimens, and included CLL patients and a range of lymphoma patients. Median time on study is now greater than six months, and no cases of drug-related hepatotoxicity or pneumonitis have been reported, and no cases of colitis. Thirteen of fourteen patients had achieved nodal partial response, and concomitant lymphocytosis was seen33. Dose escalation is ongoing, and combination phase 1 studies, including with ibrutinib, have been initiated.
Pan-PI3K Inhibitors Experience with other PI3K inhibitors, in particular pan PI3K inhibitors that inhibit all class I isoforms, is currently quite limited in CLL and B cell malignancies. Our group led a phase 1b expansion cohort study of a pan-PI3K inhibitor, SAR245408, in CLL and lymphoma. This multicenter study enrolled 25 relapsed patients, 10 with CLL and 15 with lymphoma, and
treated them with the dose established for solid tumors, a 600 mg daily capsule34. In CLL, the expected pattern of response with lymphocytosis was observed. The nodal response rate was 60%, and the PR rate was 50%, with four patients showing PFS greater than 15 months. Thus this agent showed meaningful activity, although likely was not as efficacious as the delta inhibitors studied to date. Toxicities were also similar and included rash and diarrhea sometimes severe with colitis34. The other relevant study is ARD12130, which looked at SAR245409 (XL765), a panPI3K and mTOR inhibitor, in four cohorts of B cell malignancies, namely CLL, follicular lymphoma, mantle cell lymphoma and diffuse large B cell lymphoma. SAR245409 is a potent pan-class I PI3K inhibitor (IC50 for
39 nM,
43 nM,
9 nM, and
113 nM), that also
inhibits mTORC1 (IC50 190 nM) and mTORC2 (IC50 908 nM). Each cohort except DLBCL had a two stage design based on a targeted ORR, and unfortunately the ORR in the CLL cohort was not sufficient to move to stage 2, which required at least a 17% ORR35. Both the follicular and mantle cell lymphoma cohorts went forward to stage 2, but the results have not yet been reported. The limited results to date with pan-PI3K isoform inhibition in CLL do not suggest that these drugs will have greater activity than the delta inhibitors, and, with the caveat of small studies, appear to suggest less activity. The latter may not be an entirely fair conclusion, however, since it is likely that neither of the two drugs discussed above has the same level of bioavailability and effective drug-like properties that the delta inhibitors tested thus far have. Thus any conclusions about the relative efficacy of pan-PI3K inhibition in CLL may need to await a molecule that has better drug-like properties in vivo.
Summary PI3K inhibitors specific for the delta isoform have shown profound activity in CLL, yet also have an interesting and characteristic pattern of likely autoimmune toxicity in a subset of patients. Understanding the basis of this toxicity to better manage it and/or select the most appropriate patients for PI3K inhibitor therapy will be critical moving forward. In addition, the design of the most rational and effective combination or sequential therapies will depend on understanding the molecular basis of primary and acquired resistance, which at present is still in its infancy.
REFERENCES 1.
Brown, J.R. The treatment of relapsed refractory chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program 2011, 110-8 (2011).
2.
Davids, M.S. & Brown, J.R. Targeting the B Cell Receptor Pathway in Chronic Lymphocytic Leukemia. Leuk Lymphoma (2012).
3.
Chantry, D. et al. p110delta, a novel phosphatidylinositol 3-kinase catalytic subunit that associates with p85 and is expressed predominantly in leukocytes. J Biol Chem 272, 19236-41 (1997).
4.
Vanhaesebroeck, B., Leevers, S.J., Panayotou, G. & Waterfield, M.D. Phosphoinositide 3-kinases: a conserved family of signal transducers. Trends Biochem Sci 22, 267-72 (1997).
5.
Vanhaesebroeck, B., Ali, K., Bilancio, A., Geering, B. & Foukas, L.C. Signalling by PI3K isoforms: insights from gene-targeted mice. . Trends Biochem Sci 30, 194-204 (2005).
6.
Vanhaesebroeck, B. et al. P110delta, a novel phosphoinositide 3-kinase in leukocytes. Proc Natl Acad Sci U S A 94, 4330-5 (1997).
7.
Ali, K. et al. Inactivation of PI(3)K p110delta breaks regulatory T-cell-mediated immune tolerance to cancer. Nature 510, 407-11 (2014).
8.
Hirsch, E. et al. Central role for G protein-coupled phosphoinositide 3-kinase gamma in inflammation. Science 287, 1049-53 (2000).
9.
Reif, K. et al. Cutting edge: differential roles for phosphoinositide 3-kinases, p110gamma and p110delta, in lymphocyte chemotaxis and homing. J Immunol 173, 2236-40 (2004).
10.
Brown, J.R. et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia. Blood 123, 3390-7 (2014).
11.
Herman, S.E. et al. Phosphatidylinositol 3-kinase-delta inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood 116, 2078-88 (2010).
12.
Lannutti, B.J. et al. CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood 117, 591-4 (2011).
13.
Hoellenriegel, J. et al. The phosphoinositide 3'-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood 118, 3603-12 (2011).
14.
Brown, J.R. et al. Integrative genomic analysis implicates gain of PIK3CA at 3q26 and MYC at 8q24 in chronic lymphocytic leukemia. Clin Cancer Res 18, 3791-802 (2012).
15.
Flinn, I.W. et al. Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase-delta, as therapy for previously treated indolent non-Hodgkin lymphoma. Blood 123, 3406-13 (2014).
16.
Kahl, B.S. et al. A phase 1 study of the PI3Kdelta inhibitor idelalisib in patients with relapsed/refractory mantle cell lymphoma (MCL). Blood 123, 3398-405 (2014).
17.
Brown, J.R. et al. Preliminary Evidence of Clinical Activity in a Phase I Study of CAL101, a Potent Selective Inhibitor of the p110 Delta Isoform of Phosphatidylinositol-3Kinase, in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia. Haematologica 94, S88 (2009).
18.
Advani, R.H. et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol 31, 88-94 (2013).
19.
Cheson, B.D. et al. Novel targeted agents and the need to refine clinical end points in chronic lymphocytic leukemia. J Clin Oncol 30, 2820-2 (2012).
20.
Hallek, M. et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 111, 5446-56 (2008).
21.
Furman, R.R. et al. A Phase 1 Study Of The Selective PI3Kδ Inhibitor Idelalisib (GS1101) In Combination With Therapeutic Anti-CD20 Antibodies (Rituximab or Ofatumumab) In Patients With Relapsed Or Refractory Chronic Lymphocytic Leukemia, 4180-4180 (2013).
22.
Barrientos, J. et al. Long-term follow-up of a phase 1b trial of idelalisib (IDELA) in combination with chemoimmunotherapy (CIT) in patients with relapsed/refractory (R/R) CLL including pts with del17p/TP53 mutation. ASCO Meeting Abstracts 33, abstr 7011 (2015).
23.
Furman, R.R. et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 370, 997-1007 (2014).
24.
Sharman, J.P. et al. Second Interim Analysis of a Phase 3 Study of Idelalisib (ZYDELIG®) Plus Rituximab (R) for Relapsed Chronic Lymphocytic Leukemia (CLL): Efficacy Analysis in Patient Subpopulations with Del(17p) and Other Adverse Prognostic Factors, 330-330 (2014).
25.
Jones, J. et al. Results of a Phase 3 Randomized, Controlled Study Evaluating the Efficacy and Safety of Idelalisib (IDELA) in Combination with Ofatumumab (OFA) for Previously Treated Chronic Lymphocytic Leukemia (CLL). ASCO Meeting Abstracts 33, abstr 7023 (2015).
26.
O'Brien, S.M. et al. A phase II study of the selective phosphatidylinositol 3-kinase delta (PI3K{delta}) inhibitor idelalisib (GS-1101) in combination with rituximab (R) in treatment-naive patients (pts) ≥65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Journal of Clinical Oncology, 2013 ASCO Annual Meeting Abstracts 31, 7005 (2013).
27.
Coutre, S.E. et al. Management of adverse events associated with idelalisib treatment: expert panel opinion. Leuk Lymphoma, 1-8 (2015).
28.
Coutre, S. et al. Safety of idelalisib in B-cell malignancies: Integrated analysis of eight clinical trials. ASCO Meeting Abstracts 33, abstr e18030 (2015).
29.
Horwitz, S.M. et al. Preliminary safety and efficacy of IPI-145, a potent inhibitor of phosphoinositide-3-kinase-{delta},{gamma}, in patients with relapsed/refractory lymphoma. Journal of Clinical Oncology, 2013 ASCO Annual Meeting Abstracts 31, 8518 (2013).
30.
Flinn, I. et al. Preliminary Safety and Efficacy Of IPI-145, a Potent Inhibitor Of Phosphoinositide-3-Kinase-δ,γ, In Patients With Chronic Lymphocytic Leukemia. Blood 122, 677 (2013).
31.
O'Brien, S.M. et al. Duvelisib (IPI-145), a PI3K-d,g Inhibitor, Is Clinically Active in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia. Blood 124, 3334 (2014).
32.
Patel, M.R. et al. Early Clinical Activity and Pharmacodynamic Effects of Duvelisib, a PI3K-d,g Inhibitor, in Patients with Treatment-Naive CLL. ASCO Meeting Abstracts 33, 7074 (2014).
33.
Burris, H.A. et al. TGR-1202, a Novel Once Daily PI3Kd Inhibitor, Demonstrates Clinical Activity with a Favorable Safety Profile, Lacking Hepatotoxicity, in Patients with Chronic Lymphocytic Leukemia and B-Cell Lymphoma. Blood 124, 1984 (2014).
34.
Brown, J.R. et al. Phase I trial of the pan-PI3K inhibitor pilaralisib (SAR245408/XL147) in patients with chronic lymphocytic leukemia (CLL) or relapsed/refractory lymphoma. Clinical Cancer Research epub ahead of print (2015).
35.
Brown, J.R. et al. SAR245409 Monotherapy In Relapsed/Refractory Follicular Lymphoma: Preliminary Results From The Phase II ARD12130 Study. Blood 122, 86 (2013).
Table 1: CLL Trials with PI3K Inhibitors Drug Idelalisib
IPI-145
TGR-1202
Target PI3Kδ δ
PI3Kδ δγ
PI3Kδ δ
SAR245408 PanPI3K SAR245409 PanPI3K + mTOR35
Study Type Phase 1 Single Agent10
Patients Rel/refr CLL (n=54)
ORR 72% (39% PR + 33% PR-L)
+ anti-CD2021 + CIT22
Rel/refr CLL (n=40) Rel/refr CLL (n=114)
Phase III Idela- R vs Placebo-R24 Phase III Idela Ofa vs Ofa25
Rel/refr CLL (n=110 per arm)
83% 82.5% (70% in 17p pts) 81% ORR vs 13% (p<0.001)
Rel/refr CLL (n=174 idela ofa, 87 ofa)
75% ORR vs 18% (p<0.001)
Phase II, + R26
Untreated, >65 yo (n= 64) Rel / refr CLL (n=55)
97%, with 19% CRs 58% ORR
Untreated (n=18) Rel / refr CLL and NHL (n= 55) Rel / refr CLL (n=10) and lymphoma (n=15) Rel / refr CLL
88% ORR 93% PR-L (13/14 CLL pts) 50%
Phase 1 single agent31 Phase 1b32 Phase 1 single agent33 Phase 1b expansion cohort34 Phase II
Cohort stopped at first stage due to inadequate response
PFS 29 mos median at RPD2 >= 150 mg BID 24 mos median 26.1 mos median 19.4 mo median vs 7.3 mo (p<0.0001) 16.3 mos median vs 8 mos (p<0.0001) 93% at 24 mos 59% at 24 mos 92% at 18 mos Too early N.R.