Idelalisib: A PI3K Inhibitor on the Horizon

Seema Bhat, MD

Assistant Professor of Oncology

Department of Medicine, Roswell Park Cancer Institute,

Buffalo, NY

Myron S.Czuczman, MD

Professor of Oncology

Chief, Lymphoma/Myeloma Service,

Department of Medicine, Roswell Park Cancer Institute,

Buffalo, NY

Abstract

Idelalisib is a potent and highly selective PI3K inhibitor that promotes apoptosis in primary cells from patients with different B-cell malignancies. Idelalisib has been shown to affect microenvironmental signaling and cell survival both in vitro and in vivo. Data from studies with idelalisib have shown promising clinical efficacy, both as a single agent, as well as in combination with other agents. It is an orally active agent that has been shown to be well tolerated, with diarrhea and a transient increase in transaminases being the most common reported adverse effects. The FDA currently has a New Drug Application under review for use of idelalisib for the treatment of indolent non-Hodgkin lymphoma that is refractory to rituximab and chemotherapy.

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western hemisphere. It is a clonal malignancy of mature B lymphocytes and is characterized by the accumulation of CD5+/ CD23+ monoclonal B cells in the blood and tissue compartments, including bone-marrow and secondary lymphatic tissues.¹However, at a genetic level, there is a difference between CLL cells present in different compartments: CLL cells in the blood compartment are resting cells with a gene expression profile akin to memory B cells,¹whereas CLL cells in the lymph node and bone marrow compartment show characteristics of activated B cells and exhibit increased proliferation.²Moreover, the biology of CLL cells is influenced by extrinsic signals from the tissue microenvironment. In vitro, CLL cells cannot sustain themselves and undergo apoptosis unless appropriate microenvironmental factors are provided by co-culturing them with accessory stromal cells, like marrow stromal cells (MSCs)3 or monocyte-derived nurse-like cells (NLCs).⁴This reliance of CLL cells on pathways that are also involved in promoting normal B-cell development, expansion, and survival^{2,5- 8}indicates that these tumor cells are “addicted to the host,” constituting an instance of a novel model termednon-oncogene addiction.⁹

The Phosphatidylinositol-3-kinase (PI3K) Pathway

This cross-talk between CLL cells and supporting stromal cells in the tissue microenvironment involves a complex signaling network that may be critical for disease progression and drug resistance. Interference with this cross-talk may represent a new therapeutic strategy of targeting these cancer cells. Several molecular pathways related to leukemia cell migration, B-cell receptor (BCR) signaling, and interactions between CLL cells and T cells have been identified.⁷Especially interesting are the chemokines, CXCL12 and CXCL13, which are constitutively secreted by MSCs and NLCs^10,11and attract CLL cells via their respective cognate chemokine receptors, CXCR4 and CXCR5, thereby facilitating leukemic cell homing in and retention into the tissue compartments. Additionally, BCR signaling in the tissue microenvironment promotes the clonal expansion of both normal and malignant B cells.^1,2,12CLL cells isolated from lymph nodes2 or high-risk patients¹³exhibit gene expression profiles that point toward BCR activation. In response to BCR activation and in NLC co-cultures, CLL cells secrete the chemokines CCL3 and CCL4 (also called MIP-1α and β),¹⁴apparently for recruitment of accessory cells, such as regulatory T cells.^15,16The BCR complex is composed of a surface transmembrane immunoglobulin (Ig) receptor associated with the Ig α (Ig α, CD79A) and Ig β (Ig β, CD79B) chains.¹⁷Two distinct types of signals originate from the BCR: a “tonic” survival signal and an antigen-induced activation signal. A functional BCR is essential for B-cell development and survival. This “tonic” survival signal is antigen independent and is mediated by phosphatidylinositol-3-kinase (PI3K) α and δ. Conversely, the antigen-induced BCR signaling activates several other tyrosine kinases in addition to PI3Kδ to promote cell growth, proliferation, maturation, and survival.¹⁸The PI3K pathway is considered a key focus connecting many signaling pathways to cellular growth, proliferation, and survival.^{19, 20}

The PI3Ks are divided into three classes: I, II, and III; however, only class I phosphorylates inositol lipids to form secondary messengers. The class I kinases are further divided into four isoforms designated as PI3K α, β, γ, and δ.PI3K α and β isoforms are ubiquitously expressed on tissues and knock-out mice for both are embryonically lethal.21 While PI3K γ isoform has a particular role in T-cell activation, PI3K δ expression is largely restricted to hematopoietic cells and plays a critical role in B-cell homeostasis and function.22 Mice with deleted or mutated PI3K-δ exhibit B-cell defects: lack of B1 lymphocytes, decreased number of mature B cells, and impaired antibody production.^21,22,23

B cells from PI3K-δ knockout mice also show decreased AKT (a serine threonine kinase) phosphorylation when activated and have decreased phosphatidylinositol 3, 4, 5-triphosphate levels and phosphopeptide activity.²¹In contrast, PI3K-γ isoform knockout mice, even though not embryonic lethal, have predominately a T-cell defect with no B-cell developmental or functional abnormalities.²¹These mouse studies imply that isoform-specific targeting of the PI3K-δ isoform may be preferentially cytotoxic to B cells with minimal toxicity to other hematopoietic cell types.

Dysregulation of the PI3K pathway has been shown to play an important role in the etiology of a number of human malignancies, including hematologic malignancies.^24,25Particularly, in B-cell malignancies, aberrant PI3K signaling may be the consequence of constitutive BCR activation and/or the response to prosurvival factors present in the bone marrow and lymph node microenvironments.^12,26,27

In CLL cells, PI3K signaling has been shown to be constitutively activated and also, at least in IgVH-unmutated CLL, has been found to be overexpressed at the gene level.²⁸In vitro studies have demonstrated increased activity of PI3K in the pathogenesis of CLL and other B-cell malignancies with convergence of CD40L, BAFF, fibronectin, and BCR signaling through this pathway.^{29,30- 33}

Since the PI3K/AKT pathway plays an essential role in the regulation of cell survival/apoptosis, it is a potentially prime target for drug development for the treatment of B-cell malignancies. However, the inhibition of the PI3K/AKT pathway has proved quite challenging, as this pathway is critical to fundamental cell processes such as metabolism, growth, proliferation, and survival.^34,35

Indeed, it is this widespread functionality of PI3K signaling that is, at least partially, responsible for the significant toxicity associated with pan-PI3K inhibitors, (LY294002 and wortmannin) because these inhibitors typically inhibit all of the class I PI3K isoforms.³⁶However, the specificity of the PI3Kδ makes it a promising target for B-cell malignancies, including CLL, because it decreases the possibility of toxicity associated with nonspecific PI3K inhibitors, while still maintaining the ability to inhibit the PI3K pathway in a meaningful way to alter B-cell survival.

Idelalisib (CAL-101; GS-1101) is a potent and highly selective PI3Kδ inhibitor37 that promotes apoptosis in primary cells from patients with different Bcell malignancies.37-39 Idelalisib has been shown to inhibit constitutive and CD40-, TNF-α—, fibronectin-, and BCR-derived PI3K signaling, which leads to suppression of Akt activation.^37-39

Preclinical Antitumor Activity of Idelalisib

These studies propose that disruption of these intrinsic and extrinsic survival signals could be critical mechanisms associated with the clinical activity of idelalisib.Idelalisib has been shown to affect microenvironmental signaling and cell survival both in vitro and in vivo. In vitro, idelalisib has been shown to be highly selective for PI3Kδ, with the selectivity of idelalisib to PI3Kδ reported to be an IC50 of 2.5 nmol/L compared with 820, 565, and 89 nmol/L for PI3K α, β, and γ, respectively.37 Idelalisib was also reported to be 400-fold more selective for the class I PI3 kinases compared with other related kinases.³⁷

Idelalisib was noted to induce apoptosis in CLL cells in vitro. Lannutti and colleagues37 further showed an observed significant sensitivity (defined as an EC50 <1 mmol/L) to idelalisib in 26% of the CLL samples assessed. Herman and colleagues³⁸demonstrated that the induction of apoptosis was selective for CLL cells as compared with normal B cells or other hematopoietic cells and occurred independently of traditional prognostic factors like cytogenetic abnormality or IgVH mutational status. Idelalisib induced apoptosis via the caspase-dependent pathway.³⁸In addition to direct apoptosis, idelalisib was found to inhibit induced survival mechanisms by preventing activation of downstream signaling like phosphorylation of AKT.³⁸Fiorcari and colleagues⁴⁰also presented data suggesting that idelalisib inhibits MSC-derived prosurvival signals.

Further experiments showed that idelalisib can inhibit chemotaxis toward CXCL12 and CXCL13, as well as migration beneath stroma cell layers, suggesting a potential effect on mobilization.⁴¹Idelalisib also inhibits both chemokine (CCL3 and CCL4) and cytokine (interleukin-6 and TNF) secretion mediated by BCR stimulation or NLCs.⁴¹Idelalisib also chemosensitized CLL cells to other cytotoxic drugs such as fludarabine and bendamustine.⁴¹Davids and colleagues42 showed that idelalisib can sensitize stroma-exposed CLL cells to agents like fludarabine by inhibition of stroma—CLL contact, leading to an increase in mitochondrial apoptotic priming of the CLL cells.

Clinical Experience With Idelalisib

These preclinical studies suggest that idelalisib, alone or in combination with other agents, shows promise in the treatment of B-cell malignancies by either directly inducing apoptosis and/or by inhibiting microenvironmental interactions.Data from studies with idelalisib have shown promising clinical efficacy, both as a single agent as well as in combination with other agents. Furman and colleagues⁴³detailed the results from the first 37 patients treated with idelalisib at the American Society of Hematology (ASH) Annual Meeting in 2010. All patients with bulky lymphadenopathy showed a significant shrinkage of lymph nodes, with 91% of patients having at least a 50% reduction in lymph node size.Curiously, significant lymphocytosis (absolute lymphocyte count [ALC] rising by more than 50% compared with baseline) was noted in 60% of patients during the first two cycles of treatment.⁴³However, despite the lymphocytosis, which traditionally could be considered disease progression, when traditional nodal response criteria were applied, the overall progressive response rate was 33%.⁴³Pharmacodynamic correlative studies on peripheral blood mononuclear cells showed a decrease in phosphorylated AKT after just 1 week of treatment.⁴³Hoellenriegel and colleagues41 also showed that patients with CLL treated with idelalisib showed decreases in CLL3, CLL4, and CXCL13, as well as reduced phosphorylation of AKT (threonine-308) by the end of the first cycle.

Following up on the initial presentation, Coutre and colleagues⁴⁴updated the patient responses in 2011 at the American Society of Clinical Oncology (ASCO) annual meeting with a total of 54 patients enrolled. The increase in ALC was still noted leaving the overall intention- to-treat response rate by International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria at 26%.However, despite this, 46% of patients remained on treatment⁴⁴and progression-free survival (PFS) was not reached at >11 months. Interestingly, responses were independent of classic risk factors and were also seen in high-risk patients with 17p deletion. Treatment was, overall, well tolerated; grade &ge;3 adverse events included pneumonia (24%), neutropenia (24%), neutropenic fever (7%), thrombocytopenia (7%), anemia (6%), and ALT/AST increase (6%). The relatively high rates of infection may reflect the heavily pretreated patient population. Other side effects were generally mild.

Brown and colleagues presented a phase I doseranging study of treatment with idelalisib for up to 48 weeks at the ASCO annual meeting in 2013. The trial enrolled 54 patients with CLL; 70% had refractory disease and had received a median of five prior therapies. Overall response rate was 72% with a lymph-node response of 81%.⁴⁵Median time to response was 1 month, and median duration of response was 16.8 months. Treatment with idelalisib improved baseline cytopenias, which were seen in many patients (63% had low platelets, 46% had low hematocrit/anemia, and 28% had low neutrophils). Progression-free survival was 17.1 months, and median overall survival (OS) has not yet been reached.

Responses were seen at all dosage levels and also in patients with high-risk mutations. The best nodal response was observed at dosages of 150 mg twice daily. The pattern of response to single-agent idelalisib again showed a rapid decline in lymphoid mass accompanied by a rise in peripheral lymphocyte count. Idelalisib was well tolerated, with no doselimiting toxicities. A total of 31 patients discontinued treatment due to progressive disease and other causes, and 23 entered an extension phase (10 are still in remission).

Idelalisib has shown clinical efficacy in indolent non-Hodgkin`s lymphoma (iNHL) as well. Results of a phase II study (Study 101-09) were presented at the 12th International Conference on Malignant Lymphoma in Lugano, Switzerland.⁴⁶Study 101-09 was a single-arm, open-label phase II study evaluating efficacy and safety of idelalisib for the treatment of patients with iNHL who were refractory to rituximab and to alkylating-agent-containing chemotherapy. The study enrolled 125 patients from approximately 50 centers in the United States and Europe. Patients were a median age of 64 and had confirmed diagnoses of follicular lymphoma (n=72), small lymphocytic lymphoma (n=28), lymphoplasmacytic lymphoma/Waldenstr&ouml;m macroglobulinemia (n=10), or marginal zone lymphoma (n=15). Patients had received a median of four prior treatment regimens before study entry, with 79% of patients refractory to two or more prior regimens and 74% refractory to their most recent regimen. All patients received idelalisib 150 mg twice daily. The overall response rate was 53.6%,with 5 complete responses (4%), 60 partial responses (48%), 2 minor responses, and 46 patients with stable disease (36.8%). The overall response rate was highly consistent across all subgroups analyzed. Median PFS for all patients was 11.4 months. Most patients (89%) experienced some shrinkage in lymph node size. Among patients who responded, the median duration of response was 11.9 months and the median time to response was 1.9 months. The most common grade &ge;3 adverse event was diarrhea (10%). Grade &ge;3 transaminase elevations were reported in 13% of patients; grade &ge;3 neutropenia occurred in 26% of patients. Sixteen percent of patients discontinued due to adverse events. The study is ongoing. Based on this phase II study, Gilead Sciences, Inc (NAS: GILD) has submitted a New Drug Application (NDA) to the FDA for approval of idelalisib for the treatment of iNHL. Mature response data and extended followup of this study was scheduled to be presented at the 2013 annual ASH meeting in New Orleans this month.

Clinical Pearls

• The clinical landscape for B-cell malignancies, especially CLL, is rapidly changing with the development of targeted therapies.
• Idelalisib is an active oral agent that is very well tolerated.
• Idelalisib has shown clinical efficacy even in patients with high-risk CLL (eg,17p deletion) who typically have a poor prognosis with few therapeutic options.

In addition to idelalisib as a single agent, it is also being studied in combination with other agents like rituximab, ofatumumab, bendamustine, and fludarabine. In 2011, Flinn and colleagues⁴⁷reported on a phase I study evaluating idelalisib in combination with anti-CD20 monoclonal antibody therapy and/ or bendamustine in patients with previously treated iNHL and CLL. All patients received idelalisib 100 or 150 mg orally twice per day in 28-day cycles for up to 12 cycles. idelalisib was administered starting on Day 1 of Cycle 1 with rituximab 375 mg/m2 given weekly for 8 weeks (RC regimen), or bendamustine 90 mg/m2 given on Days 1 and 2 of each cycle for 6 cycles (BC regimen). Tumor response was evaluated according to standard criteria that compared with baseline. On-treatment peripheral lymphocyte counts were stable or decreased in 8 of 8 patients with CLL.⁴⁷A total of 20 patients were enrolled; 12 for iNHL and 8 for CLL. Median age of patients was 64 years; 40% had refractory disease with median number of three prior therapies. Grade &ge;3 adverse events including neutropenia and thrombocytopenia each occurred in 2/9 patients receiving BC, and increased transaminases occurred in 3/12 patients with iNHL. Among 18 evaluable patients using standard criteria, there were preliminary overall response rates of 10/11 (including 1 complete response) in patients with iNHL, and 5/7 in patients with CLL. Compared with baseline, on-treatment peripheral lymphocyte counts were stable or decreased in 8/8 patients with CLL.

Following up on this study, Sharman and colleagues⁴⁸presented data at ASH meeting 2011 on 55 patients with CLL who were administered idelalisib monotherapy and 54 patients who received idelalisib- based combination therapies. Idelalisib, as single agent or in combination-therapy caused lymph node shrinkage in a large majority of patients with CLL (>79%) across all dosage levels. Nodal size shrinkage was seen in two phases: a steep initial reduction (>50% reduction by week 8) that was followed by a more persistent continuing decline over several months. The extent and kinetics of the nodal responses were similar in patients treated with single-agent idelalisib or with combination therapies. A significant percentage of patients showed durable responses (approximately 25% overall response rate) with single-agent idelalisib and remained on study for many cycles of treatment. However, compared with single-agent therapy, idelalisib-based combinations substantially increased the overall response rate to 81%. The median PFS in patients on idelalisib monotherapy was >12 months and the median PFS for any combination therapy has not yet been reached but has exceeded 12 months. As noted in previous studies, the initial lymph node reduction observed in the majority of patients with CLL that were treated with single-agent idelalisib was accompanied by an initial increase in circulating lymphocyte counts. With continued idelalisib treatment, this lymphocytosis resolved over several months. Curiously, this pattern and extent of lymphocytosis in patients with CLL was altered by combination therapy. The combination of idelalisib with rituximab or fludarabine led to a shorter duration of lymphocytosis, while the combination with bendamustine largely eliminated the increase in circulating lymphocyte counts. Concurrently with the responses, there was noted a decrease in CLL-associated chemokines and cytokines such as CCL3, CLL4, CXCL13, and TNF-&alpha;.⁴⁸

deVos and colleagues⁴⁹reported similar promising results in a phase I study of idelalisib as a single agent, as well as in combination with rituximab and/ or bendamustine for treatment of patients with relapsing/ remitting iNHL. Data were presented from 63 patients with iNHL on idelalisib monotherapy and 52 iNHL patients on idelalisib-based combination therapies. Follicular lymphoma (FL) was the most common subgroup in all treatment arms. The overall response rate for idelalisib monotherapy was 38% across all dosage levels and 59% at dosages &ge;100 mg twice daily. As combination therapy, substantial increase in the overall response rate to 83% compared with single-agent therapy was noted. Complete remission was achieved in 15%—25% of patients on idelalisib-based combination therapies. Both idelalisib monotherapy and combination therapy were associated with durable tumor response. The median PFS in patients receiving idelalisib monotherapy at dosages &ge;100 mg twice daily and receiving any combination therapy, was >12 months, similar to clinical data in patients with CLL. Also similar to the patients with CLL, treatment of patients with iNHL who were taking single-agent GS-1101 or combinations significantly decreased plasma levels of chemokines and cytokines like CCL17, CCL22, CXCL13, and TNF-&alpha; . However, a few differences in response kinetics were observed. Unlike the biphasic nodal response and transient lymphocytosis observed in patients with CLL, who were treated with idelalisib monotherapy, iNHL patients showed profound and rapid reductions in lymphadenopathy. The lymphocytosis has not been reported in patients with iNHL treated with single-agent idelalisib or with combination therapies, suggesting that redistribution of cells to the periphery may not be a critical mechanism of antitumor activity of idelalisib in iNHL. This is also consistent with the observation that iNHL cells are not generally found in circulation; hence, they are likely being cleared in the tissue sites rather than in the blood.

In another phase II single-arm study with an extension phase presented at the ASCO annual meeting in 2013, 64 patients with treatment-na&iuml;ve CLL requiring treatment received idelalisib in combination with rituximab.⁵⁰An overall response rate of 97% (19% complete response and 78% partial response) was noted.With a PFS of 93% at 24 months, no disease progression was observed in the study, even in the high-risk patients with 17p deletions and TP53 mutations. Interestingly, the addition of rituximab shifted the pattern of response seen in the phase I study reported earlier, showing a nodal response at 8 weeks, as well as a rapid decline of lymphocytosis. At 48 weeks, median lymphocyte count returned to normal.

This study had an extension phase where patients completing 48 weeks of therapy and free of progression could continue on an extension study; 43 patients completed 48 weeks, and 40 entered the extension phase. At the time of the ASCO 2013 annual meeting, 33 patients were still on treatment.

The combination was well tolerated, with the most common adverse effect being diarrhea and laboratory abnormalities in transaminases. Myelosuppression was infrequent. The rate of infection of any grade was 67%; 23% of patients had infections classified as grade &ge;3.

During both the primary and extension study, grade &ge;3 diarrhea and/or colitis occurred in 33% of patients, and were the most common reasons for late discontinuations. Grade &ge;3 pneumonia was reported in 17% of patients, and grade 3 transaminase elevations were seen in 23%.Thus, idelalisib plus rituximab is a highly active combination in treatment-na&iuml;ve CLL. The high overall response rate and durable disease control observed in this phase II study suggest that idelalisib plus rituximab could become an important new therapeutic option for treatment-na&iuml;ve patients with CLL.

Most recently, a phase III study (Study 116) evaluating idelalisib in combination with rituximab in previously-treated patients with CLL who were not fit for chemotherapy was accepted for presentation during a late-breaking abstract session at the ASH 2013 annual meeting in New Orleans (Abstract LBA- 6).⁵¹Study 116 was a randomized, double-blind, placebo-controlled, phase III study evaluating the efficacy and safety of idelalisib in combination with rituximab. The study enrolled 220 adult patients at approximately 70 study sites in the United States and Europe. Eligible patients had previously treated recurrent CLL, with measurable lymphadenopathy that had progressed within 24 months since completion of prior therapy. The patients required treatment (based on IWCLL criteria) but were not fit to receive cytotoxic therapy. Patients were randomized to receive eight infusions of rituximab over 24 weeks plus either idelalisib (150 mg) or placebo taken orally twice daily continuously until disease progression or unacceptable toxicity. Patients from Study 116 randomized to idelalisib will continue receiving idelalisib and patients in the control arm (placebo plus rituximab) were eligible to receive open-label idelalisib, therapy in an extension study. Study 116 was stopped early based on a prespecified interim analysis performed by an external Data Monitoring Committee (DMC) showing a highly statistically significant effect on the primary endpoint of PFS. Safety was in line with previous observations, and was largely consistent with advanced disease patients receiving CD20 antibody therapy. Detailed results from this study were scheduled to be presented at the ASH annual meeting on December 10, 2013, in New Orleans.

Conclusions

Together, this suggests that although idelalisib is showing promising results as a single agent, it is showing even greater antitumor activity when used in combination studies.Inhibition of PI3K&delta; signaling is evolving as a promising new therapeutic approach in CLL and other B-cell malignancies. Presently, idelalisib is the only well-described PI3K&delta; inhibitor for the treatment of B-cell malignancies; several other compounds directed against the PI3K target are currently also being developed, reinforcing the clinical potential of targeting this important kinase within B-cell neoplasms. Clinical trials have shown encouraging results with single-agent idelalisib, and combination studies are of even greater interest, given the distinct differences in the mechanisms of action of such kinase inhibitors compared with traditional chemotherapeutics or antibody-based therapy. Ongoing studies will further define the role of PI3K&delta; inhibition in the changing clinical landscape of B-cell malignancies, and will likely be incorporated into treatment paradigms for indolent NHL and CLL in the very near future.

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