On the Horizon: Novel Inhibitors for Hematologic Malignancies

Cell-Signaling Pathways Explored in Hematologic Malignancies

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ALL indicates acute lymphocyctic leukemia; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; DLBCL, diffuse large B-cell lymphoma; ET, essential thrombocythemia; FL, follicular lymphoma; MCL, mantle cell lymphoma; MDS, myelodysplastic syndrome; MF, myelofibrosis; NHL, non-Hodgkin lymphoma; PV, polycythemia vera; SLL, small lymphocytic lymphoma.

Targeted agents have a history of success in the treatment of hematologic malignancies, illustrated by the number of monoclonal antibodies and small-molecule inhibitors currently in clinical use. However, none of these agents are curative, and new treatment options are needed for patients who experience disease relapse.

Increased understanding of the molecular mechanisms underlying the pathogenesis of these cancers has led to the development of several promising new classes of targeted therapies. The first JAK pathway inhibitor, ruxolitinib (Jakafi; Incyte), gained FDA approval last year, and other drugs in this class are being explored. (Related: JAK Pathway Yielding Results)

At the 16th Annual International Congress on Hematologic Malignancies, held February 23-26, 2012, in Utah, a special workshop session was devoted to reviewing recent data regarding emerging signal transduction inhibitors currently in clinical development, which have the potential to impact the treatment of hematologic cancers. Highlights of the presentations are summarized below.

Bruton’s Tyrosine Kinase

Signaling through the B-cell receptor (BCR) is necessary for the proliferation and survival of many B-cell malignancies, and Bruton’s tyrosine kinase (BTK) is a key downstream mediator of this signal. In preclinical studies, inhibitors of BTK have been shown to block BCR signaling and induce apoptosis, making this molecule an attractive therapeutic target.

PCI-32765 (Ibrutinib; Pharmacyclics), a selective and irreversible inhibitor of BTK, is currently in the early stages of clinical investigation. A phase I study was conducted in previously treated, recurrent B-cell malignancies. While grade 1 events were common, there were no grade 4 toxicities, and grade 2/3 events were infrequent. In addition, there were no serious hepatic or renal toxicities, and no evidence of cumulative hematologic toxicity. PCI-32765 was most active in indolent malignancies, with both partial and complete responses seen in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), and follicular lymphoma (FL), although partial responses were also observed in more aggressive lymphoma subtypes.

A phase II trial in relapsed/refractory MCL recently reported an overall response rate (ORR) of 69%, with no difference in outcome between bortezomib-naïve versus bortezomib-treated patients. In addition, a phase II study in relapsed/refractory CLL reported ORRs of 70% (420-mg cohort) and 44% (840-mg cohort), with six-month progression- free survival (PFS) >90%. Transient lymphocytosis peaking at two months after drug initiation was also observed.

A pilot study is also ongoing in activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL), based on the observation that NF-κB signaling is constitutively active in this subtype, often as a result of chronically active signaling through the BCR. A number of responses have been observed in the 10 patients enrolled to date. A phase II trial will evaluate PCI-32765 in both ABC and germinal center DLBCL, and will assess whether there is a differential response between these two subtypes.

PI3K-delta

PI3 kinases (PI3K) are a family of lipid kinases that play an integral role in regulating intracellular signaling networks involved in cell growth, survival, and metabolism. Dysregulation of this pathway has been implicated in the development and progression of many forms of cancer, as well as resistance to current therapies. There are four different isoforms (alpha, beta, gamma, and delta), each with different biologic roles. The delta isoform in particular is expressed in leukocytes and plays a key role in B-cell signaling, development, and survival, leading to interest in the evaluation of PI3K inhibitors in B-cell malignancies.

The first PI3K-delta-specific inhibitor to enter clinical trials is CAL-101 (GS-1101; Gilead Sciences). Results were recently reported from a large phase I study that enrolled patients with previously treated hematologic malignancies. Responses were observed in CLL, indolent non-Hodgkin lymphoma (NHL), and MCL, and enrollment was expanded for these malignancies. No responses were seen in DLBCL, acute myeloid leukemia (AML), or multiple myeloma, however, leading to closure of enrollment for these tumor types.

In general, CAL-101 was well tolerated, although grade 3/4 neutropenia and/or infection were each seen in 24% of patients with CLL, while reversible grade 3/4 transaminitis occurred in 27% of patients with NHL. Responses were seen in 48% of the 21 patients with MCL, and in 63% of 30 patients with indolent NHL, with median durations of response of three cycles and nine cycles, respectively. In the 54 patients with CLL, nodal responses were seen in 80% of patients. This was accompanied by rapid lymphocyte redistribution, for an ORR of 26%. However, CLL-related thrombocytopenia and anemia were improved, and the median duration of response was >11 cycles.

Selected Signal Transduction Inhibitors in Clinical Development

Agent

Target

Stage

Comments

PCI-32765

BTK

Phase I/II

Activity has been demonstrated in CLL/SLL, MCL, FL, and DLBCL; ongoing studies are evaluating this agent in combination with other targeted agents and chemotherapy regimens.

CAL-101 (GS-1101)

PI3K-delta

Phase II/III

A large phase I study reported single-agent activity in CLL, MCL, and indolent NHL; phase III trials are currently evaluating GS-1101 in combination with rituximab or bendamustine-rituximab in patients with previously treated CLL.

Temsirolimus

mTOR

Phase II

Several phase I and II trials have been completed and activity has been seen in MCL, FL, DLBCL; combination studies are ongoing.

Everolimus

mTOR

Phase II/III

Several phase I and II trials have been completed, and activity has been seen in all NHL subtypes; a phase III trial is comparing everolimus versus placebo in patients with DLBCL who have achieved a complete response following a rituximab-containing front-line regimen.

SAR245409

PI3K/mTOR

Phase I/II

Phase I single-agent study completed; a phase II trial in MCL, FL and CLL/SLL and a phase Ib combination study are currently recruiting patients.

Midostaurin

FLT3

Phase III

Phase IB complete in AML; CALGB 10603 phase III trial completed accrual.

Lestaurtinib

FLT3

Phase III

Phase II in AML recently completed; phase III trial ongoing.

CLL indicates chronic lymphocytic leukemia; SLL, small lymphocytic lymphoma; MCL, mantle cell lymphoma; FL, follicular lymphoma;

NHL, non-Hodgkin lymphoma; DLBCL, diffuse large B-cell lymphoma; AML, acute myeloid leukemia.

mTOR

The serine/threonine kinase mTOR functions downstream of PI3K to regulate several essential cellular functions. In particular, mTOR acts as a sensor of external growth signals and stress conditions, and one of its most important functions involves the regulation of protein translation initiation. Aberrant activation of mTOR has been associated with a wide variety of solid and hematologic tumors, leading to the successful investigation of mTOR inhibition as a therapeutic strategy in several tumor types to date, including renal cell carcinoma and pancreatic neuroendocrine tumors.

The first-generation mTOR inhibitors temsirolimus (Torisel; Pfizer) and everolimus (Afinitor; Novartis) have both demonstrated preliminary activity in MCL in small studies, with response rates ranging from 6% to 41%. They have also been evaluated in other NHL subtypes, with promising results. As single agents, activity has been observed in FL (ORR approximately 50%), with somewhat lower levels seen in DLBCL (ORR approximately 30%).

Unfortunately, resistance to these agents inevitably develops. Resistance may be related to the fact that mTOR exists in one of two intracellular complexes, mTORC1 and mTORC2, and first-generation inhibitors only block the formation of the mTORC1 complex. Continued activation of mTORC2 leads to a paradoxical increase in the phosphorylation and activation of the upstream kinase Akt, resulting in continued stimulation of this pathway.

Several second-generation inhibitors have been developed to block the activity of both mTOR complexes, and these agents are just beginning to enter clinical trials. Another strategy to enhance the efficacy of these agents is through combinations with other targeted agents, and trials are under way combining first-generation inhibitors with rituximab (Rituxan; Genentech), bortezomib (Velcade; Millennium), lenalidomide (Revlimid; Celgene), or histone deacetylase (HDAC) inhibitors in various lymphoma subtypes.

FLT3

FLT3 (Fms-like tyrosine kinase 3) is a transmembrane receptor that provides a primarily proliferative signal in myeloblasts and is mutated in approximately 30% to 35% of AML cases. Mutations, either through internal tandem duplications or point mutations in the tyrosine kinase domain, lead to constitutive activation of the receptor. This contributes to proliferative and survival signaling in AML blasts. In addition, FLT3 mutation has been associated with a higher relapse rate, as well as shorter disease-free and overall survival times, although allelic ratios may have an impact on this effect. These characteristics led researchers to hypothesize that FLT3 inhibition may provide a clinical benefit in AML.

A number of FLT3 inhibitors are undergoing clinical evaluation in patients with AML. Early studies suggest that as single agents, currently available inhibitors can decrease circulating blasts, but none clear the bone marrow or induce durable responses, leading to studies of these agents in combination with established chemotherapy regimens.

Results from a phase IB trial of midostaurin (PKC412; Novartis) in combination with chemotherapy in 40 newly diagnosed patients with AML have been reported. Midostaurin was included with both induction and consolidation therapy, and patients with either wild-type or mutant FLT3 were enrolled. The complete response rate was 74% in patients with wild-type AML and 92% in those with mutations. Notably, overall survival was similar between both arms, although only 13 patients had FLT3-mutated AML. The phase III CALGB 10603 trial is currently evaluating midostaurin in combination with induction/consolidation chemotherapy followed by one year of maintenance therapy with the inhibitor in patients ≤60 years old with newly diagnosed AML with FLT3 mutations. Accrual was completed in October 2011.

A second FLT3 inhibitor, lestaurtinib, is also in phase III clinical development. A randomized phase II trial of lestaurtinib in combination with chemotherapy in 224 patients with AML in first relapse, harboring a FLT3 mutation, found no difference in either response rate or survival. However, unfavorable pharmacokinetics may have played a role, and sustained FLT3 inhibition was difficult to achieve. A correlative study suggested a higher response rate in the 58% of patients who achieved target FLT3 inhibition at day 15. A phase III trial is ongoing, and results are awaited.

Conclusion

These results suggest that the next generation of targeted therapies has the potential to further improve outcomes in patients with a variety of hematologic malignancies. Additional gains are likely to be achieved through rationally designed combination regimens, which may offer synergistic efficacy or delay the emergence of resistance, and a number of such studies are either under way or in the planning stages. Correlative studies are also being undertaken to identify biomarkers to better select those patients who will, or will not, benefit from a particular therapy.

In the future, it is likely that therapies for hematologic malignancies will not only contain targeted agents, but will be targeted toward specific subpopulations of patients, in order to maximize benefits. Better outcomes will be achieved by matching the right therapy to the right patients, based on knowledge of the molecular makeup of the individual malignancies.

Key Research

Presentations at the 16th International Congress on Hematologic Malignancies PI3 Kinase in Hematologic Malignancies

Brad S. Kahl, MD

Director, Lymphoma Service

University of Wisconsin

Molecular Lesions in BCR Signaling and BTK Inhibitors

Kieron M. Dunleavy, MD

Staff Clinician, Lymphoma Therapeutics Section

National Cancer Institute

mTOR Inhibitors in Lymphoma

Sonali M. Smith, MD

Director, Lymphoma Program

University of Chicago Medicine

Treating AML: Inhibition of FLT3

Richard A. Larson, MD

Director, Hematologic Malignancies Program

University of Chicago