The Hematologic Drug Pipeline: Exciting New Treatment Options Looming

February 2016, Vol 7, No 1

Many presentations at ASH 2015 focused on novel therapies currently in development for the treatment of patients with hematologic malignancies, including a second generation of new agents recently approved by the FDA for a variety of hematologic cancers. The information below provides a quick bird's-eye view of some of the most promising in the pipeline that are furthest along in development or drugs that have demonstrated significant effectiveness in early-stage clinical trials.

Myelodysplastic Syndrome and Myeloproliferative Disorders

Luspatercept (Acceleron; Celgene) is a fusion protein that inhibits Smad2/3 signaling and increases the production of red blood cells and is intended for the treatment of anemia in patients with rare blood disorders, including beta thalassemia and myelodysplastic syndromes (MDS). Preliminary results of an ongoing phase 2 open-label, 24-month extension study (PACE-MDS extension study) showed that in the majority of 31 enrolled lower-risk patients with MDS, treatment with luspatercept resulted in increased hemoglobin levels, decreased transfusion requirement, or transfusion independence. Luspatercept was well-tolerated, and phase 3 studies are planned.

Rigosertib (Oncova Therapeutics), a small-molecule inhibitor of cellular signaling acting as an RAS mimetic, in combination with standard-dose azacitidine, showed in a phase 1/2 study an overall response rate (ORR) in 23 (77%) of 30 evaluable high-risk patients with MDS, including 6 patients with a complete response. The median duration of treatment for patients with MDS was 4 months. Hematologic improvement was observed in 13 (50%) of the 26 patients evaluable for this parameter. In treatment-naive patients with MDS, the ORR was 84%; the ORR was 64% in patients with MDS who previously failed with hypomethylating agent therapy. The side effects were similar to those previously reported with azacitidine alone.

Pacritinib (CTI BioPharma), an oral JAK2/FLT3 multikinase inhibitor, is in phase 3 development for myelofibrosis. This drug had a strong showing in the phase 3 PERSIST-1 trial. Treatment with pacritinib was compared with best available therapy in 327 patients with myelofibrosis who were randomized in a 2:1 ratio. The percentage of patients achieving a ≥35% reduction in spleen volume was consistently higher with pacritinib than with best available therapy, and the greatest differences in spleen volume reduction from baseline compared with best available therapy were observed in younger patients with lower baseline platelets, JAK-negative patients, and patients aged <65 years (for all 3 subgroups, a difference of approximately 22% vs best available therapy).


Chronic Lymphocytic Leukemia

The most exciting drug in the chronic lymphocytic leukemia (CLL) space is venetoclax (Genentech), a small-molecule inhibitor of BCL-2 that is being studied in patients with and without 17p deletions (worse prognosis; see article). Several studies at ASH 2015 focused on venetoclax in combination with novel CLL agents and with rituximab (Rituxan).

Acalabrutinib (Acerta Pharma), a second-generation Bruton's tyrosine kinase (BTK) inhibitor, achieved an ORR of 95% in a single-arm phase 1/2 trial of 61 patients with relapsed CLL. The remainder of the patients had stable disease. Overall, 98% of patients had reductions in lymphadenopathy, and 60% to 80% of patients with cytopenias at baseline had improvements in platelets, hemoglobin, and neutrophil count. The median treatment duration was 14.3 months. The drug was well-tolerated, with headache as the most common adverse effect; few grade 3 or 4 events were reported.

Entospletinib (Celgene) is an oral selective inhibitor of spleen tyrosine kinase (Syk), a mediator of B-cell receptor signaling in normal and transformed B-cells. Targeting the B-cell receptor signaling pathway has proved successful with ibrutinib (Imbruvica) and idelalisib (Zydelig). Preliminary data suggest that entosple­tinib may be effective in patients with CLL as well as in those with non-Hodgkin lymphoma (NHL) that is resistant to ibrutinib and other BTK inhibitors. An ongoing phase 2 trial showed that entospletinib has clinical activity after treatment with BTK inhibitors or PI3K inhibitors, such as idelalisib. No additional safety signals were reported.

Afuresertib (GlaxoSmithKline), a pan–protein kinase B (Akt) inhibitor, is being evaluated in combination with ofatumumab (Arzerra) in a phase 2 study of 27 previously treated patients with CLL that was relapsed or refractory to ≥ 1 fludarabine (Fludara)-containing regimens. The combination showed good antitumor activity and was well-tolerated, with minimal myelotoxicity. A rapid onset of effect was seen at 1.4 months, but the ORR was 48% and the median progression-free survival (PFS) was 8.6 months, suggesting that afuresertib may not provide a significant benefit over ofatumumab alone. The drug is also being studied in patients with myeloma.

Acute Myeloid Leukemia

The promising results of the phase 3 RATIFY trial suggest that midostaurin (Novartis), an FLT-3 inhibitor, will find a role in combination with chemotherapy for the treatment of patients with acute myeloid leukemia (AML) and the FLT3 mutation.

Maintenance therapy with tipifarnib (BioSight), a farnesyl transferase inhibitor, had a promising clinical benefit in a phase 3 trial of patients with AML whose disease was in remission but who had a high risk for relapse. Although no significant benefit was seen for tipifarnib versus observation for the primary end point of disease-free survival (DFS), when the analysis was restricted to eligible patients, the median DFS was 10.81 months for patients receiving tipifarnib versus 5.26 months for the observation group (P = .019), a 31% improvement favoring tipifarnib. Furthermore, female patients receiving tipifarnib had an approximate 3-fold longer DFS than the observation-alone group (12.09 months vs 3.91 months, respectively; P = .002). Similar sex-related results were seen for overall survival.

Acute Lymphoblastic Leukemia

The phase 2 results of a study showed that the investigational antibody-drug conjugate inotuzumab ozogamicin (Pfizer) combined with deintensified chemotherapy achieved excellent results in elderly patients with Philadelphia-negative (Ph–) acute lymphoblastic leukemia (ALL). This combination may turn out to be a new standard of care for patients with Ph–ALL.


Entospletinib (Celgene) at dosing of 800 mg twice daily is being investigated in an ongoing phase 2 trial with 204 previously treated patients with indolent NHL. Preliminary results were presented for a cohort of 69 patients. Overall, 38 (62%) of 61 patients had a reduced tumor burden at a median of 28 weeks; 15% achieved a ≥50% decrease of tumor burden. The ORR was 13%, with 7 patients achieving a partial response; 1, a molecular response; and 1, a complete response. Entospletinib was well-tolerated and demonstrated activity in advanced, relapsed NHL, even in patients with poor prognostic features.

Abexinostat (Pharmacyclics), an oral HDAC inhibitor, showed advantages over approved HDAC inhibitors, including oral dosing twice daily, which allows for continuous exposure to tumor cell killing. Abexinostat may also be less toxic, with a wider therapeutic index compared with its competitors. In a phase 2 trial of 100 patients with heavily pretreated, refractory NHL or CLL, single-agent abexinostat achieved an ORR of 28% in 87 evaluable patients. The highest responses were observed in follicular lymphoma, T-cell lymphoma, and diffuse large B-cell lymphoma (DLBCL), with ORRs of 56%, 40%, and 31%, respectively, and median response duration of 26 weeks, 32.1 weeks, and 8.1 weeks, respectively. A study for these indications using a less dose-intense interval is planned.

Treatment with buparlisib (Novartis), an oral PI3K inhibitor, showed moderate tolerability, an acceptable safety profile, and sustained reduction in tumor burden in a multicenter, parallel-arm, open-label, global phase 2 study of patients with relapsed or refractory DLBCL, mantle-cell lymphoma (MCL), or follicular lymphoma. A 6-month analysis after continuous treatment for 22 patients with MCL demonstrated an ORR of 22.7%, with 1 complete response and 4 partial responses; an additional 13 patients had stable disease. The disease control rate was 81.8%, and the median PFS was 11.3 months. This drug is also in development for other solid tumors.

The oral Aurora A kinase inhibitor alisertib (Spectrum) had disappointing results in a randomized phase 3 trial, showing no superiority in efficacy or PFS in adults with relapsed or refractory peripheral T-cell lymphoma over the investigator's choice of pralatrexate (Folotyn), romidepsin (Istodax), or gemcitabine (Gemzar). The study was stopped prematurely; analysis of the data will continue.

Multiple Myeloma

Among the exciting drugs in the multiple myeloma pipeline is the novel kinesin spindle protein (KSP) inhibitor filanesib (Array BioPharma). Filanesib targets KSP, which is a microtubule motor protein critical to the function of proliferating cells. In a dose-escalation study of 34 patients with relapsed or refractory filanesib plus carfilzomib (Kyprolis) produced responses in 44% of carfilzomib-naive patients, but showed less activity among patients whose disease was refractory to carfilzomib. In the carfilzomib-naive patients, the median PFS with the combination was 12.9 months, and the median overall survival had not been reached at 24 months. A phase 2 study of 77 patients with relapsed or refractory disease compared the combination versus carfilzomib alone, showing a doubling of PFS (8.5 months vs 3.7 months, respectively). The ORRs were 28% and 24%, respectively.

The novel peptidase-targeted therapy, melflufen (Oncopeptides AB), an antiangiogenic compound that triggers irreversible DNA damage, showed interesting activity. Melflufen was evaluated in combination with dexamethasone in a phase 2 study of 55 patients with relapsed or refractory myeloma. In 23 evaluable patients, the ORR was 48%, the clinical benefit was 61%, and the median PFS was 7.6 months. Hematologic toxicity was common, but nonhematologic events were uncommon.

Added to a growing list of monoclonal antibodies is the CD38-targeting agent isatuximab (SAR650984; Sanofi). Isatuximab was evaluated as a single agent in a dose-finding phase 2 study of 97 patients with relapsed or refractory myeloma. The preliminary response rates were 24% and 29% in the 2 most dose-intense cohorts. Isatuximab was well-tolerated; the main toxicity involved infusion-related reactions. The drug is entering phase 3 trials.

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