Promising Therapies in Development for Hematologic Cancers

VBCC - February 2015, Vol 6, No 1 - Emerging Therapies
Dana Taylor

San Francisco, CA—Many of the presentations at the 2014 annual meeting of the American Society of Hematology centered on the abundance of new molecules being developed for hematologic cancers, including new immunotherapies, and drugs that are expanding from one tumor type to another. Some of the most promising compounds in development are described below.

Hodgkin Lymphoma

Nivolumab and pembrolizumab, the 2 most recently approved programmed-­cell death receptor (PD)-1 inhibitors for patients with melanoma, show promise in patients with Hodgkin lymphoma. Although the results for these 2 PD-1 inhibitors came from small, phase 1 studies, they received much press coverage and drew many attendees at the meeting. The overall response rate (ORR) was 87% for nivolumab and 66% for pembrolizumab in patients with Hodg­kin lymphoma that has progressed despite the use of standard therapies.

MK2206, an oral AKT inhibitor, induced response in patients with classic Hodgkin lymphoma and indolent lymphoma; however, its single-agent activity was low in patients with diffuse large B-cell lymphoma (DLBCL), T-cell lymphoma, or mantle-cell lymphoma in a phase 2 study of 50 patients with refrac­tory disease. MK2206 is the first oral ­non-ATP competitive allosteric inhibitor of the AKT pathway 1, 2, and 3 that is currently in clinical development. Objective responses were observed in 14% of patients (20% among patients with Hodgkin lymphoma), and 40% of patients showed some tumor reduction. The median response duration was approximately 6 months. MK2206 was well-­tolerated, with rash being the main toxicity.

Non-Hodgkin Lymphoma

Polatuzumab vedotin and pinatuzumab vedotin, 2 antibody-drug conjugates, showed activity and tolerability in a phase 2 randomized ROMULUS trial of patients with relapsed or refractory non-Hodgkin lymphoma (NHL). Patients received polatuzumab or pina­tuzumab, plus rituximab. Both regimens were generally well-tolerated, with similar toxicities, including neutropenia, peripheral neuropathy, and diarrhea. In patients with DLBCL, the ORR was 56% with polatuzumab and 57% with pinatuzumab (plus rituximab), and the complete response (CR) was 15% and 24%, respectively.

MOR00208, an Fc-engineered humanized anti-CD19 antibody, was evaluated as a single agent in a phase 2a study of patients with relapsed or refractory B-cell NHL. Among the first 51 patients in the trial, the response rate was 24%. The drug was well-tolerated, without significant toxicity from the infusion. Accrual to the study is continuing.

Alisertib (MLN8237), an oral Aurora A kinase inhibitor, was investigated alone and in combination with rituximab in a phase 2 study of 11 patients with high-risk relapsed or refractory B-cell NHL. Alisertib was well-tolerated, with 1 patient responding and able to proceed to transplant. Enrollment is continuing.

Copanlisib, a novel PI3K inhibitor, was explored in 33 patients with indolent NHL or with chronic lymphocytic leukemia (CLL). The ORR in both patient populations was 44%; when divided by disease state, the ORR was 48% in patients with NHL and 38% in patients with CLL. The combined median duration of response was 390 days, and the median progression-free survival was 288 days. Grade ≥3 events included hypertension (48%), neutropenia (33%), hyperglycemia (30%), anemia (15%), and thrombocytopenia (15%). A phase 2b study in patients with relapsed or refractory indolent NHL has been initiated.

Mogamulizumab, a humanized monoclonal antibody targeting the CC chemokine receptor 4 (CCR4), achieved stable disease or better in 46% of patients (11% responses) with peripheral T-cell lymphoma, with an acceptable safety profile, in a multicenter phase 2 study of heavily pretreated relapsed or refractory patients. The CCR4 is expressed on 30% to 65% of tumor cells in patients with peripheral T-cell lymphoma, whose prognosis is generally poor. Mogamulizumab binds to CCR4. The drug is already approved outside of the United States for this patient population.

Multiple Myeloma

Monoclonal antibodies may be poised to be the “rituximab of myeloma,” experts predict. Elotuzumab (which received breakthrough therapy designation for myeloma in May 2014), in combination with lenalidomide and dexamethasone, induced an 84% ORR in a phase 1b/2 study of patients with relapsed or refractory myeloma.

The data were less mature but were at least as impressive for the 2 anti-CD38 antibodies, SAR650984 and daratumumab. SAR650984 yielded a 63% response rate in optimally treated patients with myeloma. Daratumumab (which received a breakthrough therapy designation for myeloma in 2013) showed impressive results in combination with standard regimens, yielding a 100% response rate in some cohorts.

Ricolinostat (ACY-1215), a selective oral histone deacetylase (HDAC) 6 inhibitor, is in early-phase studies but has shown promising results. In a phase 1b study of 42 patients with relapsed or refractory myeloma, ricolinostat, in combination with bortezomib and dexamethasone, was well-tolerated, with diarrhea as the only dose-related side effect. The response rate was 44%, and only 3 patients showed progressive disease. Responses were also seen in bor­tezomib-refractory patients.

Panobinostat, another HDAC inhibitor, is in phase 3 development. In a study of panobinostat in combination with bortezomib, lenalidomide, and dexamethasone, 31 newly diagnosed patients with myeloma showed an ORR of 95%, including 50% CRs or near-CRs. The regimen was well-tolerated, with limited grade 3 or 4 toxicity.

Ixazomib and oprozomib, 2 novel oral proteasome inhibitors, have shown promising results in myeloma. Long-term data were presented for ixazomib; oprozo­mib is in earlier-stage development.

Leukemia

Chronic Lymphocytic Leukemia
Olaptesed pegol, a novel L-stereoisomer RNA aptamer that binds and neutralizes CXCL12/SDF-1, produced an 82% ORR when combined with bendamustine and rituximab in an open-label study of 28 patients with relapsed or refractory CLL. The ORR of bendamustine plus rituximab without olaptesed has historically been 59%. Olaptesed in combination with bendamustine and rituximab was safe and well-tolerated.

XmAb5574, a novel humanized immunoglobulin G1 CD19 monoclonal antibody with an engineered Fc region to enhance Fc gamma receptor binding affinity, showed promising preliminary efficacy in high-risk patients with heavily pretreated CLL. Responses were reported in 67% of 16 patients who received XmAb5574. The results with this drug compare favorably with single-agent CD20 antibodies in relapsed CLL. Current studies are investigating XmAb5574 in combination with other agents.

Another anti-CD19 antibody, MEDI-551, was evaluated in combination with bendamustine versus ri­tuximab and bendamustine in 147 patients with relapsed or refractory CLL in a phase 2 trial that was presented by Douglas E. Gladstone, MD, of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center. The preliminary results showed clinical activity, with comparable safety observed between the MEDI-551 and rituximab arms. The investigators may also have identified a biomarker of response—low baseline levels of a microRNA signature.

Acute Myeloid Leukemia
ABT-199, an oral selective BCL-2 inhibitor, showed considerable clinical activity in patients with poor-prognosis acute myeloid leukemia (AML). ABT-199 selectively binds to and is inhibiting the BCL-2, a key regulator of apoptosis.

AG-221, an oral selective inhibitor of the IDH2 gene, showed preliminary efficacy in patients with IDH2-positive AML or with myelodysplastic syndrome (MDS). AG-221 was used in 45 patients with IDH2-mutated AML or MDS at escalating doses. Responses were seen in 56% of patients, including 15 CRs and 10 partial responses. Responses were durable, with CRs lasting up to 8 cycles. Many patients continue to receive AG-221, reported Eytan M. Stein, MD, of Memorial Sloan Kettering Cancer Center, New York. Dr Stein called the 56% response rate “a very big deal” in this hard-to-treat population. The targeting of a specific genotype will increase efficacy, he said, and potentially “extend life spans and minimize toxicity.”

Pracinostat, an investigational oral HDAC inhibitor, resulted in a rate of 45% for the composite end point of CR and CR with incomplete blood count recovery and morphologic leukemia-free status when combined with azacitadine in a phase 2 trial of 33 patients with AML and intermediate- or unfavorable-risk cytogenetics.

Vosaroxin, a first-in-class anticancer quinolone derivative, in combination with cytarabine improved the median overall survival compared with placebo plus cytarabine (7.5 months vs 6.1 months, respectively) in a phase 3 study of patients with relapsed or refractory AML.

Acute Lymphocytic Leukemia
CTL019, a chimeric antigen receptor targeting CD19, achieved durable remission in children with relapsed or refractory acute lymphocytic leukemia who were given T-cells engineered with CTL019.

Related Items
Dichlorphenamide Improves Outcomes in Periodic Paralysis
Chase Doyle
VBCN - July 2016 Volume 3, No 2 published on July 25, 2016 in Emerging Therapies
Emerging Disease-Modifying Therapies for Multiple Sclerosis
Chase Doyle
VBCN - July 2016 Volume 3, No 2 published on July 25, 2016 in Emerging Therapies
Ocrelizumab Promotes No Evidence of Disease Activity in Multiple Sclerosis
Chase Doyle
VBCN - July 2016 Volume 3, No 2 published on July 25, 2016 in Emerging Therapies
Promising Antitumor Activity of ODM-201 in Metastatic Prostate Cancer
Wayne Kuznar
VBCC - June 2016, Vol 7, No 5 published on June 17, 2016 in Emerging Therapies
Entrectinib Shows Strong Activity Against a Range of Rare Solid Tumors with Molecular Abnormalities
Wayne Kuznar
VBCC - June 2016, Vol 7, No 5 published on June 17, 2016 in Emerging Therapies
Transplant Remains Best Upfront Treatment Option in Newly Diagnosed Myeloma
Dana Taylor
VBCC - April 2016, Vol 7, No 3 published on April 21, 2016 in Hematologic Cancers
Atezolizumab, a PD-L1 Inhibitor, Shows Impressive Results in Metastatic Urothelial Cancer
Charles Bankhead
VBCC - March 2016, Vol 7, No 2 published on March 21, 2016 in Emerging Therapies
New Biosimilar Demonstrates Equivalence and Noninferiority to Pegfilgrastim
Corbin Davis
VBCC - March 2016, Vol 7, No 2 published on March 21, 2016 in Emerging Therapies
A 3-Drug Regimen the Preferred Approach in Newly Diagnosed Multiple Myeloma
Dana Taylor
VBCC - March 2016, Vol 7, No 2 published on March 21, 2016 in Hematologic Malignancies
First-in-Human CAR T-Cell Trial Demonstrates Activity in Multiple Myeloma
Dana Taylor
VBCC - March 2016, Vol 7, No 2 published on March 21, 2016 in Emerging Therapies
Last modified: February 19, 2015
  • Rheumatology Practice Management
  • American Health & Drug Benefits
  • Value-Based Cancer Care
  • Value-Based Care in Myeloma
  • Value-Based Care in Neurology