San Francisco, CA—With new signaling pathways being explored, established drug classes expanding across the tumor spectrum, and immunotherapies investigated across tumor types, the hematology pipeline is abundant. Here are some of the most promising compounds in development presented at ASH 2014.
Leukemia and Myelodysplastic Syndrome
ABT-199, an oral selective BCL-2 inhibitor, had considerable clinical activity in patients with poor-prognosis acute myeloid leukemia (AML). ABT-199 is designed to selectively bind to and inhibit BCL-2, a critical regulator of apoptosis.
AG-221, an oral selective inhibitor of the IDH2 gene, showed preliminary efficacy in patients with IDH2-positive AML or 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 complete responses (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.”
Olaptesed pegol, a novel L-stereoisomer RNA aptamer that binds and neutralizes CXCL 12/SDF-1, produced an 82% overall response rate (ORR) when combined with bendamustine and rituximab in an open-label study of 28 patients with relapsed or refractory chronic lymphocytic leukemia (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 agent, 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.
Pracinostat, an investigational oral histone deacetylase (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 (see article, page 21).
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.
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 (see article, page 22).
In patients with MDS, rigosertib did not meet the primary end point in the phase 3 ONTIME trial; however, it did improve survival in several subgroups, including patients whose disease progressed with or failed to respond to previous treatment with hypomethylating agents, patients at very high risk, and patients with certain karyotypic abnormalities. “Patients in these subgroups have a very poor prognosis, and currently there is no approved drug available to treat their disease, once they have failed hypomethylating agents,” said Guillermo Garcia-Manero, MD, of M.D. Anderson Cancer Center, Houston.
Dr Garcia-Manero also presented findings for SGI-110, a novel subcutaneous hypomethylating agent, in 102 patients with MDS and chronic myelomonocytic leukemia (CMML). CRs plus minor CRs were reported in 19% to 22% of patients, depending on the dose used. Transfusion independence for ≥8 weeks was reported in approximately 33% of patients in total, and in 50% of the treatment-naïve patients. The investigators noted that SGI-110 was well-tolerated and showed biological and clinical activity in intermediate- and high-risk patients with MDS and CMML. SGI-110 has “particularly promising activity” in patients who previously received azacitidine or decitabine, the researchers noted.
Sotatercept (ACE-011), a first-in-class activin type-2A receptor fusion protein, may have a role in patients with MDS and anemia, especially when their disease does not respond to erythropoiesis-stimulating agents. In a phase 2 study from the Moffitt Cancer Center, 45% of 54 patients receiving intravenous sotatercept demonstrated a reduced need for transfusion or an increase in hemoglobin level.
Polatuzumab vedotin and pinatuzumab vedotin, 2 antibody-drug conjugates, showed activity and tolerability in a phase 2 randomized trial of patients with relapsed or refractory non-Hodgkin lymphoma (NHL). In the ROMULUS trial, patients received polatuzumab or pinatuzumab, plus rituximab. Both regimens were generally well-tolerated, with similar toxicity profiles. Neutropenia, peripheral neuropathy, and diarrhea were the principal toxicities. In patients with diffuse large B-cell lymphoma (DLBCL), the ORRs were 56% with polatuzumab and 57% with pinatuzumab (plus rituximab), and the CRs were 15% and 24%, respectively.
In follicular lymphoma, the ORRs were 70% and 62%, and the CRs were 40% and 10%, respectively. The higher CR rate with polatuzumab plus rituximab compared with pinatuzumab plus rituximab suggests that polatuzumab may have greater clinical activity in this patient population. Combination studies of polatuzumab plus rituximab with chemotherapy and with antibody drug conjugate schedules to reduce peripheral neuropathy are ongoing or in planning.
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, wi th 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 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%). The investigators noted that copanlisib is active as a single agent in heavily pretreated patients with advanced refractory or relapsed follicular NHL, marginal zone lymphoma, small lymphocytic lymphoma, and CLL, and its toxicity level is acceptable. Based on these results, a phase 2b study in patients with relapsed or refractory indolent NHL has been initiated.
DLBCL is a particularly aggressive subtype of NHL, and novel treatments are clearly needed. A number of novel agents were presented at ASH 2014, but their efficacy was modest. Buparlisib (BKM120), an oral pan-class I PI3K inhibitor, was active among 64 patients with relapsed or refractory DLBCL NHL in a phase 2 study presented by Anas Younes, MD, of Memorial Sloan Kettering Cancer Center. Tumor reduction was observed in 67% of heavily pretreated patients; durable CRs were seen in 31% and 88% of the DLBCL and follicular lymphoma subsets, respectively; however, the primary objective of ORR was not met in either cohort. The investigators indicated that “targeting all 4 PI3K isoforms in DLBCL is a viable strategy and worthy of further exploration in patients with NHL.”
Barasertib, a potent Aurora B kinase inhibitor, showed promising results in a phase 2 trial of patients with relapsed or refractory DLBCL. In 15 patients, the response rate was 20%, and 33% attained stable disease. The median PFS was 60 days. The study provided proof of concept that Aurora B kinase is a valid target in DLBCL.
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.
Nivolumab and pembrolizumab, the 2 most recently approved programmed cell death receptor (PD)-1 inhibitors approved for patients with melanoma, showed exciting findings in patients with classic Hodgkin lymphoma. Although the results for these 2 PD-1 inhibitors came from small, phase 1 studies in patients with Hodgkin lymphoma, they earned spots at press conferences at the meeting and drew large attendance at ASH 2014 sessions. In this patient population, the ORR was 87% for nivolumab and 66% for pembrolizumab in patients with disease progression with standard therapies (see article, page 25).
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 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; rash was the main toxicity.
Monoclonal antibodies may be poised to be the “rituximab of myeloma,” experts predicted at ASH 2014. 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 (see article, page 18).
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 (see article, page 18).
Ricolinostat (ACY-1215), a selective oral HDAC6 inhibitor, is in early-stage studies but is of particular interest to myeloma specialists. 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 seen even in bortezomib-refractory patients.
Panobinostat, another HDAC inhibitor, is in phase 3 development. Jatin Shah, MD, of M.D. Anderson Cancer Center, presented data for panobinostat in combination with bortezomib, lenalidomide, and dexamethasone in 31 newly diagnosed patients with myeloma. He reported an ORR of 95%, including 50% CRs or near-CRs. Dr Shah pronounced the regimen “very well-tolerated,” with limited grade 3 or 4 toxicity. Panobinostat was also combined with carfilzomib in a phase 1 study of 28 heavily pretreated patients with relapsed or refractory myeloma. Jonathan L. Kaufman, MD, of Emory University, reported an ORR of 46% (44% in patients refractory to bortezomib) and no unexpected toxicities. The median PFS was 11.4 months.
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 (see articles, page 19 and page 20).