Hematologic Pipeline Abundant

Many Drugs Show Impressive Results
February 2012 Vol 5, No 1, Special Issue
Caroline Helwick
Caroline Helwick

The hematology drug pipeline is chock full of novel agents that are yielding impressive re­sponses in patients with various tumor types, often with less toxicity than seen with standard agents and, in some cases, overcoming adverse cytogenetic profiles.

Chronic Myeloid Leukemia
Ponatinib
, an oral third-generation tyrosine kinase inhibitor (TKI), appears capable of overcoming the T315I mutation in chronic myeloid leukemia (CML), a mutation that makes it extremely difficult to treat the tumor. In the PACE (Ponatinib Ph+ ALL and CML Evaluation) trial, major cytogenetic response was 47% after treatment with ponatinib, and 65% among patients with the mutation. PACE included 499 patients with CML or with Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) who were resistant to or intolerant of nilotinib or dasatinib, or who had the T315I mutation. High levels of response were seen in all patient types, including major histologic responses in 74% and major cytologic responses in more than 50%.

In the 12-month data from the BELA (Bosutinib versus Imatinib in Newly Diagnosed Chronic Myeloid Leukemia) trial, which evaluated the TKI bosutinib in 502 treatment-naïve CML patients, the rate of complete response (CR) plus major molecular response was 67% with bosutinib versus 52% with imatinib. The US Food and Drug Administration has accepted a new drug application for bosutinib on January 27, 2012.

Other Leukemias
Blinatumomab
more than doubled the CR rate in adult patients with relapsed or refractory B-precursor ALL compared with standard therapies. Blinatumomab is a BiTE (bispecific T-cell engager) antibody that directs the patient’s cytotoxic T-cells to attack CD19-expressing cancer cells. In a phase 2 study of 25 patients, 68% achieved a CR or a CR with partial hematologic recovery with blinatumomab. Median duration of CR was 7.1 months, and median overall survival (OS) has not been reached.

PCI-32765, a novel inhibitor of B-cell receptor signaling, this oral drug in early development achieved high rates of remission and was well tolerated in patients with chronic lymphocytic leukemia who were refractory to at least 2 previous treatments, according to updated results of a phase 1b/2 study. This drug represents the first in class of Bruton’s TKIs. In a phase 1b/2 study of 61 patients, response rates approached 50%, depending on dose, and seemed independent of molecular risk features. The 6-month progression-free survival is >90%. Phase 3 trials are planned.

Updated interim results of a phase 2 monotherapy study of quizartinib (AC220), a new FLT3 inhibitor, suggest that this drug can achieve clinically meaningful responses in patients with both refractory and relapsed FLT3-ITD–positive acute myeloid leukemia (AML). In an exploratory analysis of the 62-patient trial, many patients who were treated with this drug were able to go on to hematopoietic stem-cell transplant. The composite CR rate reached 46%, with partial responses (PRs) in up to 22%. Quizartinib is one of the first drugs to induce CRs as a single agent in AML.

Multiple Myeloma
Data are maturing for carfilzomib, the next-generation proteasome in­hibitor, and US Food and Drug Administration approval is expected soon. High response rates and minimal toxicity (including less peripheral neuropathy) were observed when carfilzomib was combined with lenalidomide and low-dose dexa­methasone in a phase 2 study of 53 patients. PRs or greater (≥PR) were observed in 94% of pa­tients after 1 cycle, and 53% achieved CR or a stringent CR. Response was not affected by stage or cytogenetics.

Still in early-phase studies but already generating excitement is the first oral proteasome inhibitor, MLN9708. In a phase 1 study of 56 heavily pretreated patients (46 can be evaluated), 6 achieved ≥PR, 1 patient achieved a minimal response, and 28 patients achieved stable disease, some lasting >16 months. In previously untreated patients, the drug is highly active, according to a phase 1/2 study that showed 9 of 10 patients achieved ≥PR. No peripheral neuropathy grade 3 or higher has been reported with MLN9708. Phase 3 trials will begin next year.

Monoclonal antibodies are also entering the treatment arena for myeloma. Elotuzumab, the first of these agents, led to very high response rates (82%) and prolonged remissions when combined with lenalidomide in 73 relapsed/refractory patients in a phase 2 study. Median progression-free survival had not been reached by the time of the report, and the responses were highly durable. The drug also appears active even in cytogenetically high-risk patients. Phase 3 trials are ongoing, both in previously untreated patients and in relapsed/refractory patients.

A novel immunomodulatory drug, pomalidomide, also earned high praise from myeloma experts. In a phase 2 study in 221 relapsed/refractory patients, pomalidomide plus low-dose dexamethasone led to PRs in 34% of patients, and minor responses in 11%. Median OS was nearly 17 months. In treatment-refractory pa­tients, a French phase 2 study of pomalidomide plus low-dose dexa­methasone showed similar activity, with median OS of 13 months. Phase 3 trials are currently evaluating pomalidomide in various combinations.

Two histone deacetylase inhibitors showed activity in patients with relapsed/refractory myeloma. In the global phase 3 VANTAGE trial of 635 patients, vorinostat plus bortezomib significantly prolonged remission compared with bortezomib alone, reducing the risk of progression by 23% (P = .01) and improving response rates from 41% to 56% (P <.001).

In the phase 2 PANORAMA-2 study of 55 treatment-refractory patients, pano­binostat plus bortezomib and dexa­methasone produced a clinical benefit rate of 49%. Panobinostat is being combined with a number of different drugs in ongoing studies in myeloma.

Lymphoma
In patients with relapsed indolent non-Hodgkin lymphoma (NHL), a “glycoengineered” humanized antibody against CD20, obinutuzumab (GA101) produced comparable outcomes to rituximab in the first head-to-head comparison of these drugs, the phase 2 GAUSS trial of 175 pa­tients. Response rates to induction were significantly higher with obinutuzumab than with rituxumab by independent radiology review: 44.6% versus 26.7% (P = .01). The primary end point, however, response according to local investigators, was numerically although not significantly different: 44.6% and 33.3% (P = .08). Median progression-free survival was approximately 17 months in each arm. The study was not designed to show superiority, but to determine if a randomized trial was justified, and trials are now under way comparing the 2 drugs, which are given with chemotherapy.

In systemic anaplastic large-cell lymphoma, an aggressive subtype of mature T-cell NHL, a multicenter phase 2 study in relapsed/refractory patients found durable clinical remissions and high response rates after treatment with brentuximab vedotin, an anti-CD30 antibody conjugated to an antimicrotubule agent. Overall response rates were 86%, and CRs were achieved by 56% of patients, with a median duration of response that had not been reached by the time of the analysis.

Myelofibrosis
CYT387
, a new Janus kinase (JAK) inhibitor, proved capable of keeping patients with myelofibrosis free of transfusion in a phase 1/2 trial of 166 patients. In the study, 54% of the 68 patients who were transfusion-dependent at baseline became transfusion-independent by 12 weeks, with a mean duration of response >6 months. Phase 3 trials for CYT387 are slated to begin soon.
 

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