Hematologic Drug Pipeline Is Bustling

February 2013 Vol 6, No 1, Special Issue
Caroline Helwick

Targeted therapies, immunomodulatory agents, and monoclonal antibodies with impressive response rates for the treatment of various hematologic malignancies were among the agents in late-stage development that were featured during oral and poster sessions at the ASH 2012 meeting. Success with some of these therapies was groundbreaking.

Leukemias
Quizar­tinib. A selective inhibitor of FLT3, quizar­tinib, cleared leukemia cells from the bone marrow in a significant proportion of patients with acute myeloid leukemia (AML), thereby permitting transplant in many of them. Quizartinib is currently in phase 2 trials showing a more than 33% remission rate in patients with refractory AML.

Inotuzumab ozogamicin is an antibody-drug conjugate in early development; it is composed of a monoclonal antibody targeting CD22 that is linked to a cytotoxic agent.

Data from a phase 1 clinical trial of weekly inotuzumab in patients with relapsed or refractory CD22-positive acute lymphoblastic leukemia (ALL) showed that a best overall response was achieved by 83% of the participating patients; a hematologic remission rate was achieved by 74% of the patients.

Response to therapy with inotuzumab ozogamicin was achieved shortly after induction therapy, with a median time to remission of 28 days.
Blinatumomab, a bispecific T-cell–engaging antibody construct that directs cytotoxic T-cells to CD19-­expressing B-cells, induced complete remission in 12 of 18 (67%) of the patients within the first 2 cycles of treatment when used as a single agent in a phase 2 clinical trial of patients with B-precursor ALL.

Blinatumo­mab as a single agent induced an unprecedented high rate of complete hematological and MRD [minimal residual disease] responses in adult patients with relapsed/refractory B-precursor ALL,” said lead investigator Max S. Topp, MD, from Wuerzburg University Medical Center, Wuerzburg, Germany.

Lymphoma
Ibrutinib. The Bruton’s tyrosine kinase inhibitor ibrutinib demonstrated robust single-agent activity in patients with relapsed or refractory mantle-cell lymphoma, according to the international, phase 2 PCY-1104-CA trial. “Ibrutinib produced the highest response rate ever observed with a single drug in the history of relapsed mantle-cell lymphoma,” said Michael Wang, MD, University of Texas M.D. Anderson Cancer Center. Among the 115 patients, including those with and without previous exposure to bortezomib, the overall response rate (ORR) was 68%, and complete response (CR), >20%.
The median progression-free survival (PFS) was 13.9 months for the whole population and has not yet been reached among responders. Ibrutinib is active in other lymphomas as well, including in patients with diffuse large B-cell lymphoma, follicular lymphoma, and multiple myeloma. Response rates in patients with these tumors and relapsed or refractory disease ranged from 23% to 44%; these rose to 55% with optimal dosing, according to other investigators at the meeting (see article on page 20).

Multiple Myeloma
MLN9708. The oral investigational proteasome inhibitor MLN9708 produced impressive results in a phase 1/2 study of patients with treatment-naïve multiple myeloma. MLN9708, given in combination with lenalidomide, achieved an ORR exceeding 90%, CRs in 25% of pa­­tients, and a low rate of peripheral neuropathy (grade 3 in 3%). As an oral proteasome inhibitor with a good tolerability profile, MLN9708 may help achieve the goal of having a convenient, all-oral, first-line treatment for myeloma.

Pomalidomide. In the phase 3 MM-003 trial of patients with advanced multiple mye­loma, the oral immunomodulatory agent pomalidomide was associated with an improvement not only in PFS but also in overall survival (OS). After a median follow-up of 18 months, the median PFS was 15.7 weeks versus 8 weeks with high-dose dexamethasone, a 55% reduction in risk (P <.001). The OS was 34 weeks with high-dose dexamethasone, but has not been reached with pomalidomide plus low-dose dexamethasone, translating into a 47% risk reduction (P <.001).

Pomalidomide combined with low-dose dexamethasone essentially doubled the median PFS versus high-dose dexamethasone alone. Pomalidomide is considered more potent than the 2 available immunomodulatory agents, thalidomide and lenalidomide, and is expected to become approved by the US Food and Drug Administration soon.

Daratumumab and elotuzumab. The data continue to accumulate for novel monoclonal antibodies in pa­tients with myeloma. In a phase 1/2 study of 32 patients, daratumumab produced clinical benefit in almost 50% of the heavily pretreated relapsed/refractory population, and 47% of patients had a reduction in the amount of monoclonal protein in the blood or in the urine.

Elotuzumab, another monoclonal antibody, given with lenalidomide and dexamethasone, was evaluated in a dose-finding study of 73 patients who had received a median of 2 previous lines of therapy, showing a 92% ORR and a median PFS that has not been reached after 21 months of follow-up.
Phase 3 trials are evaluating 10-mg/kg elotuzumab and a lenalidomide plus dexamethasone combination in newly diagnosed patients.

ARRY-520. In a phase 2 clinical trial, the kinesin spindle protein inhibitor ARRY-520, given with or without dexamethasone, produced responses in 19% to 22% of enrolled patients with myeloma, with median response durations of 5.4 to 8.6 months. The side effect profile was mild, and no cases of peripheral neuropathy were reported. In a phase 1 clinical trial, therapy with ARRY-520 plus carfilzomib in patients with relapsed and/or refractory myeloma produced a 22% response rate, of which 11% were CRs. These studies further suggest that level of protein alpha-1-acid glycoprotein may serve as a biomarker for response in this patient population.

Lorvotuzumab mertansine. A new class of drugs in early development has also impressed myeloma specialists at the meeting. Lorvotuzumab mertansine is a chemotherapy agent that is attached to an antibody. In a phase 1 clinical trial of 44 pretreated patients with myeloma, lorvotuzumab mertansine, in combination with len­alidomide plus dexamethasone, led to a very high response rate—57%; however, peripheral neuropathy was reported by 56% of the patients.

Myelofibrosis
SAR302503. An open-label phase 2 study showed that a novel, investigational selective Janus kinase (JAK)2 inhibitor, SAR302503, reduced spleen size and improved constitutional symptoms in patients with intermediate-2 or high-risk primary or secondary myelofibrosis. The reductions in spleen size from baseline were 30% to 42% depending on the dosage of SAR302503. A phase 3 trial of 289 patients is ongoing, with results expected in the second quarter of 2013.

CYT387. An investigational selective JAK1/JAK2 inhibitor in early development, CYT387 produced dur­able responses in anemia, splenomegaly, and constitutional symptoms in a phase 1/2 open-label study of 166 patients with myelofibrosis. At 12 weeks, the proportion of patients with transfusion independence ranged from 57% to 75%, depending on the dose of CYT387 that was used.

The median duration of the transfusion-free period has not yet been reached. The median spleen decrease ranged from 36% to 46% with this new agent, with a median duration of response of 744 days. Fever resolved in 100% of the patients, and night sweats and pruritus either resolved or were markedly improved in more than 70% of the patients.

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