June 2015 Edition Vol.11, Issue 6

Targeted Therapies for Hematologic Malignancies Attract Attention at ASCO 2015

Targeted Therapies for Hematologic Malignancies Attract Attention at ASCO 2015

By Lynne Lederman, PhD

During this year’s ASCO Annual Meeting, progress was presented in the development of targeted therapies for hematologic malignancies, including multiple myeloma, chronic lymphocytic leukemia (CLL), indolent non-Hodgkin lymphoma (iNHL), and myelofibrosis. Results of four clinical trials that address unmet needs of patient with these incurable diseases are highlighted below.

Daratumumab Monotherapy Effective in Double Refractory Multiple Myeloma

Sagar Lonial, MD, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA, presented a phase 2 study of daratumumab monotherapy in patients with ≥3 lines of prior therapy or multiple myeloma refractory to both proteasome inhibitors and immunomodulatory drugs1 [54767414MMY2002 (Sirius); NCT019851262], funded by Janssen Research & Development, LLC. Daratumumab is a human monoclonal antibody against CD38, a highly and ubiquitously expressed molecule on myeloma cells. The binding of daratumumab to CD38-expressing cells induces cell death through multiple pathways (Figure 1).

The primary objective was the overall response rate (ORR); secondary objectives included progression-free survival (PFS), overall survival (OS), duration of response (DOR), time to response (TTR), and safety. Response was assessed by an independent review committee (IRC).

In this open-label study, patients were randomly assigned to 16 mg/kg (n = 16) or 8 mg/kg (n = 18) daratumumab for dose selection based on efficacy. An additional 90 patients were treated with the 16 mg/kg dose, and results from the 106 patients receiving the 16 mg/kg dose are reported here.

At a median follow-up of 9.3 months, ORR was 29%; there were 3% stringent complete responses (CR) and 12% very good partial responses (VGPR) or better. Dr. Lonial said, “What is striking about this is not just that one in three patients with refractory, one would argue almost end-stage, myeloma had responses, but that we actually saw stringent complete responses with a median of 5 prior lines of therapy. It is not only a testament to the activity of the agent but a testimony that the novel mechanism may be really important.”

Median TTR was 1 month; median DOR was 7.4 months. The initial response deepened with continued treatment in many patients. Median PFS 3.7 was months, and OS was not reached. The estimated 1-year survival rate was 65%.

There were no discontinuations due to daratumumab-associated adverse events (AEs), including infusion-related reactions (IRRs). IRRs occurred in 43% of patients, and were mostly grade 1 or 2; 90% of IRRs occurred during the first infusion.

Dr. Lonial concluded, “Daratumumab is a fully human monoclonal antibody with remarkable single-agent activity in a heavily pretreated and refractory myeloma in patients with no other therapeutic options. Daratumumab represents a new standard of care in the relapsed and refractory myeloma setting.”

Discussant Suzanne Lentzsch, MD, PhD, Columbia University, New York, New York, USA, called the 29% response rate with daratumumab “remarkable” for a single agent, noting that combining antibodies with other agents greatly improves response rates. Daratumumab is being studied in less heavily treated patients in combination with a variety of anti-myeloma therapies. “I think that the monoclonal antibodies will be the backbone of multiple myeloma treatments in the future,” she concluded.

Ibrutinib Added to Standard Therapy Improves Outcomes in
Treatment-Resistant CLL

Ibrutinib combined with bendamustine and rituximab in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): First results from a randomized, double-blind, placebo-controlled, phase 3 study, (NCT016110903) also supported by Janssen, was presented by Asher Chanan-Khan, MD, Mayo Clinic Cancer Center, Jacksonville, Florida, USA4.

Ibrutinib is a first-in-class oral agent that targets Bruton’s tyrosine kinase, an important signaling enzyme for survival of CLL cells. Patients with previously treated CLL/SLL were randomly assigned to ibrutinib plus bendamustine and rituximab (n = 289) or placebo plus bendamustine and rituximab (n = 289). Patients in the placebo arm who experienced progressive disease were allowed to cross over to the ibrutinib arm. The primary endpoint was PFS assessed by an IRC. Other endpoints included ORR, OS, minimal residual disease (MRD) rate, and safety.

At the median follow-up of 17 months, PFS was not reached in the ibrutinib arm and was 13.3 months in the placebo arm (IRC-assessed HR, 0.203; 95% CI, 0.150 to 0.276; P <.0001). Dr. Chanan-Khan said at a press briefing, “The ibrutinib combination significantly reduced the risk of progression by 80% compared with the placebo combination. You cannot get a better hazard ratio than this.”

ORR was significantly higher in the ibrutinib arm than placebo arm (IRC-assessed, 82.7% vs 67.8%; P<.0001). Median OS was not reached in either arm; OS results are confounded by the crossing over of 90 patients (31%) from placebo to ibrutinib. In the intent-to-treat population of those who had MRD assessed, MRD-negative response was 12.8% with ibrutinib vs 4.89% with placebo (P = .0011).

The safety profile of the ibrutinib combination was consistent with the known safety profiles of the individual components. The most frequent AEs were cytopenias, nausea, and diarrhea. Bleeding and atrial fibrillation were higher with ibrutinib.

Lloyd Earl Damon, MD, University of California, San Francisco, California, USA, wondered if a better study would have been of ibrutinib monotherapy vs a combination with immunotherapy. He would also like to see the results of ibrutinib in combination with a monoclonal antibody.

Obinutuzumab Plus Bendamustine Improves Progression-Free Survival in Rituximab-Refractory iNHL

Primary results from a phase 3 study of obinutuzumab plus bendamustine compared with bendamustine alone in patients with rituximab-refractory iNHL (NCT010596305), sponsored by Genentech, Inc. and Roche Pharma AG, was presented by Laurie Helen Sehn, MDCM, MPH, British Columbia Cancer Agency and the University of British Columbia, Vancouver, British Columbia, Canada.6 Although the addition of rituximab to chemotherapy has significantly improved outcomes, patients with iNHL that is refractory to a rituximab-containing regimen have limited treatment options and poorer outcomes.

Obinutuzumab is a novel anti-CD20 monoclonal antibody glycoengineered to induce greater cell death than rituximab. In this open-label trial, patients with rituximab-refractory CD20-positive iNHL (n = 413) were randomly assigned to bendamustine monotherapy or to obinutuzumab plus bendamustine. Those with CR, PR, or stable disease were eligible for obinutuzumab maintenance every 2 months for 2 years or until progression (n = 143).

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