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ASH 2016: Informative and Clinical Useful

Published on 22nd November

Each year, ahead of key annual medical society meetings we ask the same question: What to expect during the upcoming meeting.  Are we going to learn something new, something exciting? Will there be anything interesting and clinically useful presented?  Are there any breakthroughs? And each year we’re surprised when there is again an overload of valuable information.

The same will be true this year.

1, according to Charles S. Abrams, MD, Professor of Medicine, Pathology, and Laboratory Medicine, and the Director of the Blood Center for Patient Care & Discovery at the University of Pennsylvania and Children’s Hospital of Philadelphia as the 2016 President of the Society and Stephanie Lee, MD, the organization’s Secretary and a hematologist who provides hematopoietic cell transplants using bone marrow, peripheral blood and cord blood for patients with hematological diseases such as leukemia and myelodysplastic syndrome, overflowing with interesting, informative, and clinically useful news and research updates. [1]

Alcanza Trial
“At this year’s ASH meeting, we will present data from 18 abstracts, highlighting brentuximab vedodin, vadastuximab talirine and multiple pipeline programs,” noted Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics.

During the upcoming ASH meeting, the results of the Phase III Alcanza Trial are featured as one of the key presentations (abstract #182). This trial is a randomized clinical study evaluating brentuximab vedodin (Adcetris®; Seattle Genetics/Takeda Pharmaceutical Co.) versus investigator’s choice of methotrexate or bexarotene in 132 patients with CD30-expressing Cutaneous T-cell Lymphoma (CTCL), a relatively rare disease, who received prior systemic therapy.

Alcanza trial
Figure 1.0: The Alcanza trials is a randomized , open label, Phase III study of Brentuximab Vedotin vs. Physician’s Choice (Methotrexate or Bexarotene) in patients with CD30+ Cutaneous T-Cell Lymphoma. (Study: NCT01578499).

Brentuximab vedodin is an antibody-drug conjugate or ADC directed to CD30, which is expressed on skin lesions in at least 50% of patients with CTCL. The Alcanza trial is being conducted under a Special Protocol Assessment (SPA) agreement from the U.S. Food and Drug Administration (FDA). In addition, Takeda received European Medicines Agency (EMA) scientific advice.

The Alcanza trial included 128 randomized patients followed for 17.5 months. For the primary endpoint, Overall Response Rate (ORR) at 4 months, brentuximab vedotin was significantly superior to physician’s choice of therapy: 56% versus 13%, respectively (P<.0001). Median progression-free survival (PFS) was 16.7 months versus 3.5 months, a highly significant difference favoring brentuximab (P<.0001).

Commenting on the results of this study, Lee noted: “This study shows that brentuximab vedotin has a significant advantage over the other two options used to treat cutaneous T-cell lymphoma.”

“The oral presentation of the complete results of the Alcanza trial represents the fourth consecutive registrational trial for brentuximab vedodin with a positive outcome. Data across our pipeline programs continue to support the potential for antibody-drug conjugates to improve outcomes for patients with cancer,” Seattle Genetics’ Drachman added.

Other investigational agents
Seattle Generics’ proprietary technology is designed to harness the targeting ability of antibodies to deliver cell-killing agents directly to cancer cells. There are more than 20 antibody-drug conjugates in clinical development that utilize the company’s proprietary technology.

In addition to the results from the Alcanza trial, Seattle Genetics is expected to present a large number of oral and poster presentations, including results from the Cascade trial, a global Phase III study with  vadastuximab talirine (SGN-CD33A) in newly diagnosed, older AML, denintuzumab mafodotin (SGN-CD19A) for the treatment of patients with B-cell ALL, aggressive NHL and relapsed or refractory (r/r) DLBCL.

IMMU-140
Based on promising results in solid cancers Immunomedics is expanding its antibod-drug conjugate program to include hematological malignancies. Using the same CL2A linker and the SN-38 toxic payload,  the company’s scientists have developed a novel antibody-drug conjugate, IMMU-140.

The antibody used in IMMU-140 is IMMU-114, an anti-HLA-DR IgG4 antibody that has demonstrated evidence of treatment responses in more than 50% of assessable patients in a Phase I study in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) without reaching a maximum tolerated dose.

During the ASH meeting, Immunmedics will present preclinical results on in vitro and in vivo activity of IMMU-140 in animal models of five liquid cancers, NHL, CLL, acute myelocytic and lymphocytic leukemia, and multiple myeloma.

Indatuximab Ravtansine
Interesting data will also be presented for Indatuximab Ravtansine (BT062; Biotest AG, Dreieich, Germany) in combination with low-dose dexamethasone and lenalidomide or pomalidomide in patients with relapsed/refractory Multiple Myeloma (abstract #4486). Indatuximab Ravtansine is an antibody-drug conjugate comprising a CD138-binding chimerized antibody and the cytotoxic maytansinoid, DM4. It is designed to target and kill CD138-positive cancer cells. CD138 (Syndecan-1) is highly expressed on a number of solid tumors and hematological malignancies and is one of the most reliable markers for multiple myeloma.

Novel CD123 and CD33-targeting ADCs
During the annual meeting, new preclinical data on ImmunoGen’s novel ADCs, IMGN632 and IMGN779 will be presented. IMGN632, is a CD123-targeting ADC while IMGN779, targets CD33. Both investigational agents use ImmunoGen’s new family of indolino-benzodiazepine cancer-killing agents called IGNs. Scientists at ImmunoGen designed IGN payloads to alkylate DNA without crosslinking it. The data being presented in both oral as we’ll as poster presentations demonstrates that DNA-alkylating IGNs are ultra-potent, yet provide increased tolerability compared with DNA crosslinking versions.

“Accelerating our earlier-stage portfolio with an emphasis on our IGN ADCs is one of [our] strategic priorities, and we believe the IMGN632 and IMGN779 preclinical … further demonstrates why we are excited about the potential of these programs,” explained Richard Gregory, Ph.D., executive vice president and chief scientific officer of ImmunoGen.

The preclinical data to be presented shows activity of IMGN632 in multiple acute myeloid leukemia (AML) models and patient samples at concentrations far below levels that affect normal bone marrow cells, suggesting the potential for efficacy in AML patients in the absence of or with limited myelosuppression (abstract #768) In a separate poster presentation, preclinical data for IMGN632 will be reported demonstrating prolonged survival in AML xenograft models (abstract #2832).

During the ASH meetig preclinical data from a combination study of IMGN779 with a PARP inhibitor, demonstrating enhanced activity in several AML models including patient derived tumor cells and a disseminated AML xenograft model, will also be presented in an investigator poster presentation (abstract #1645).

Finally, data on agents which use ImmunoGen’s maytansinoid ADC technology, including IMGN529, will also be presented.

Early development
Researchers at Sutro Biopharma and Celgene, present early development and pre-clinical data for SP7676 and SP7675 (STRO-001), antibody-drug conjugates comprised of an anti-CD74 human IgG1 antibody (SP7219) using novel Fab-based ribosome display methods and conjugated to non-cleavable DBCO-maytansinoid linker-payload with an average drug-antibody ratios (DAR) of 2. These novel CD74-targeting ADCs demonstrate significant, potent, cell activity in multiple B-cell tumor lines in vitro, and anti-tumor activity in preclinical multiple myeloma cell lines and xenograft models (abstract #4465).

Trainee Abstracts
During the annual meeting, the American Society of Hematology also recognize a number of trainees with the highest-scoring abstracts in the categories of undergraduate student, medical student, graduate student, resident physician, and postdoctoral fellow.

“I am delighted to recognize these talented early-career researchers for their outstanding contributions to the study of hematology,” Abrams, the 2016 President of the American Society of Hematology explained.

“These individuals are shining examples of the promise of the next generation of scientists, and I am pleased that ASH provides the opportunity for rising stars to gain recognition by presenting their work in front of thousands of their distinguished colleagues from all over the world,” Abrams concluded.

Based on the preliminary announcements, this year, the annual meeting of the American Society of Hematology will indeed offer exciting data of ADC in the clinic as well as early and pre-clinical data showing great promise for the ongoing, successful, development of novel, innovative agents.

For an overview of oral and poster presentations presented at the 58th Annual Meeting of the American Society of Hematology, click here.


Last Editorial Review: November 22, 2016

Featured Image: Blood Courtesy: © Fotolia. Used with permission.

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