More than 50 monoclonal antibodies (mAbs), including several antibody-drug conjugates, are in advanced clinical development, forming an important part of the many molecularly targeted anticancer therapeutics currently in development. Drug development is a relatively slow and expensive process, limiting the number of drugs that can be brought into late-stage trials. Development decisions could benefit from quantitative biomarkers, enabling visualization of the tissue distribution of (potentially modified) therapeutic mAbs to confirm effective whole-body target expression, engagement, and modulation and to evaluate heterogeneity across lesions and patients. Such biomarkers may be realized with positron emission tomography imaging of radioactively labeled antibodies, a process called immunoPET. This approach could potentially increase the power and value of early trials by improving patient selection, optimizing dose and schedule, and rationalizing observed drug responses. In this review, we summarize the available literature and the status of clinical trials regarding the potential of immunoPET during early anticancer drug development.
© 2015 by American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper).

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On April 20, 2016 Emergent BioSolutions Inc. (NYSE:EBS) reported that it presented preclinical data on its bispecific ADAPTIRTM (modular protein technology) molecule, ES425, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, Louisiana. The ES425 molecule is being developed as a potential therapeutic for triple-negative breast cancer (TNBC) (Press release, Emergent BioSolutions, APR 20, 2016, View Source;p=RssLanding&cat=news&id=2158702 [SID:1234511142]). This product candidate was constructed using the ADAPTIR platform technology and will be further developed by Emergent’s planned spin-off company Aptevo Therapeutics.

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ES425 is a bispecific immunotherapeutic protein that redirects T-cell cytotoxicity to tumor cells expressing ROR1 (receptor tyrosine kinase-like orphan receptor 1), an oncofetal antigen expressed on TNBC and other solid tumor and hematologic malignancies.
The presentation, "Anti-ROR1 x Anti-CD3 ADAPTIRTM Molecule, ES425, Redirects T-Cell Cytotoxicity and Inhibits Tumor Growth in Preclinical Models of Triple-Negative Breast Cancer," shared results of preclinical studies examining in vitro and in vivo activity of ES425. Results showed that ES425 efficiently redirected T-cell cytotoxicity against ROR1(+) cell lines at low picomolar concentrations in vitro. T cells were activated and proliferated in response to ES425 in the presence of ROR1(+) target cells. In vivo, pharmacokinetic analysis showed inhibition of tumor growth and an improvement in overall survival in preclinical models of TNBC.

"The encouraging preclinical data demonstrate that ES425 effectively redirects T-cell cytotoxicity in preclinical TNBC models and merits investigation as a potential therapeutic in TNBC and other malignancies," said Scott C. Stromatt, M.D., chief medical officer of Emergent BioSolutions. "Effective treatment of metastatic, triple-negative breast cancer remains a highly unmet medical need and we look forward to continuing development of this molecule to enable filing an Investigational New Drug application in the next year."

About the ADAPTIR Platform

ADAPTIR bispecific proteins are modular, single chain polypeptides that are comprised of two separate binding domains, a hinge segment, and an effector domain. They have a differentiated structure from monoclonal antibodies and can generate a unique signaling response. Some ADAPTIR molecules may mediate T-cell cytotoxicity by redirecting T cells against tumor cells and some by targeted cytokine delivery. In addition, other ADAPTIR proteins may mediate complement dependent cytotoxicity and Fc dependent cytotoxicity, similar to monoclonal antibodies. ADAPTIR and any and all Emergent BioSolutions Inc. brand, product, service and feature names, logos, and slogans are trademarks or registered trademarks of Emergent BioSolutions Inc. or its subsidiaries in the United States or other countries. All rights reserved.

Joint modelling of longitudinal and survival data is increasingly used in clinical trials on cancer. In prostate cancer for example, these models permit to account for the link between longitudinal measures of prostate-specific antigen (PSA) and time of clinical recurrence when studying the risk of relapse. In practice, multiple types of relapse may occur successively. Distinguishing these transitions between health states would allow to evaluate, for example, how PSA trajectory and classical covariates impact the risk of dying after a distant recurrence post-radiotherapy, or to predict the risk of one specific type of clinical recurrence post-radiotherapy, from the PSA history. In this context, we present a joint model for a longitudinal process and a multi-state process, which is divided into two sub-models: a linear mixed sub-model for longitudinal data and a multi-state sub-model with proportional hazards for transition times, both linked by a function of shared random effects. Parameters of this joint multi-state model are estimated within the maximum likelihood framework using an EM algorithm coupled with a quasi-Newton algorithm in case of slow convergence. It is implemented under R, by combining and extending mstate and JM packages. The estimation program is validated by simulations and applied on pooled data from two cohorts of men with localized prostate cancer. Thanks to the classical covariates available at baseline and the repeated PSA measurements, we are able to assess the biomarker’s trajectory, define the risks of transitions between health states and quantify the impact of the PSA dynamics on each transition intensity. Copyright © 2016 John Wiley & Sons, Ltd.
Copyright © 2016 John Wiley & Sons, Ltd.

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On April 20, 2016 Genmab A/S (Nasdaq Copenhagen: GEN) reported that two daratumumab abstracts have been accepted for presentation at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, June 3 — 7 (Press release, Genmab, APR 20, 2016, View Source [SID:1234511144]). The titles of the abstracts are available on the ASCO (Free ASCO Whitepaper) website at www.asco.org via ASCO (Free ASCO Whitepaper)’s iPlanner. With the exception of the daratumumab Phase III Castor study data, which has been designated as a late breaking abstract by ASCO (Free ASCO Whitepaper), the full abstracts are scheduled to be published on the ASCO (Free ASCO Whitepaper) website on May 18 at 5:00PM EDT.

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Daratumumab Phase III Castor Study Data
Safety and efficacy data from the Phase III study of daratumumab in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma will be presented in the Plenary Session at the ASCO (Free ASCO Whitepaper) meeting on June 5. A total of 498 patients with relapsed or refractory multiple myeloma were enrolled in the study. The study met the primary endpoint of improving progression free survival (PFS); Hazard Ratio (HR) = 0.39, p<0.0001. The median PFS for patients treated with daratumumab has not been reached, compared to median PFS of 7.2 months for patients who did not receive daratumumab.

Daratumumab showed a manageable safety profile in the study consistent with the reported safety profile of monotherapy and background bortezomib/dexamethasone therapy.

As announced on March 30, 2016 an Independent Data Monitoring Committee recommended stopping the study as the primary endpoint had been reached at the time of the pre-specified interim analysis. Patients originally assigned to the bortezomib plus dexamethasone treatment group will be offered the option of receiving daratumumab following confirmed disease progression. Patients continue to be monitored for safety and overall survival.

Abstract details: Phase 3 randomized controlled study of daratumumab, bortezomib and dexamethasone (DVd) vs bortezomib and dexamethasone (Vd) in patients (pts) with relapsed or refractory multiple myeloma (RRMM): CASTOR study— Abstract # LBA4, Oral presentation, Sunday, June 5 at 3:10PM-3:25PM CDT

This abstract has been designated a late breaking abstract and the embargo will be lifted on Sunday, June 5 at 6:30AM CDT.
"ASCO is one of the premier medical conferences of the year and we are very pleased that highly impressive data with one of our key programs, daratumumab, will be presented again this year," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

List of Further Abstracts to Be Presented

Daratumumab
An open-label, dose-escalation Phase 1b study of subcutaneous daratumumab with recombinant human hyaluronidase in patients with relapsed or refractory multiple myeloma (PAVO) — Abstract # 333b, Trials in progress poster presentation, Monday, June 6 at 8:00AM -11.30AM CDT
The study described in this abstract is ongoing.

About DARZALEX (daratumumab)
DARZALEX (daratumumab) injection for intravenous infusion is indicated in the United States for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.1 DARZALEX is the first monoclonal antibody (mAb) to receive U.S. Food and Drug Administration (FDA) approval to treat multiple myeloma. For more information, visit www.DARZALEX.com.

Daratumumab is a human IgG1k monoclonal antibody (mAb) that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. It is believed to induce rapid tumor cell death through programmed cell death, or apoptosis,1,2 and multiple immune-mediated mechanisms, including complement-dependent cytotoxicity,1,2 antibody-dependent cellular phagocytosis3,4 and antibody-dependent cellular cytotoxicity.1,2 In addition, daratumumab therapy results in a reduction of immune-suppressive myeloid derived suppressor cells (MDSCs) and subsets of regulatory T cells (Tregs) and B cells (Bregs), all of which express CD38. These reductions in MDSCs, Tregs and Bregs were accompanied by increases in CD4+ and CD8+ T cell numbers in both the peripheral blood and bone marrow.1

Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license to develop, manufacture and commercialize daratumumab from Genmab. Five Phase III clinical studies with daratumumab in relapsed and frontline settings are currently ongoing, and additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant diseases on which CD38 is expressed, such as smoldering myeloma, non-Hodgkin’s lymphoma and a solid tumor indication.

On April 20, 2016 Kolltan Pharmaceuticals, Inc., a privately held clinical-stage company focused on the discovery and development of novel antibody-based drugs targeting receptor tyrosine kinases (RTKs) for use in oncology and immunology, reported the presentation of preclinical data relating to its KTN0158 drug development program at the AACR (Free AACR Whitepaper) Annual Meeting, taking place in New Orleans, Louisiana, April 16-20, 2016 (Press release, Kolltan Pharmaceuticals, APR 20, 2016, View Source [SID:1234511162]). KTN0158 is a proprietary, clinical-stage, humanized anti-KIT IgG1 monoclonal antibody drug candidate that selectively and potently inhibits KIT and is being developed as a potential therapy for cancer and mast cell-related diseases.

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"The compelling preclinical data that were presented at AACR (Free AACR Whitepaper) support our plans to evaluate KTN0158 in combination with T-cell checkpoint inhibitors in the clinic near-term. This expands our current clinical focus beyond gastrointestinal stromal tumors (GIST) and further broadens the opportunity to investigate the treatment of cancer patients through targeting KIT, with potential to affect immunosuppressive mast cells and myeloid cells. Developing innovative biologics with a focus on RTKs expressed on innate immune cells is an exciting new area for Kolltan with KTN0158 in clinical development," stated Gerald McMahon, Ph.D., President and Chief Executive Officer of Kolltan.

Rich Gedrich, Ph.D., Senior Director of Translational Medicine of Kolltan, added, "KTN0158 represents a novel approach to inhibit KIT on tumor cells by blocking the dimerization of the receptor through an allosteric mechanism. Previous preclinical data have shown significant anti-tumor activity in KIT-driven tumors such as GIST, targeted in our Phase 1 trial of KTN0158, and now the current findings in combination with anti-PD-1 and anti-CTLA4 antibodies support a second distinct approach to develop KTN0158 as an anti-cancer therapy."

Following are the key data and results from the two presentations at AACR (Free AACR Whitepaper) relating to KTN0158:
On Sunday, April 17, KTN0158 was highlighted as a novel experimental treatment approach for GIST in an oral presentation titled "Experimental Treatment Options for Gastrointestinal Stromal Tumors with Primary or Secondary Resistance to Tyrosine Kinase Inhibitors". The presentation reviewed previously disclosed preclinical data including:

An overview of KTN0158’s unique mechanism of action which inhibits KIT activation by blocking receptor dimerization; and
The preclinical activity of KTN0158 in GIST models with activating KIT mutations and also activity in dogs with spontaneous mast cell tumors driven by KIT activation.

On Tuesday, April 19, "Inhibition of KIT In Vivo Modifies Immune Cell Populations to Improve the Efficacy of Checkpoint Inhibitors in Syngeneic Mouse Tumor Models" (Abstract Number 4020), was presented in a poster session.

The poster presentation reported the following data and results:

Enhanced anti-tumor activity with the combination of a surrogate mouse anti-KIT monoclonal antibody with either anti-PD-1 or anti-CTLA4 monoclonal antibodies in several syngeneic mouse tumor models; and

Mechanistic studies showed a significant decrease in monocytic myeloid-derived suppressor cells (mMDSCs) in the tumor and in the spleen of the anti-KIT antibody treated groups. High levels of circulating mMDSCs have been associated with reduced survival in melanoma patients treated with ipilimumab or nivolumab.

The poster is available on the Kolltan website.

About KTN0158

KTN0158 is a proprietary, humanized monoclonal antibody designed using structure-based approaches to block the activation of KIT, an RTK that is expressed on many cancers and mast cells. There are currently no KIT-targeting antibodies on the market for any disease indication. In oncology, KIT is expressed in tumors such as GIST, melanoma, acute myeloid leukemia (AML), small cell lung cancer (SCLC), and others. Additionally, KIT is expressed in immune suppressive cells in the tumor microenvironment and thus may provide a novel combination treatment for immuno-oncology. Kolltan has initiated a Phase 1 study for the treatment of GIST and other KIT-expressing tumors (NCT02642016) and plans to move into combination studies with other targeted therapies and T cell checkpoint inhibitors.