publication date: Apr. 6, 2018

Drugs and Targets

EC expands  XGEVA indications for prevention of skeletal events in multiple myeloma

European Commission has approved an expanded indication for XGEVA (denosumab) for the prevention of skeletal-related events in adults with advanced malignancies involving bone.

The indication now covers patients with bone metastases from solid tumors and those with multiple myeloma. The approval is based on data from the phase III ‘482 study, the largest international trial ever conducted for the prevention of skeletal-related events in multiple myeloma patients.

XGEVA is sponsored by Amgen Inc.

In the ‘482 study, XGEVA met the primary endpoint, demonstrating non-inferiority to zoledronic acid in delaying the time to first on-study skeletal-related event in patients with multiple myeloma (HR=0.98, 95 percent CI: 0.85-1.14).

The median time to first on-study skeletal-related event was 22.8 months for XGEVA and 24.0 months for zoledronic acid. The safety profile was consistent with known adverse events of XGEVA.

XGEVA is the first fully human monoclonal antibody that binds to and neutralizes RANK ligand, a protein essential for the formation, function and survival of osteoclasts, thereby inhibiting osteoclast-mediated bone destruction.

On Jan. 5, FDA approved the supplemental Biologics License Application for XGEVA to expand the currently approved indication for the prevention of skeletal-related events in patients with bone metastases from solid tumors to include patients with multiple myeloma.

Additional regulatory applications for XGEVA for the prevention of skeletal-related events in patients with multiple myeloma are underway and have been submitted to health authorities worldwide.

The ‘482 study was an international, phase III, randomized, double-blind, multicenter trial of XGEVA compared with zoledronic acid in the prevention of skeletal-related events in adult patients with newly diagnosed multiple myeloma and bone disease.

In the study, a total of 1,718 patients (859 on each arm) were randomized to receive either subcutaneous XGEVA 120 mg and intravenous placebo every four weeks, or intravenous zoledronic acid 4 mg (adjusted for renal function at baseline) and subcutaneous placebo every four weeks, plus investigators’ choice first-line antimyeloma therapy.

Skeletal surveys using conventional radiography were obtained every 12 to 24 weeks per protocol. The primary endpoint of the study was non-inferiority of XGEVA versus zoledronic acid with respect to time to first on-study skeletal-related event (pathologic fracture, radiation to bone, surgery to bone or spinal cord compression).

Secondary endpoints included superiority of XGEVA versus zoledronic acid with respect to time to first on-study skeletal-related event and first-and-subsequent on-study skeletal-related event and evaluation of overall survival.

Progression-free survival was a prespecified, exploratory endpoint and was not powered for statistical significance. The secondary endpoints, delaying time to first skeletal-related event and delaying time to first-and-subsequent skeletal-related events, did not demonstrate superiority.

Overall survival was comparable between XGEVA and zoledronic acid, with a hazard ratio of 0.90 (95 percent CI: 0.70, 1.16). Median progression-free survival was 46.1 months (95 percent CI: 34.3 months, not estimable, n=219) for XGEVA and 35.4 months (95 percent CI: 30.2 months, NE, n=260) for zoledronic acid.

The safety and tolerability of XGEVA were also compared with zoledronic acid. The safety profile was consistent with known adverse events of XGEVA. The most common adverse reactions (greater than or equal to 10 percent) were diarrhea, musculoskeletal pain, hypocalcaemia, and dyspnea.


NCI launches resource for specimens and data from clinical trials

NCI has launched a resource for cancer researchers interested in conducting studies using specimens and clinical data collected from cancer treatment trials in NCI’s National Clinical Trials Network and former NCI Cooperative Group Program.

Known as NCTN Navigator, the resource includes information about specimens, such as tumor and blood samples, donated by patients in NCI-sponsored clinical trials. The clinical trials included in Navigator are published phase 3 studies that evaluated cancer treatments.

Investigators can use the NCTN Navigator website Exit Disclaimer to search the inventory for specimens with specific characteristics. Investigators who develop proposals and get approval can use the specimens, along with the trial participants’ clinical information, in their research.

NCI has supported large cancer treatment trials for decades through what is now the NCTN. For many of the trials, donated specimens were collected and stored in NCI-funded specimen banks. The clinical data from the trials include detailed information about patient responses to treatments and their outcomes.

The NCTN Navigator inventory includes data from more than 80 trials, 50,000 patients, and 600,000 specimens.

Although the researchers who conducted these clinical trials have long been using the specimens and clinical data in studies, Navigator will now make the materials available to any investigators who submit research proposals that are approved by a scientific review board.

To ensure the optimal use of the resources in Navigator, the scientific review committee will consider the importance of a proposed project with the value of the specimens in mind.

In general, successful Navigator proposals will use the specimens and data to test a research question that builds on prior knowledge and has potential clinical implications, noted Mishkin. The specimens in Navigator will generally not be appropriate for studies that are more exploratory in nature, she added.

Before developing or submitting a research proposal to the Navigator program, investigators can perform searches on the program’s website to ensure there are specimens and related data to meet their research needs.

If they would then like to move ahead, they can use the website to submit a proposal for how they would like to use the specimens.

There is no charge for the specimens or clinical data in Navigator, but investigators with approved proposals will be responsible for the costs associated with processing and delivering the specimens and clinical data.

Although Navigator currently includes only specimens and information from adults, specimens, and data from patients with pediatric cancers are expected to be added later this year.


Boehringer Ingelheim, OSE collaborate to develop checkpoint inhibitor  

Boehringer Ingelheim and OSE Immunotherapeutics announced a worldwide collaboration and license agreement to jointly develop OSE-172, a SIRP-alpha antagonist targeting myeloid lineage cells.

SIRP-alpha is a receptor expressed by myeloid lineage cells such as dendritic cells, tumor-associated macrophages, and myeloid-derived suppressor cells. In targeting SIRP- alpha, OSE-172 prevents the ligand CD47 from binding to and triggering the cellular inhibitory effects of SIRP-alpha.  

OSE-172 has the potential to enhance anti-tumor immunity by improving T cell activity through enhancement of DC antigen presentation functionality, potentiating the phagocytic and inflammatory properties of macrophages in the tumor microenvironment and enabling differentiation of MDSCs to an effector state.

Boehringer Ingelheim has acquired the global rights to develop, register, and commercialize OSE-172, a monoclonal antibody targeting SIRP-alpha which is expressed in myeloid lineage cells, as part of their continued commitment to research and innovation in immuno-oncology.

Under the agreement, OSE Immunotherapeutics will receive a €15 million upfront payment from Boehringer Ingelheim, and potential additional short-term milestones of up to €15 million upon initiation of a phase 1 clinical study. OSE Immunotherapeutics stands to receive more than €1.1 billion upon reaching pre-specified development, commercialization and sales milestones, plus royalties on worldwide net sales.

Neoepitopes innovation (Tedopi) is in phase III in advanced lung cancers after checkpoint inhibitors failure (anti PD-1 and anti PD-L1). An option to license was exercised in July 2016 by Janssen Biotech to continue clinical development of FR104 (an anti CD28 mAb) in auto-immune diseases after positive phase I results.

A two-step license option was signed in 2017 with Servier Laboratories to develop OSE-127 (Effi-7) up to the completion of a phase 2 clinical trial planned in autoimmune bowel disease and Sjogren’s syndrome.

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