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FDA Pipeline: Treatments for Tenosynovial Giant Cell Tumor and Pancreatic Cancer, Plus a Statement on Breast Implant–Associated Lymphoma

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The U.S. Food and Drug Administration (FDA) recently granted the following designations and applications and also issued a statement:

Priority Review for Pexidartinib in Tenosynovial Giant Cell Tumor

The FDA has accepted a new drug application (NDA) and granted Priority Review for pexidartinib for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT), which is associated with severe morbidity or functional limitations, and which is not amenable to improvement with surgery. The FDA has designated August 3, 2019, as the Prescription Drug User Fee Act (PDUFA) action date for the pexidartinib application.

Also referred to as pigmented villonodular synovitis (PVNS) or giant cell tumor of the tendon sheath (GCT-TS), TGCT is a nonmalignant tumor of the joint or tendon sheath, which can be locally aggressive and debilitating in some patients. There are no currently approved systemic therapies for TGCT.

Pexidartinib is an investigational, novel, oral small molecule that potently inhibits CSF1R (colony stimulating factor-1 receptor), which is a primary growth driver of abnormal cells in the synovium that cause TGCT. The drug also inhibits c-kit and FLT3-ITD.    

The NDA is based on results of the pivotal phase III ENLIVEN study of oral pexidartinib, the first placebo-controlled study of a systemic investigational therapy in patients with TGCT. Results of the ENLIVEN study were presented at the 2018 ASCO Annual Meeting (Abstract 11502).

ENLIVEN was a pivotal, double-blind, randomized, global multicenter trial that evaluated pexidartinib in patients with symptomatic advanced TGCT for whom surgical removal of the tumor would be associated with potentially worsening functional limitation or severe morbidity. The first part of the study, the double-blind phase, enrolled 120 patients who were randomly assigned 1:1 to receive either pexidartinib or placebo at 1,000 mg/d for 2 weeks followed by 800 mg/d for 22 weeks to evaluate the efficacy and safety of pexidartinib vs placebo.

The primary endpoint of the ENLIVEN study was the percentage of patients achieving a complete or partial response after 24 weeks of treatment (week 25), as assessed with centrally read magnetic resonance imaging scans using Response Evaluaton Criteria in Solid Tumors, version 1.1. Key secondary endpoints included range of motion, response by tumor volume score, PROMIS physical function, stiffness, and measures of pain reduction.

On January 31, ASCO recognized progress in treating rare cancers as the ‘Advance of the Year,’ and selected pexidartinib as one of five significant advancements in rare disease treatment, calling it the first promising investigational therapy for TGCT. 

ODD for BL-8040 in Pancreatic Cancer

The FDA has granted Orphan Drug designation to BL-8040 for the treatment of pancreatic cancer.

BL-8040 is a short synthetic peptide for the treatment of hematological malignancies, solid tumors, and stem cell mobilization. It functions as a high-affinity best-in-class antagonist for CXCR4, a chemokine receptor that is directly involved in tumor progression, angiogenesis, metastasis, and cell survival. CXCR4 is overexpressed in many human cancers and its expression often correlates with disease severity. In a number of clinical and preclinical studies, BL-8040 has shown robust mobilization of cancer cells and immune cells, sensitization of cancer cells to chemo- and bio-based anticancer therapies, and direct anticancer effect by inducing apoptosis.

BL-8040 is currently being investigated in clinical studies for the treatment of pancreatic cancer under two separate immuno-oncology collaborations.

Orphan Drug Designations for Itolizumab for Prevention and Treatment of Acute Graft-vs-Host Disease

The FDA has granted Orphan Drug designations for itolizumab for both the prevention and treatment of acute graft-vs-host disease.

Itolizumab is a clinical-stage, first-in-class monoclonal antibody that selectively targets the novel immune checkpoint receptor CD6. CD6 plays a central role in modulating the activation, proliferation, differentiation, and trafficking of Teff cells that drive a number of immunoinflammatory diseases.

The phase Ib/II EQUATE clinical trial (NCT 03763318) in set to launch in early 2019, which will evaluate EQ001 in combination with corticosteroids for the initial treatment of patients presenting with acute graft-vs-host disease.

IND Application for Cell Therapy Derived From an Engineered Pluripotent Stem Cell

The FDA has allowed an investigational new drug (IND) application for FT516, an off-the-shelf natural killer (NK) cell product candidate derived from a clonal master-induced pluripotent stem cell (iPSC) line engineered to express a novel CD16 Fc receptor. FT516 is the first-ever cell therapy derived from a genetically engineered pluripotent stem cell cleared for clinical testing in the world. Clinical testing of FT516 is to be initiated in patients with certain relapsed/refractory hematologic malignancies, including acute myelogenous leukemia as a monotherapy, non-Hodgkin's lymphoma in combination with rituximab, and multiple myeloma in combination with elotuzumab.

CD16 is naturally expressed on NK cells and mediates antibody-dependent cellular cytotoxicity (ADCC), a potent immune mechanism through which NK cells can recognize, bind, and kill antibody-coated cancer cells. ADCC is an underlying mechanism associated with the clinical efficacy of many monoclonal antibodies that are approved for the treatment of various cancers, including hematologic malignancies and solid tumors. The expression of CD16 on NK cells can undergo considerable downregulation in patients with cancer, which significantly inhibits the immune system’s antitumor response. FT516 incorporates a novel CD16 Fc receptor, which has been modified to prevent its downregulation and to augment its binding to tumor-targeting antibodies, for enhanced ADCC.

Statement from FDA’s Center for Devices and Radiological Health on Known Risk of Lymphoma From Breast Implants

Binita Ashar, MD, a general surgeon and Director of the Division of Surgical Devices in the FDA’s Center for Devices and Radiological Health, recently issued the following statement:

One of the most important roles we have as a public health agency is educating patients and health-care providers about both the benefits and risks of medical products, including breast implants.

I know there are many choices of breast implants available to patients, including the size, implant fill, and surface texture. We want to provide patients with the most up-to-date information about the variety of breast implants available so that patients and providers can have thorough and thoughtful discussions weighing the benefits and risks of different products. We also want to be transparent in sharing the information we regularly gather and analyze in a way that provides important context to help inform these discussions.

…We are providing an update regarding the number of cases of breast implant–associated anaplastic large cell lymphoma (BIA-ALCL), a type of non-Hodgkin's lymphoma and a known risk from breast implants. In 2011, the FDA was the first public health agency in the world to communicate about the risks of BIA-ALCL, warning women that the available information at the time indicated that there is a risk for women with breast implants for developing this disease. Since then, we have regularly updated the information available on our website regarding known BIA-ALCL cases, including deaths and known risks.

We hope that this information prompts providers and patients to have important, informed conversations about breast implants and the risk of BIA-ALCL. At the same time, we remain committed to working in partnership with all stakeholders to continue to study, understand, and provide updates about this important public health issue.

Today, the agency is providing an updated number of medical device reports (MDRs), also known as adverse event reports. After a thorough data analysis, we are reporting that, as of September 2018, the agency has received a total of 660 total medical device reports regarding BIA-ALCL cases in the U.S. since 2010. Of the 660 MDRs, our in-depth analysis suggests that there are 457 unique cases of BIA-ALCL, including 9 patient deaths.

We understand that the information presented shows an increase of 246 new MDRs since last year. Given the agency’s continued efforts to communicate with stakeholders about BIA-ALCL risks and our work to encourage patients and providers to file MDRs with the agency, these types of increases in the MDRs are to be expected and may include past cases that were not previously reported to the FDA. The increased number of MDRs contributes to our evolving understanding of BIA-ALCL and represents a more thorough and comprehensive analysis.

The number of unique cases is lower than the total number of reports because the FDA’s medical device reporting system allows patients, providers, and manufacturers to each file their own reports even if it’s about the same case, which can lead to duplicative reports of BIA-ALCL. Through our review of each report, our team of experts works to remove duplicative information and analyze the data provided to help better understand what these reports may or may not tell us about the benefits and risks of the device. For example, our analysis of these reports is better when there is a wide-range of information provided concerning the breast implant texture and implant fill, and other helpful details like a patient’s age, how long a patient has been implanted, and time from implantation to diagnosis. This information helps us understand how and why this lymphoma may be occurring. Unfortunately, not every report provides thorough information about each case, including what type of breast implant (eg, surface texture) the patient received, which makes it more difficult to know if any particular breast implant characteristic is associated with BIA-ALCL or if higher reports of BIA-ALCL are simply due to higher implantation rate of a particular manufacturer. In the interest of transparency, on our webpage, we provide a breakdown of the data and an analysis of that information that was provided to the agency.

For patients, we know the information regarding breast implants can be overwhelming, which is why we are committed to continuing our efforts to provide up-to-date publicly available resources to help understand the known benefits and risks of implants. We encourage patients to review our website and read specific device labeling, including patient labeling information, for any product they may consider implanting. Choosing to obtain a breast implant is a very personal decision that patients and their providers should make based on individual needs and with the most complete information about products.

We are also aware that our counterparts in different countries are taking certain actions or may be reporting different information about breast implant safety than the FDA. The different devices approved in each country, availability of products, variation in market share, extent of medical device adverse event reporting, and availability of information regarding the total number of implants sold differs from country to country. This makes it difficult for the regulatory bodies of different countries to compare data and determine risk rates on a global scale.

We recognize the limitations of medical device reports, which is why we review other sources of information, including medical literature and the Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma Etiology and Epidemiology (PROFILE). PROFILE collects real-world data regarding patients who have a confirmed diagnosis of BIA-ALCL. Our participation in this registry reflects the FDA’s commitment to implementing our Medical Device Safety Action Plan, in which we are streamlining and modernizing how we implement postmarket actions to address device safety issues to make our responses to risks more timely and effective.

In addition to updating our medical device reports, we are issuing today a Letter to Health Care Providers to encourage those who regularly treat patients, including primary care physicians and gynecologists, to learn about BIA-ALCL in patients with breast implants. We want to ensure that all providers who treat patients with breast implants have information regarding identification, diagnosis, and treatment. Patients are more likely to seek routine care from primary care physicians, gynecologists, and others besides their treating plastic surgeon. By providing information to health-care providers, we believe more providers will be empowered with information to assist patients who may have BIA-ALCL. We also encourage patients and providers to file medical device reports with the FDA via MedWatch, the FDA Safety Information and Adverse Event Reporting program.

The FDA remains committed to thoughtful, scientific and transparent, public dialogue concerning breast implant safety and effectiveness. We know BIA-ALCL will be one important topic of discussion at the agency’s upcoming public meeting of the General and Plastic Surgery Devices Panel at the FDA’s headquarters in Silver Spring, Maryland March 25–26, 2019. We look forward to engaging with patients, providers, and manufacturers about a range of topics concerning the benefit-risk profile of breast implants in that public forum. The topics we will discuss at this meeting highlight the importance of continuing to monitor, assess, and advance our understanding of breast implant safety. We will publish additional information regarding the meeting agenda on our breast implant webpage soon.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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