Immunotherapies in Genitourinary Oncology: Where Are We Now? Where Are We Going?

For decades, limited options existed to treat metastatic genitourinary cancers, including treatment options that could be classified as immunotherapy. Historically, immunotherapy centered on systemic cytokines for the treatment of metastatic kidney cancer, which had several adverse effects, as well as the Bacillus Calmette–Guérin vaccine for non-metastatic bladder cancer. Within the past decade, advances in immunotherapy have led to several approvals from the United States Food and Drug Administration, particularly in the field of immune checkpoint inhibition. Immune checkpoint inhibitors (ICIs) are now being used extensively to treat multiple solid tumors, including kidney and bladder cancers, and they are also being tested in many other cancers. Despite encouraging data from phase 2/3 clinical trials, less is known about biomarkers that may predict better response to ICIs. The effect of ICIs in genitourinary cancers is heterogeneous, with some tumor types having little clinical data available, or ICIs having limited activity in other tumors. In this review, we briefly discuss approved immunotherapy agents prior to the time of ICIs. Then, given the emergence of this class of agents, we summarize the several important ICIs and the clinical trials that led to their approval. Finally, we mention ongoing and future clinical trials.

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Emerging treatment options for patients with high-risk myelodysplastic syndrome

Therapeutic Advances in Hematology ◽

10.1177/2040620720955006 ◽

2020 ◽

Vol 11 ◽

pp. 204062072095500

Author(s):

Jan Philipp Bewersdorf ◽

Hetty Carraway ◽

Thomas Prebet

Keyword(s):

Checkpoint Inhibitors ◽

Treatment Options ◽

The United States ◽

Driver Mutations ◽

Hematopoietic Stem ◽

Oral Agents ◽

United States Food ◽

Risk Of Progression ◽

Variable Success ◽

States Food

Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis with peripheral blood cytopenias, dysplastic cell morphology, and a variable risk of progression to acute myeloid leukemia (AML). The hypomethylating agents (HMA) azacitidine and decitabine have been used for over a decade in MDS treatment and lead to a modest survival benefit. However, response rates are only around 40% and responses are mostly transient. For HMA-refractory patients the prognosis is poor and there are no therapies approved by the United States Food and Drug Administration. Combinations of HMAs, especially along with immune checkpoint inhibitors, have shown promising signals in both the frontline and HMA-refractory setting. Several other novel agents including orally available and longer acting HMAs, the BCL-2 inhibitor venetoclax, oral agents targeting driver mutations ( IDH1/2, FLT3), immunotherapies, and new options for intensive chemotherapy have been studied with variable success and will be reviewed herein. Except for the minority of patients with targetable driver mutations, HMAs – likely as part of combination therapies – will remain the backbone of frontline MDS treatment. However, the wider use of genetic testing may enable a more targeted and individualized therapy of MDS patients.

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Advances in drug development for hepatocellular carcinoma: clinical trials and potential therapeutic targets

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01968-w ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Xiang-Yuan Luo ◽

Kong-Ming Wu ◽

Xing-Xing He

Keyword(s):

Hepatocellular Carcinoma ◽

Clinical Trials ◽

Checkpoint Inhibitors ◽

The United States ◽

New Drugs ◽

Clinical Phase ◽

United States Food ◽

Fundamental Research ◽

States Food ◽

Health Burdens

AbstractAlthough hepatocellular carcinoma (HCC) is one of the deadliest health burdens worldwide, few drugs are available for its clinical treatment. However, in recent years, major breakthroughs have been made in the development of new drugs due to intensive fundamental research and numerous clinical trials in HCC. Traditional systemic therapy schemes and emerging immunotherapy strategies have both advanced. Between 2017 and 2020, the United States Food and Drug Administration (FDA) approved a variety of drugs for the treatment of HCC, including multikinase inhibitors (regorafenib, lenvatinib, cabozantinib, and ramucirumab), immune checkpoint inhibitors (nivolumab and pembrolizumab), and bevacizumab combined with atezolizumab. Currently, there are more than 1000 ongoing clinical trials involving HCC, which represents a vibrant atmosphere in the HCC drug research and development field. Additionally, traditional Chinese medicine approaches are being gradually optimized. This review summarizes FDA-approved agents for HCC, elucidates promising agents evaluated in clinical phase I/II/III trials and identifies emerging targets for HCC treatment. In addition, we introduce the development of HCC drugs in China. Finally, we discuss potential problems in HCC drug therapy and possible future solutions and indicate future directions for the development of drugs for HCC treatment.

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New drug developments in metastatic gastric cancer

Therapeutic Advances in Gastroenterology ◽

10.1177/1756284818808072 ◽

2018 ◽

Vol 11 ◽

pp. 175628481880807 ◽

Cited By ~ 6

Author(s):

Aaron C. Tan ◽

David L. Chan ◽

Wasek Faisal ◽

Nick Pavlakis

Keyword(s):

Gastric Cancer ◽

Clinical Trials ◽

Targeted Therapies ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Predictive Biomarkers ◽

Metastatic Gastric Cancer ◽

New Era

Metastatic gastric cancer is associated with a poor prognosis and novel treatment options are desperately needed. The development of targeted therapies heralded a new era for the management of metastatic gastric cancer, however results from clinical trials of numerous targeted agents have been mixed. The advent of immune checkpoint inhibitors has yielded similar promise and results from early trials are encouraging. This review provides an overview of the systemic treatment options evaluated in metastatic gastric cancer, with a focus on recent evidence from clinical trials for targeted therapies and immune checkpoint inhibitors. The failure to identify appropriate predictive biomarkers has hampered the success of many targeted therapies in gastric cancer, and a deeper understanding of specific molecular subtypes and genomic alterations may allow for more precision in the application of novel therapies. Identifying appropriate biomarkers for patient selection is essential for future clinical trials, for the most effective use of novel agents and in combination approaches to account for growing complexity of treatment options.

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Immunotherapy in Hepatocellular Carcinoma: Is There a Light at the End of the Tunnel?

Cancers ◽

10.3390/cancers11081078 ◽

2019 ◽

Vol 11 (8) ◽

pp. 1078 ◽

Cited By ~ 11

Author(s):

Amit Mahipal ◽

Sri Harsha Tella ◽

Anuhya Kommalapati ◽

Alexander Lim ◽

Richard Kim

Keyword(s):

Hepatocellular Carcinoma ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Primary Liver Cancer ◽

Progression Free Survival ◽

The United States ◽

Hepatic Reserve ◽

Dismal Prognosis ◽

United States Food

Hepatocellular carcinoma (HCC) is the most common primary liver cancer with dismal prognosis when diagnosed at advanced stages. Surgical resection of the primary tumor or orthotropic liver transplantation serves as a potential curative option. However, this approach is highly dependent on the hepatic reserve and baseline functional status of the patient. Liver directed therapies such as portal vein embolization (PVE), trans-arterial chemoembolization (TACE), and systemic chemotherapy are employed in non-surgical candidates. Sorafenib was the only approved systemic therapeutic agent for almost a decade until the recent approval of lenvatinib by the United States Food and Drug Administration (FDA) as an alternate first-line agent. Regorafenib, nivolumab, pembrolizumab and cabozantinib are approved by the FDA as second-line agents in patients who failed or could not tolerate sorafenib. Ramucirumab was recently FDA approved for the subset of patients that have high alfa-fetoprotein levels (>400 ng/mL). A better understanding of tumorigenesis and encouraging clinical trial results that evaluated immune-checkpoint inhibitors opened doors for immunotherapy in HCC. Immune checkpoint inhibitors have demonstrated a prolonged median overall and progression-free survival in a subset of patients with HCC. On-going translational and clinical research will hopefully provide us with a better understanding of tumor markers, genetic aberrations and other factors that determine the immunotherapy response in HCC. In this review, we sought to summarize the potential role and future directions of immunotherapy in the management of HCC.

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Immunmoduláló antitestek alkalmazása – az onkológia új fejezete

Orvosi Hetilap ◽

10.1556/oh.2016.30507 ◽

2016 ◽

Vol 157 (Supplement 2) ◽

pp. 9-16 ◽

Cited By ~ 1

Author(s):

Szilvia Szamosi ◽

László Váróczy ◽

Zoltán Szekanecz

Keyword(s):

Metastatic Melanoma ◽

Immune Checkpoint ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Hematologic Malignancies ◽

The United States ◽

Clinical Development ◽

Clinical Activity ◽

The European Union ◽

Tumor Types

In the past decade major advances in tumor immunology, a better understanding of antigen recognition by T-cells likewise discovering the regulatory inhibitory signals resulted in the development of new immunotherapies with promising durable responses in various solid tumor types and in hematologic malignancies. This review focuses on immunomodulatory antibodies, namely immune checkpoint inhibitor therapy. The prototype of this new class of immune stimulating agents was cytotoxic T-lymphocyte antigen-4 (CTLA-4) antagonists. After demonstrating enhanced survival, ipilimumab was approved first in the United States in 2011, further on in the European Union for second-line (2011) and for first-line therapy (2013) of metastatic melanoma. Additional T-cell intrinsic pathways were identified and targeted for clinical development. Antibodies blocking the PD-1 pathway also showed promising clinical activity and objective tumor response in several types of tumors, including metastatic melanoma, non-small- cell lung cancer. On the other hand antitumor activity is frequently accompanied by significant reversible immune-related adverse events. To explore potential new immune checkpoint targets bring forth several challanges. Future clinical development will involve identifying potential biomarkers anticipating responsiveness to pathway blockade and additional tumor types likely to respond to the therapy. Furthermore, combination strategies, immune checkpoint inhibitors combined with cancer vaccines, targeted inhibitors and traditional chemotherapies are being evaluated in pre-clinical studies. Orv. Hetil., 2016, 157(Suppl. 2), 9–16.

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Placebo Orthodoxy in Clinical Research II: Ethical, Legal, and Regulatory Myths

The Journal of Law Medicine & Ethics ◽

10.1111/j.1748-720x.1996.tb01860.x ◽

1996 ◽

Vol 24 (3) ◽

pp. 252-259 ◽

Cited By ~ 76

Author(s):

Benjamin Freedman ◽

Kathleen Cranley Glass ◽

Charles Weijer

Keyword(s):

Clinical Trials ◽

Clinical Research ◽

The United States ◽

Human Experimentation ◽

Medical Interventions ◽

Placebo Controls ◽

United States Food ◽

Considerable Controversy ◽

States Food ◽

Continued Use

Placebo-controlled trials are held by many, including regulators at agencies like the United States Food and Drug Administration (FDA), to be the gold standard in the assessment of new medical interventions. Yet the use of placebo controls in clinical trials has been the focus of considerable controversy. In this two-part article, we challenge a number of common beliefs concerning the value of placebo controls. Part I critiques statistical and other scientific justifications for the use of placebo controls in clinical research. The continued use of placebo controls in clinical trials on diseases for which accepted treatment exists raises equally important ethical, legal, and regulatory issues for which various justifications have been given. Defense of this practice relies on normative as well as empirical myths.In their attack on the prevailing use of placebo controls, Kenneth Rothman and Karin Michels emphasize that this practice stands in violation of the World Medical Association's guidelines on the ethics of human experimentation, most commonly known as the Helsinki Declaration.

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The United States Food and Drug Administration and Noninferiority Margins in Clinical Trials of Antimicrobial Agents

Clinical Infectious Diseases ◽

10.1086/339072 ◽

2002 ◽

Vol 34 (6) ◽

pp. 879-881 ◽

Cited By ~ 14

Author(s):

John H. Powers ◽

David B. Ross ◽

Erica Brittain ◽

Renata Albrecht ◽

Mark J. Goldberger

Keyword(s):

United States ◽

Clinical Trials ◽

Drug Administration ◽

Antimicrobial Agents ◽

Food And Drug Administration ◽

The United States ◽

United States Food ◽

States Food

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New Treatment Options in Advanced Squamous Cell Lung Cancer

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_237829 ◽

2019 ◽

pp. e198-e206 ◽

Cited By ~ 3

Author(s):

Paul K. Paik ◽

Rathi Narayana Pillai ◽

Christopher S. Lathan ◽

Sylvia A. Velasco ◽

Vassiliki Papadimitrakopoulou

Keyword(s):

Squamous Cell ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Substantial Improvement ◽

Lung Cancers ◽

The Past ◽

New Treatment ◽

Line Setting ◽

Rapid Shift

The past few years have witnessed a rapid shift in the treatments for patients with squamous cell lung cancers (SQCLCs) after the U.S. Food and Drug Administration approval of a number of immune checkpoint inhibitors as second-line therapies for patients with non–small cell lung cancers. These series of approvals marked the first substantial improvement in overall survival for patients with SQCLC in over a decade. Further gains have been made more recently with the incorporation of immune checkpoint inhibition in the first-line setting, either as monotherapy or in combination with chemotherapy. These advances have, however, exposed existing deficiencies in the management of this disease. Despite a deeper understanding of the genomic alterations that characterize SQCLCs and years of trial work targeting these alterations, personalized therapies remain out of hand. Future studies will continue to focus on identifying targeted approaches to expand the treatment options for our patients.

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Checkpoint inhibition in myeloma

Hematology ◽

10.1182/asheducation-2016.1.528 ◽

2016 ◽

Vol 2016 (1) ◽

pp. 528-533 ◽

Cited By ~ 5

Author(s):

Don M. Benson

Keyword(s):

Clinical Trials ◽

Immune System ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Immune Checkpoint Blockade ◽

Checkpoint Inhibition ◽

The Past ◽

Complementary Approach ◽

Fundamental Biology ◽

System Interfaces

Abstract Historically, attempts at cancer immunotherapy have emphasized strategies designed to stimulate or augment the immune system into action. In the past decade, a complementary approach has developed, that of releasing immune cells from inhibitory restraint. Discoveries in the fundamental biology of how immunity is regulated, how the immune system interfaces with malignancy, and how cancer cells may exploit these processes to evade detection have all been translated into the rapidly growing field of therapeutic immune checkpoint inhibition for cancer. Myeloma is a malignancy associated with significant immune dysfunction imparted both by the disease itself as well as by many of the immunosuppressive therapies that have been used in the past. The growing body of preclinical data regarding immunoregulatory mechanisms that appear active in myeloma has begun to be translated to clinical trials targeting these signaling axes. This review will attempt to summarize the current understanding of the basic biology of several immune checkpoint pathways that may be important in myeloma and provide an up-to-date overview of recent and ongoing clinical trials of immune checkpoint inhibitors in myeloma. Finally, several current challenges and possible future directions of immune checkpoint blockade in myeloma will be reviewed.

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Publication statuses of clinical trials supporting immune checkpoint inhibitors recently approved by the United States Food and Drug Administration: A meta-epidemiological investigation.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.8_suppl.89 ◽

2019 ◽

Vol 37 (8_suppl) ◽

pp. 89-89

Author(s):

Kenji Omae ◽

Yuki Kataoka ◽

Yasushi Tsujimoto ◽

Yusuke Tsutsumi ◽

Shunichi Fukuhara ◽

...

Keyword(s):

Clinical Trials ◽

Anticancer Drugs ◽

Drug Administration ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Food And Drug Administration ◽

The United States ◽

Publication Rate ◽

Significant Difference

89 Background: The low trial publication rate for drugs approved by the U.S. Food and Drug Administration (FDA) and the discrepancies between data submitted to the FDA and data found in published trials remain concerning. We investigated the publication statuses of trials of recently approved anticancer drugs documented by the FDA, especially immune checkpoint inhibitors (ICPis), to determine the discrepancies between data submitted to the FDA and those published. Methods: We identified all ICPis approved between 2011 (the year the first ICPi was approved by the FDA) and 2014 (selected to assure a follow-up of at least 3 years post-approval). We assessed the clinical trials for each drug indication and matched each trial with publications in the literature. The primary outcome was the publication status 2 years post-approval. We examined the association between time to publication and drug type using a multilevel Cox regression model, adjusted for clustering within drug indications and individual covariates. Results: Between 2011 and 2014, 36 anticancer drugs including 3 ICPis were newly approved by the FDA. Of 19 trials investigating the 3 ICPis, 11 (58%) were published within 2 years post-approval. We randomly selected 10 of the 33 remaining anticancer drugs; 68 of 101 trials investigating these drugs (67%) were published. Overall, the publication rate was 66% at 2 years post-approval with a median time to publication of 2.3 years. There was no significant difference in time to trial publication between ICPis and other anticancer drugs (adjusted hazard ratio [HR], 1.1; 95% confidence interval [CI], 0.8–1.7; P = 0.55); however, non-ICPIs investigated specifically in randomized phase 2 or 3 trials were significantly more likely to be published earlier than ICPis (adjusted HR, 7.4; 95% CI, 1.8–29.5; P = 0.005). Conclusions: One in three trials of the newest anticancer drugs remained unpublished 2 years after FDA approval. The ICPi publication rate was similar to that of other anticancer drugs. (Protocol registration: UMIN000030475).

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