scholarly journals Management of metastatic cutaneous melanoma: updates in clinical practice

2019 ◽  
Vol 11 ◽  
pp. 175883591985166 ◽  
Author(s):  
Gustavo Schvartsman ◽  
Patricia Taranto ◽  
Isabella C. Glitza ◽  
Sanjiv S. Agarwala ◽  
Michael B. Atkins ◽  
...  
Keyword(s):  
Cutaneous Melanoma ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Immune Therapy ◽  
Treatment Options ◽  
Single Agent ◽  
Current Data ◽  
Treatment Modalities ◽  
Duration Of Treatment ◽  
Programmed Cell Death 1

In recent years, several drugs have been approved for the treatment of patients with metastatic cutaneous melanoma, completely reshaping the landscape of this aggressive disease. Immune therapy with cytotoxic T-lymphocyte antigen 4 and programmed cell death-1 inhibitors yielded significant and durable responses, achieving long-term disease control in up to 40% of the patients. BRAF inhibitors (BRAFi), in combination with MEK inhibitors, also resulted in improved overall survival compared with single-agent BRAFi in patients with BRAFV600-mutated metastatic melanoma. The optimized sequencing and duration of treatment, however, is yet to be found. In this article, we thoroughly review current data and discuss how to best sequence the various treatment modalities available at present, based on four distinct clinical presentations commonly seen in clinic. In addition, we review treatment options beyond checkpoint inhibitors and targeted therapy, which may be required by patients failing such effective treatments.

scholarly journals Insights into Potential Pathogenesis and Treatment Options for Immune-Checkpoint Inhibitor-Related Pneumonitis

Biomedicines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1484
Author(s):  
Hiroyuki Ando ◽  
Kunihiro Suzuki ◽  
Toyoshi Yanagihara
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Frequent Adverse Event ◽  
Programmed Cell Death 1 ◽  
New Treatment

Immune-checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death-1 (PD-1), and programmed cell death-1-ligand 1 (PD-L1) have become new treatment options for various malignancies. ICIs bind to immune-checkpoint inhibitory receptors or to the foregoing ligands and block inhibitory signals to release the brakes on the immune system, thereby enhancing immune anti-tumor responses. On the other hand, unlike conventional chemotherapies, ICIs can cause specific side effects, called immune-related adverse events (irAEs). These toxicities may affect various organs, including the lungs. ICI-related pneumonitis (ICI-pneumonitis) is not the most frequent adverse event, but it is serious and can be fatal. In this review, we summarize recent findings regarding ICI-pneumonitis, with a focus on potential pathogenesis and treatment.

scholarly journals Durable Clinical Benefit in Patients with Advanced Cutaneous Melanoma after Discontinuation of Anti-PD-1 Therapies Due to Immune-Related Adverse Events

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Umang Swami ◽  
Varun Monga ◽  
Aaron D. Bossler ◽  
Yousef Zakharia ◽  
Mohammed Milhem
Keyword(s):  
Adverse Events ◽  
Cutaneous Melanoma ◽  
Clinical Benefit ◽  
Treatment Options ◽  
Single Agent ◽  
Ocular Tissue ◽  
Comprehensive Cancer Center ◽  
Cancer Center ◽  
Duration Of Treatment ◽  
Prognostic Information

Introduction. Anti-PD-1 therapies, pembrolizumab and nivolumab, are currently the standard of care for treatment of patients with metastatic melanoma. Treatment is usually continued until toxicity or disease progression. Though these therapies are well tolerated, some patients discontinue them due to immune-related adverse events (irAE). Discontinuation of therapy brings challenges to their management due to limited treatment options and lack of long-term prognostic information for these patients. Herein, we reviewed patients at our institution to analyze their clinical outcomes. Materials and Methods. Charts of 1264 consecutive patients enrolled between 8/1/2012 and 7/31/2017 at Melanoma Skin & Ocular Tissue Repositories at Holden Comprehensive Cancer Center at the University of Iowa Hospitals and Clinic were reviewed. Eligible patients were those who received single-agent anti-PD-1 therapy and subsequently discontinued it due to irAE. Reviewed data included patient demographics, prior medical history, baseline disease parameters, and outcomes. Kaplan-Meier survival analysis was done to determine progression-free survival (PFS) and overall survival (OS). Results. Overall 169 patients with advanced, unresectable, or metastatic cutaneous melanoma received anti-PD-1 therapy of which 16 (9.5%) white, non-Hispanic patients with median age of 64.5 (range 35 to 81 years) discontinued treatment due to irAE. Fifteen patients received pembrolizumab and one received nivolumab. The median duration of treatment was 4.7 (range 0.7 to 11.5) months. Median follow-up was 30.3 (range 4.6 to 49.4) months. Median PFS was 24.6 months and median OS was not reached. Durable clinical benefit (time to progression or next treatment of more than 6 months from last treatment) was observed in 13 (81.2%) patients. At the time of analysis, 8 patients had progressed and 4 patients died (all-cause). Discussion. Our results suggest that advanced melanoma patients discontinuing anti-PD-1 therapy due to irAE usually experience durable clinical benefit. However, caution is needed with these agents in patients with underlying autoimmune diseases.

scholarly journals Second-Line Therapies in the Changing Landscape of First-Line Therapies for Metastatic Clear Cell Renal Cell Cancer

ONCOLOGY ◽  
2021 ◽  
pp. 306-310
Author(s):  
Tiffany Shaw ◽  
Hannah Lee ◽  
Robert Figlin
Keyword(s):  
Renal Cell ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Cell Cancer ◽  
Single Agent ◽  
Current Data ◽  
Treatment Modalities ◽  
Second Line ◽  
First Line ◽  
Line Setting

In recent years, first-line therapies for metastatic renal cell carcinoma (mRCC) have shifted to a combination of immune checkpoint inhibitors or a combination of antiangiogenesis tyrosine kinase inhibitors (TKIs) and immunotherapy. This has led to a need to address standard-of-care treatment in the second-line setting. Our review presents an analysis of current and upcoming data to guide treatment decisions. After progression on nivolumab plus ipilimumab, current data favor monotherapy TKI with cabozantinib or axitinib. Current literature for second-line therapy given after combination TKI plus immunotherapy shows the strongest evidence for either single-agent cabozantinib or combination everolimus with lenvatinib. Investigations are ongoing for the role of TKIs with immunotherapy in the second-line setting. Novel agents, such as HIF2α inhibitors, are currently being studied as single agents and in combination with other treatment modalities in efforts to improve patient outcomes in mRCC.

scholarly journals Emerging Role of Immune Therapy in HCC

2021 ◽  
Author(s):  
Stacey M. Stein
Keyword(s):  
Kinase Inhibitors ◽  
Immune Therapy ◽  
Treatment Options ◽  
Single Agent ◽  
Small Subset ◽  
Vascular Endothelial ◽  
Number Of Patients ◽  
Endothelial Growth Factor ◽  
Expected Increase

AbstractHepatocellular carcinoma (HCC) remains a prevalent cancer diagnosis with an expected increase in incidence in the next decade. Treatment options for advanced disease have expanded significantly in the last decade since sorafenib was first approved in 2007. There have been approvals for multiple tyrosine kinase inhibitors (TKIs) with modest improvements in survival. Single-agent PD-1 inhibition has shown responses in ∼15% of patients, with a tail of the curve that is very beneficial to a small subset of patients. Most recently, studies of combination therapy with immune therapy drugs are showing more durable responses in a larger number of patients with unprecedented response rates over 30%. Different strategies have been pursued, including PD-1 and PD-L1 combinations with vascular endothelial growth factor inhibition, TKIs, and anti-CTLA-4 antibodies. This article provides a review of studies both completed and ongoing with immune therapy in advanced HCC.

scholarly journals Management of pulmonary toxicity associated with immune checkpoint inhibitors

2019 ◽  
Vol 28 (154) ◽  
pp. 190012 ◽  
Author(s):  
Myriam Delaunay ◽  
Grégoire Prévot ◽  
Samia Collot ◽  
Laurent Guilleminault ◽  
Alain Didier ◽  
...  
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Pulmonary Toxicity ◽  
Immune Checkpoint Inhibitors ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Standard Of Care ◽  
Serious Adverse Events ◽  
Programmed Cell Death 1 ◽  
Life Threatening

Immunotherapy has become a standard of care in oncology, following the recent approvals of cytotoxic T-lymphocyte-associated protein-4 and programmed cell death-1 inhibitors in lung cancer, melanoma, renal cell carcinoma, Hodgkin's lymphoma, bladder, head and neck cancers. Besides their efficacy, these agents also generate specific immune-related adverse events. Due to the increasing prescription of immune-checkpoint inhibitors, the incidence of immune toxicity will continue to rise. The awareness of immune-related adverse events is key to ensuring both diagnosis and management of the possible serious adverse events. Although severe immune-related adverse events remain rare, they can lead to discontinued treatment or to death if they are not forecasted and managed properly. Even if lung toxicity is not the most frequent adverse event, it remains critical as it can be life-threatening. Herein, the main aspects of pulmonary toxicity are reviewed and guidelines are also proposed in order to manage the possible side-effects.

scholarly journals Checkpoint Inhibitors and Their Application in Breast Cancer

Breast Care ◽  
2016 ◽  
Vol 11 (2) ◽  
pp. 108-115 ◽  
Author(s):  
Davide Bedognetti ◽  
Cristina Maccalli ◽  
Salha B.J. Al Bader ◽  
Francesco M. Marincola ◽  
Barbara Seliger
Keyword(s):  
Breast Cancer ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Immune Surveillance ◽  
Significant Proportion ◽  
Immune Checkpoints ◽  
Immune Recognition ◽  
Breast Cancers ◽  
Inhibitory Molecules

Immune checkpoints are crucial for the maintenance of self-tolerance and for the modulation of immune responses in order to minimize tissue damage. Tumor cells take advantage of these mechanisms to evade immune recognition. A significant proportion of tumors, including breast cancers, can express co-inhibitory molecules that are important formediating the escape from T cell-mediated immune surveillance. The interaction of inhibitory receptors with their ligands can be blocked by specific molecules. Monoclonal antibodies (mAbs) directed against the cytotoxic T lymphocyte-associated antigen-4 (CTLA4) and, more recently, against the programmed cell death protein 1 (PD1), have been approved for the therapy of melanoma (anti-CTLA4 and anti-PD1 mAbs) and non-small cell lung cancer (anti-PD1 mAbs). Moreover, inhibition of PD1 signaling has shown extremely promising signs of activity in breast cancer. An increasing number of molecules directed against other immune checkpoints are currently under clinical development. In this review, we summarize the evidence supporting the implementation of checkpoint inhibition in breast cancer by reviewing in detail data on PD-L1 expression and its regulation. In addition, opportunities to boost anti-tumor immunity in breast cancer with checkpoint inhibitor-based immunotherapies alone and in combination with other treatment options will be discussed.

scholarly journals Medical management of brain metastases

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Adam Lauko ◽  
Yasmeen Rauf ◽  
Manmeet S Ahluwalia
Keyword(s):  
Brain Metastases ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Tumor Biology ◽  
Therapeutic Benefit ◽  
Treatment Modalities ◽  
Primary Tumors ◽  
Mortality And Morbidity ◽  
Novel Approaches ◽  
Neurocognitive Decline

Absrtract The development of brain metastases occurs in 10–20% of all patients with cancer. Brain metastases portend poor survival and contribute to increased cancer mortality and morbidity. Despite multimodal treatment options, which include surgery, radiotherapy, and chemotherapy, 5-year survival remains low. Besides, our current treatment modalities can have significant neurological comorbidities, which result in neurocognitive decline and a decrease in a patient’s quality of life. However, innovations in technology, improved understanding of tumor biology, and new therapeutic options have led to improved patient care. Novel approaches in radiotherapy are minimizing the neurocognitive decline while providing the same therapeutic benefit. In addition, advances in targeted therapies and immune checkpoint inhibitors are redefining the management of lung and melanoma brain metastases. Similar approaches to brain metastases from other primary tumors promise to lead to new and effective therapies. We are beginning to understand the appropriate combination of these novel approaches with our traditional treatment options. As advances in basic and translational science and innovative technologies enter clinical practice, the prognosis of patients with brain metastases will continue to improve.

Preliminary safety, efficacy, and pharmacokinetics (PK) results of KN046 (bispecific anti-PD-L1/CTLA4) from a first-in-human study in subjects with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2554-2554 ◽  
Author(s):  
Jermaine Coward ◽  
Vinod Ganju ◽  
Ramin Behzadigohar ◽  
Kenneth Kwong ◽  
June Xu ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Human Study ◽  
Safety Data ◽  
Advanced Solid Tumors ◽  
Duration Of Treatment ◽  
Efficacy Evaluation

2554 Background: KN046 is a novel bispecific antibody that blocks both PD-L1 interaction with PD1 and CTLA-4 interaction with CD80/CD86. KN046 has a wild type IgG1 Fc portion that preserves intact effector functions, such as depletion of Tregs in tumor microenvironments. This first-in-human study evaluated the safety, tolerability, PK and preliminary efficacy of KN046 in subjects with advanced solid tumors. Methods: This traditional “3+3” dose-escalation design study enrolled patients (pts) with advanced unresectable or metastatic solid tumors refractory or intolerant to standard therapies. Previous treatment from PD1 or PD-L1 immune checkpoint inhibitors was allowed. KN046 was administered intravenously Q2W. Dose limit toxicity (DLT) evaluation period is 28 days. The planned dose levels (DL) were 0.3, 1, 3, 5 and 10 mg/kg. Efficacy evaluation was performed by RECIST 1.1 every 8 weeks. Results: As of Dec 13, 2018, 10 pts had been enrolled (0.3 mg/kg, n = 1; 1 mg/kg, n = 3; 3 mg/kg, n = 3; and 5 mg/kg, n = 3). Median duration of treatment was 8 (range: 2-24) weeks. 1 DLT was observed at 5 mg/kg dose (a grade 3 immune-related hepatitis without elevation in total bilirubin; reversible in two weeks). The most common (≥30%) treatment-emergent AEs (TEAE) were Fatigue, Diarrhea, Nausea, Vomiting. Six immune-related TEAEs (Abdominal pain lower, Arthralgia, Hepatic function abnormal, Hyperthyroidism, Nausea and Transaminitis) were observed in 3 pts. One pt with NSCLC from 3 mg/kg cohort had confirmed completed response. Two pts (TNBC and nivolumab refractory RCC) from 1 mg/kg cohort had shown long-term stable disease ( > 12 weeks). Faster clearance of KN046 was observed at lower dose might be due to target-mediated clearance. T1/2 is approximately 7~9 days at doses of 3 mg/kg and above when saturation occurs. Conclusions: Single agent KN046 has an acceptable safety profile and is in line with previously reported safety data from other immune checkpoint inhibitors. Preliminary efficacy results are promising. PK data from initial 4 cohorts support Q2W schedule. The study is currently ongoing at dose level of 5 mg/kg Q2W. Clinical trial information: NCT03529526.

scholarly journals Immune Checkpoint Inhibitors to Treat Malignant Lymphomas

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Magdalena Witkowska ◽  
Piotr Smolewski
Keyword(s):  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Epigenetic Changes ◽  
Significant Progress ◽  
Malignant Lymphomas ◽  
Actual Knowledge ◽  
Programmed Cell Death 1 ◽  
Individual Variations ◽  
Antineoplastic Treatment

Genetic and/or epigenetic changes provide antigen-derived diversity in neoplastic cells. Beside, these cells do not initiate immune response of host organisms. A variety of factors are responsible for the resistant to treatment, including individual variations in patients and somatic cell genetic differences in tumors, even those from the same tissue of origin. Immune system is controlled by several controlling mechanisms. Recently, a significant progress in hematologic treatment has been made; however, majority of diseases still remain incurable. Immunotherapy with checkpoint inhibitors has emerged as promising modality of antitumor treatment, showing marked response to several antigens, including cytotoxic T lymphocyte-associate protein-4 (CTLA-4) or programmed cell death 1 receptor (PD-1). In this review, we demonstrate actual knowledge on immune checkpoint function and its impact on development of new modality of antineoplastic treatment, using, for example, anti-CTLA-4 or PD-1/PD1 ligand (PD-L1) monoclonal antibodies in malignant lymphomas.

scholarly journals Emerging role of checkpoint blockade therapy in lymphoma

2016 ◽  
Vol 8 (2) ◽  
pp. 81-90 ◽  
Author(s):  
Natalie Galanina ◽  
Justin Kline ◽  
Michael R. Bishop
Keyword(s):  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Treatment Modalities ◽  
Critical Pathways ◽  
Heavily Pretreated ◽  
Relapsed Lymphoma

Following the successful application of immune checkpoint blockade therapy (CBT) in refractory solid tumors, it has recently gained momentum as a promising modality in the treatment of relapsed lymphoma. This significant therapeutic advance stems from decades of research that elucidated the role of immune regulation pathways and the mechanisms by which tumors can engage these critical pathways to escape immune detection. To date, two main pathways, the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1), have emerged as key targets of CBT demonstrating unprecedented activity particularly in heavily pretreated relapsed/refractory Hodgkin lymphoma and some forms of non-Hodgkin disease. Herein we provide a brief discussion of checkpoint blockade in the context of lymphoma biology with a specific focus on novel checkpoint inhibitors and their therapeutic activity. We discuss current clinical trials and the landscape of CBT to underscore both the remarkable progress and foreseeable limitations of this novel treatment strategy. In particular, we build upon state-of-the-art knowledge and clinical insights gained from the early trials to review potential approaches to how CBT may be integrated with other treatment modalities, including chemoimmunotherapy to improve patient outcomes in the future. Finally, as the role of CBT evolves to potentially become a cornerstone of therapy in refractory/relapsed lymphoma, we briefly emphasize the importance of predictive biomarkers in an effort to select appropriate patients who are most likely to derive benefit from CBT.

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