scholarly journals Predictive Biomarkers for Outcomes of Immune Checkpoint Inhibitors (ICIs) in Melanoma: A Systematic Review

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6366
Author(s):  
Joosje C. Baltussen ◽  
Marij J. P. Welters ◽  
Elizabeth M. E. Verdegaal ◽  
Ellen Kapiteijn ◽  
Anne M. R. Schrader ◽  
...  
Keyword(s):  
Systematic Review ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Unmet Need ◽  
Predictive Biomarkers ◽  
Suppressor Cells ◽  
Cochrane Library ◽  
Durable Response ◽  
Melanoma Patients

Immune checkpoint inhibitors (ICIs) have strongly improved the survival of melanoma patients. However, as durable response to ICIs are only seen in a minority, there is an unmet need to identify biomarkers that predict response. Therefore, we provide a systematic review that evaluates all biomarkers studied in association with outcomes of melanoma patients receiving ICIs. We searched Pubmed, COCHRANE Library, Embase, Emcare, and Web of Science for relevant articles that were published before June 2020 and studied blood, tumor, or fecal biomarkers that predicted response or survival in melanoma patients treated with ICIs. Of the 2536 identified reports, 177 were included in our review. Risk of bias was high in 40%, moderate in 50% and low in 10% of all studies. Biomarkers that correlated with response were myeloid-derived suppressor cells (MDSCs), circulating tumor cells (CTCs), CD8+ memory T-cells, T-cell receptor (TCR) diversity, tumor-infiltrating lymphocytes (TILs), gene expression profiling (GEP), and a favorable gut microbiome. This review shows that biomarkers for ICIs in melanoma patients are widely studied, but heterogeneity between studies is high, average sample sizes are low, and validation is often lacking. Future studies are needed to further investigate the predictive utility of some promising candidate biomarkers.

Evolution of Molecular Targets in Melanoma Treatment

2020 ◽  
Vol 26 (4) ◽  
pp. 396-414 ◽  
Author(s):  
Khanh B. Tran ◽  
Christina M. Buchanan ◽  
Peter R. Shepherd
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Unmet Need ◽  
Braf Inhibitors ◽  
Braf Mutations ◽  
Durable Response ◽  
History Of ◽  
Melanoma Treatment ◽  
Melanoma Patients

Melanoma is the deadliest type of skin cancers, accounting for more than 80% of skin cancer mortality. Although melanoma was known very early in the history of medicine, treatment for this disease had remained largely the same until very recently. Previous treatment options, including removal surgery and systemic chemotherapy, offered little benefit in extending the survival of melanoma patients. However, the last decade has seen breakthroughs in melanoma treatment, which all emerged following new insight into the oncogenic signaling of melanoma. This paper reviewed the evolution of drug targets for melanoma treatment based on the emergence of novel findings in the molecular signaling of melanoma. One of the findings that are most influential in melanoma treatment is that more than 50% of melanoma tumors contain BRAF mutations. This is fundamental for the development of BRAF inhibitors, which is the first group of drugs that significantly improves the overall survival of melanoma patients compared to the traditional chemotherapeutic dacarbazine. More recently, findings of the role of immune checkpoint molecules such as CTLA-4 and PD1/PD-L1 in melanoma biology have led to the development of a new therapeutic category: immune checkpoint inhibitors, which, for the first time in the history of cancer treatment, produced a durable response in a subset of melanoma patients. However, as this paper discussed next, there is still an unmet need for melanoma treatment. A significant population of patients did not respond to either BRAF inhibitors or immune checkpoint inhibitors. Of those patients who gained an initial response from those therapies, a remarkable percentage would develop drug resistance even when MEK inhibitors were added to the treatment. Finally, this paper discusses some possible targets for melanoma treatment.

scholarly journals Biomarkers for Predicting Response to Immunotherapy with Immune Checkpoint Inhibitors in Cancer Patients

2019 ◽  
Vol 65 (10) ◽  
pp. 1228-1238 ◽  
Author(s):  
Michael J Duffy ◽  
John Crown
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Future Research ◽  
Specific Gene ◽  
Tumor Type ◽  
Clinical Use ◽  
Durable Response ◽  
Cancer Types

Abstract BACKGROUND Immunotherapy, especially the use of immune checkpoint inhibitors, has revolutionized the management of several different cancer types in recent years. However, for most types of cancer, only a minority of patients experience a durable response. Furthermore, administration of immunotherapy can result in serious adverse reactions. Thus, for the most efficient and effective use of immunotherapy, accurate predictive biomarkers that have undergone analytical and clinical validation are necessary. CONTENT Among the most widely investigated predictive biomarkers for immunotherapy are programmed death-ligand 1 (PD-L1), microsatellite instability/defective mismatch repair (MSI/dMMR), and tumor mutational burden (TMB). MSI/dMMR is approved for clinical use irrespective of the tumor type, whereas PD-L1 is approved only for use in certain cancer types (e.g., for predicting response to first-line pembrolizumab monotherapy in non-small cell lung cancer). Although not yet approved for clinical use, TMB has been shown to predict response to several different forms of immunotherapy and across multiple cancer types. Less widely investigated predictive biomarkers for immunotherapy include tumor-infiltrating CD8+ lymphocytes and specific gene signatures. Despite being widely investigated, assays for MSI/dMMR, PD-L1, and TMB lack standardization and are still evolving. An urgent focus of future research should be the optimization and standardization of method for determining these biomarkers. SUMMARY Biomarkers for predicting response to immunotherapy are paving the way for personalized treatment for patients with diverse cancer types. However, standardization of the available biomarker assays is an urgent requirement.

scholarly journals Prognostic and Predictive Factors in Advanced Urothelial Carcinoma Treated with Immune Checkpoint Inhibitors: A Review of the Current Evidence

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5517
Author(s):  
Sara Elena Rebuzzi ◽  
Giuseppe Luigi Banna ◽  
Veronica Murianni ◽  
Alessandra Damassi ◽  
Emilio Francesco Giunta ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Unmet Need ◽  
Predictive Biomarkers ◽  
Standard Of Care ◽  
Current Evidence ◽  
Concomitant Medications ◽  
Advanced Urothelial Carcinoma

In recent years, the treatment landscape of urothelial carcinoma has significantly changed due to the introduction of immune checkpoint inhibitors (ICIs), which are the standard of care for second-line treatment and first-line platinum-ineligible patients with advanced disease. Despite the overall survival improvement, only a minority of patients benefit from this immunotherapy. Therefore, there is an unmet need to identify prognostic and predictive biomarkers or models to select patients who will benefit from ICIs, especially in view of novel therapeutic agents. This review describes the prognostic and predictive role, and clinical readiness, of clinical and tumour factors, including new molecular classes, tumour mutational burden, mutational signatures, circulating tumour DNA, programmed death-ligand 1, inflammatory indices and clinical characteristics for patients with urothelial cancer treated with ICIs. A classification of these factors according to the levels of evidence and grades of recommendation currently indicates both a prognostic and predictive value for ctDNA and a prognostic relevance only for concomitant medications and patients’ characteristics.

scholarly journals Role of Immune Checkpoint Inhibitors in Gastrointestinal Malignancies

2020 ◽  
Vol 9 (8) ◽  
pp. 2533
Author(s):  
Anita Mazloom ◽  
Nima Ghalehsari ◽  
Victor Gazivoda ◽  
Neil Nimkar ◽  
Sonal Paul ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Unmet Need ◽  
Predictive Biomarkers ◽  
Small Subset ◽  
Gastrointestinal Malignancies ◽  
Line Of Therapy

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of several solid and hematological malignancies. ICIs are not only able to produce long and durable responses, but also very well tolerated by patients. There are several approved indications of use of ICIs in treatment of metastatic gastrointestinal malignancies including gastric, esophageal, colorectal and hepatocellular carcinoma. In addition, ICIs can be used in microsatellite instability-high (MSI-H) and high tumor mutational burden (TMB) tumors in chemotherapy-resistant setting. Despite having good efficacy and superior safety profile, ICIs are clinically active in small subset of patients, therefore, there is a huge unmet need to enhance their efficacy and discover new predictive biomarkers. There are several ongoing clinical trials that are exploring the role of ICIs in various gastrointestinal cancers either as single agent or in combination with chemotherapy, radiation therapy, targeted agents or other immunotherapeutic agents. In this review, we discuss the published and ongoing trials for ICIs in gastrointestinal malignancies, including esophageal, gastric cancer, pancreatic, hepatocellular, biliary tract, colorectal and anal cancers. Specifically, we focus on the use of ICIs in each line of therapy and discuss the future directions of these agents in each type of gastrointestinal cancer.

scholarly journals THERAPY OF ENDOCRINE DISEASE Immunotherapy of advanced thyroid cancer: from bench to bedside

2020 ◽  
Vol 183 (2) ◽  
pp. R41-R55
Author(s):  
Sonia Moretti ◽  
Elisa Menicali ◽  
Nicole Nucci ◽  
Martina Guzzetti ◽  
Silvia Morelli ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Thyroid Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Unmet Need ◽  
Cancer Type ◽  
Durable Response ◽  
Endocrine Disease

Immunotherapy has arisen in use in the field of oncology with seven immune checkpoint inhibitors approved for the treatment of a variety of cancer histologies. Depending on the cancer type, the success rate might be different, but in average it is about 20%, with some cases showing a durable response, lasting also after the interruption of the treatment, with a clear benefit on OS. The development of an efficacious cure for advanced thyroid carcinomas is still an unmet need and immunotherapy represents an interesting alternative option also for this cancer. However, very few clinical trials have been accomplished and very few studies exploring a way to overcome resistance have been performed. In this review, we will summarize the mechanisms of immune escape, with a special reference to follicular-derived thyroid carcinoma. Furthermore, we will try to speculate on the use of immune checkpoint inhibitors for the treatment of follicular-derived advanced thyroid carcinoma. Finally, we will summarize the ongoing clinical trials and the future directions of the field.

scholarly journals Activity and Safety of Immune Checkpoint Inhibitors in Neuroendocrine Neoplasms: A Systematic Review and Meta-Analysis

2021 ◽  
Vol 14 (5) ◽  
pp. 476
Author(s):  
Alberto Bongiovanni ◽  
Brigida Anna Maiorano ◽  
Irene Azzali ◽  
Chiara Liverani ◽  
Martine Bocchini ◽  
...  
Keyword(s):  
Systematic Review ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Neuroendocrine Neoplasms ◽  
Phase Ii Trials

Immune-checkpoint inhibitors (ICIs) have widened the therapeutic scenario of different cancer types. Phase I/II trials have been designed to evaluate the role of ICIs both as single agents and in combination in neuroendocrine neoplasms (NENs), but as yet no randomized controlled phase III trials have been carried out. A systematic review and meta-analysis of studies published could help to reduce the biases of single-phase II trials. Efficacy data were obtained on 636 patients. Pooled percentages of the overall response rate (ORR) and disease control rate (DCR) were 10% (95% CI: 6–15%, I2 = 67%, p < 0.1) and 42% (95% CI: 28–56%, I2 = 93%, p < 0.1), respectively. Median progression-free survival (mPFS) was 4.1 months (95% CI 2.6–5.4; I2 = 96%, p < 0.1) and median overall survival (mOS) was 11 months (95% CI 4.8–21.1; I2 = 98%, p < 0.1). Among the ICIs used as single agents, the anti-PD1 toripalimab achieved the highest ORR. Combination regimens were superior to monotherapy, e.g., the ICI combination nivolumab + ipilimumab, and the ICI + anti-angiogenetic combination atezolizumab + bevacizumab, both of which warrant further investigation. Promising efficacy and a good safety profile of ICIs represent a valid opportunity for expanding the therapeutic landscape of NENs. Predictive biomarkers are needed to identify the most suitable candidates for these regimens.

scholarly journals Association of Steroids Use with Survival in Patients Treated with Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 546 ◽  
Author(s):  
Fausto Petrelli ◽  
Diego Signorelli ◽  
Michele Ghidini ◽  
Antonio Ghidini ◽  
Elio Gregory Pizzutilo ◽  
...  
Keyword(s):  
Systematic Review ◽  
Cancer Patients ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Symptom Control ◽  
Cochrane Library ◽  
Risk Of Death ◽  
Increased Risk

Immune checkpoint inhibitors (ICIs) can elicit toxicities by inhibiting negative regulators of adaptive immunity. Sometimes, management of toxicities may require systemic glucocorticoids. We performed a systematic review and meta-analysis of published studies to evaluate the correlation between steroids use, overall survival (OS), and progression-free survival (PFS) in cancer patients treated with ICIs. Publications that compared steroids with non-steroid users in cancer patients treated with ICIs from inception to June 2019 were identified by searching the EMBASE, PubMed, SCOPUS, Web of Science, and Cochrane Library databases. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Patients (studies, n = 16; patients, n = 4045) taking steroids were at increased risk of death and progression compared to those not taking steroids (HR = 1.54, 95% CI: 1.24–1.91; p = 0.01 and HR = 1.34, 95% CI: 1.02–1.76; p = 0.03, respectively). The main negative effect on OS was associated with patients taking steroids for supportive care (HR = 2.5, 95% CI 1.41–4.43; p < 0.01) or brain metastases (HR = 1.51, 95% CI 1.22–1.87; p < 0.01). In contrast, steroids used to mitigate adverse events did not negatively affect OS. In conclusion, caution is needed when steroids are used for symptom control. In these patients, a negative impact of steroid use was observed for both OS and PFS.

scholarly journals Retreatment with immune checkpoint inhibitors in solid tumors: a systematic review

2020 ◽  
Vol 12 ◽  
pp. 175883592097535
Author(s):  
Kaili Yang ◽  
Jiarui Li ◽  
Zhao Sun ◽  
Lin Zhao ◽  
Chunmei Bai
Keyword(s):  
Systematic Review ◽  
Disease Progression ◽  
Solid Tumors ◽  
Prospective Studies ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Cochrane Library ◽  
Efficacy And Safety ◽  
Grade 3

Background: A large proportion of patients eventually experience disease progression despite treatment with immune checkpoint inhibitors (ICIs), but subsequent treatment options are limited for this population. Retreatment with the same or different types of ICIs is a possible strategy, but the clinical efficacy and safety data are limited. This systematic review aims to evaluate the efficacy and safety of ICIs retreatment in patients with solid tumors after disease progression to previous ICIs. Methods: We searched MEDLINE, EMBASE, the Cochrane Library, and major meeting libraries for prospective studies. The primary outcomes included the objective response rate (ORR), disease control rate (DCR), median overall survival (mOS), and the incidence of grade ⩾3 immune-related adverse events (irAEs). Results: We identified 22 prospective studies including 1865 patients. For disease progression after CTLA-4 inhibitors, three studies evaluated anti-CTLA-4 retreatment. The ORR was 12–23%, the DCR was 48.4–67.7%, and the mOS was 12 months. The incidence of grade ⩾3 irAEs was 5.9–25%. Four studies evaluated anti-programmed cell death protein 1 (PD-1) retreatment. The ORR was 22–36%, the DCR was 40–64%, and the mOS was 13.4–20.6 months. The incidence of grade ⩾3 irAEs was <10%. For disease progression after PD-(L)1 inhibitors, 13 studies evaluated anti-PD-(L)1 retreatment. The ORR was 5–53%, the DCR was 38–83%, and the mOS was 13.9 months. The incidence of grade ⩾3 irAEs was 0–15% for patients retreated with single anti-PD-(L)1 agent, but was higher (0–64%) for those retreated with ICIs combined with other agents. Two studies evaluated anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) retreatment. The ORR was 0–22.4%, the DCR was 50–72%, and the mOS was 4–21 months. The incidence of grade ⩾3 irAEs was 26–61%. Conclusion: Retreatment with ICIs is feasible for cancer patients considering its encouraging efficacy and tolerable safety. Further prospective trials are needed to explore more promising strategies and identify suitable populations for retreatment.

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