scholarly journals Biomarkers Associated with Immune-Related Adverse Events under Checkpoint Inhibitors in Metastatic Melanoma

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 302
Author(s):  
Marcus Wölffer ◽  
Florian Battke ◽  
Martin Schulze ◽  
Magdalena Feldhahn ◽  
Lukas Flatz ◽  
...  
Keyword(s):  
Adverse Events ◽  
Autoimmune Diseases ◽  
Metastatic Melanoma ◽  
Blood Count ◽  
Checkpoint Inhibitors ◽  
Genetic Alterations ◽  
Copy Number Variations ◽  
Therapeutic Landscape ◽  
Melanoma Patients ◽  
Determining Factor

Immune checkpoint inhibitors (ICI) have revolutionized the therapeutic landscape of metastatic melanoma. However, ICI are often associated with immune-related adverse events (IRAE) such as colitis, hepatitis, pancreatitis, hypophysitis, pneumonitis, thyroiditis, exanthema, nephritis, myositis, encephalitis, or myocarditis. Biomarkers associated with the occurrence of IRAE would be desirable. In the literature, there is only little data available and furthermore mostly speculative, especially in view of genetic alterations. Our major aim was to check for possible associations between NGS-based genetic alterations and IRAE. We therefore analyzed 95 melanoma patients with ICI and evaluated their NGS results. We checked the data in view of potential associations between copy number variations (CNVs), small variations (VARs), human leucocyte antigen (HLA), sex, blood count parameters, pre-existing autoimmune diseases and the occurrence of IRAE. We conducted a literature research on genetic alterations hypothesized to be associated with the occurrence of IRAE. In total, we identified 39 genes that have been discussed as hypothetical biomarkers. We compared the list of these 39 genes with the tumor panel that our patients had received and focused our study on those 16 genes that were also included in the tumor panel used for NGS. Therefore, we focused our analyses on the following genes: AIRE, TERT, SH2B3, LRRK2, IKZF1, SMAD3, JAK2, PRDM1, CTLA4, TSHR, FAN1, SLCO1B1, PDCD1, IL1RN, CD274, UNG. We obtained relevant results: female sex was significantly associated with the development of hepatitis, combined immunotherapy with colitis, increased total and relative monocytes at therapy initiation were significantly associated with the development of pancreatitis, the same, pre-existing autoimmune diseases. Further significant associations were as follows: HLA homozygosity (hepatitis), and VARs on SMAD3 (pancreatitis). Regarding CNVs, significant markers included PRDM1 deletions and IL1RN (IRAE), CD274 duplications and SLCO1B1 (hepatitis), PRDM1 and CD274 (encephalitis), and PRDM1, CD274, TSHR, and FAN1 (myositis). Myositis and encephalitis, both, were associated with alterations of PRDM1 and CD274, which might explain their joined appearance in clinical practice. The association between HLA homozygosity and IRAE was clarified by finding HLA-A homozygosity as determining factor. We identified several genetic alterations hypothesized in the literature to be associated with the development of IRAE and found significant results concerning pre-existing autoimmune diseases and specific blood count parameters. Our findings can help to better understand the development of IRAE in melanoma patients. NGS might be a useful screening tool, however, our findings have yet to be confirmed in larger studies.

scholarly journals Immune checkpoint inhibitors, endocrine adverse events, and outcomes of melanoma

2022 ◽  
Author(s):  
Hanna Karhapää ◽  
Siru Mäkelä ◽  
Hanna Laurén ◽  
Marjut Jaakkola ◽  
Camilla Schalin-Jäntti ◽  
...  
Keyword(s):  
Adverse Events ◽  
Treatment Outcomes ◽  
Metastatic Melanoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Autoimmune Diabetes ◽  
Progression Free Survival ◽  
Electronic Patient Records ◽  
Melanoma Patients

Objective: Immune checkpoint inhibitors (ICI) can cause endocrine adverse events. However, endocrine AEs could be related to better treatment outcomes. Our aim was to investigate whether this holds true in a real-world setting of metastatic melanoma patients. Design: A retrospective single-institution study. Methods: We included 140 consecutive metastatic melanoma patients treated with ICI between January 2012 and May 2019. We assessed endocrine toxicity and best possible treatment outcomes from electronic patient records, including laboratory parameters, and radiological images. Results: Of the treated patients, 21 patients (15%) were treated with ipilimumab, 46 (33%) with nivolumab, 67 (48%) with pembrolizumab, and six (4%) with combination therapy (ipilimumab + nivolumab). Endocrine AEs appeared in 29% (41/140) patients. Three patients had two different endocrine AEs. Thyroid disorders were the most common: 26% (36/140), followed by hypophysitis: 4% (5/140). Three subjects (2%, 3/140) were diagnosed with autoimmune diabetes. Three patients had to terminate treatment due to endocrine toxicity. Radiological manifestations of endocrine AEs were found in 16 patients (39%, 16/41). Endocrine toxicity was associated with significantly better treatment outcomes. Median progression-free survival (8.1 months, range 5.1 – 11.1 months vs. 2.7 months, range 2.4 – 3.0 months, P < 0.001), and median overall survival (47.5 months, range 15.5 – 79.5 months vs. 23.7 months, range 15.3 – 32.1 months, P = 0.035) were longer for patients experiencing endocrine AEs. Conclusions: The higher number of endocrine AEs suggest regular laboratory monitoring aids in AE detection. Endocrine AEs in metastatic melanoma may correlate with better treatment outcomes.

scholarly journals Association of Antibiotics and Other Drugs with Clinical Outcomes in Metastatic Melanoma Patients Treated with Immunotherapy

2021 ◽  
Vol 2021 ◽  
pp. 1-5
Author(s):  
Manish D. Angrish ◽  
Arun Agha ◽  
Rossanna C. Pezo
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Adverse Events ◽  
Metastatic Melanoma ◽  
Checkpoint Inhibitors ◽  
Secondary Outcome ◽  
Lung Cancers ◽  
Gut Dysbiosis ◽  
Negative Effect ◽  
Melanoma Patients

Immune checkpoint inhibitors (ICIs) targeting the programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) have improved survival in many advanced cancers including advanced melanoma, renal cell, urothelial, and non-small-cell lung cancers. However, not all patients respond, and immune-related adverse events (irAEs) are common. Commensal gut bacteria may serve as an immunoregulatory link-mediating ICI response and toxicity. Recent studies have shown that a lack of bacterial diversity, known as gut dysbiosis, can have an adverse impact on patients’ response to ICIs and predispose to the development of irAEs. Data were collected from 167 patients with metastatic melanoma who received antibiotics within 30 days prior to and/or after initiation of ICI and patients who received NSAIDs, statins, steroids, or proton-pump inhibitors (PPI) within 30 days prior to ICI initiation. The primary outcome was time-to-discontinuation (TTD) of ICI therapy, measured from the date of ICI initiation to the last treatment date. The secondary outcome of interest was toxicity, with incidence of irAEs graded as per the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Here, we demonstrate that individuals who received antibiotics had a significantly shorter time-to-discontinuation (TTD) of the ICI therapy as opposed those who were not administered antibiotics. Consistent with results from previous research, we propose that antibiotics have a negative effect on a patient’s response to ICI therapy, most likely due to the result of gut dysbiosis, and should be critically assessed in terms of their use in patients undergoing ICI treatment.

Behcet’s-like syndrome following pembrolizumab: An immune-related adverse event associated with programmed death receptor-1 inhibitor therapy

2019 ◽  
Vol 26 (4) ◽  
pp. 995-999 ◽  
Author(s):  
Steffi Thomas ◽  
Chay Bae ◽  
Tabanor Joy-Ann ◽  
William Traverse
Keyword(s):  
Adverse Events ◽  
Metastatic Melanoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Death Receptor ◽  
Programmed Death ◽  
Organ Systems ◽  
Wide Range ◽  
The Right

Introduction The landscape for the treatment of metastatic melanoma has been revolutionized with the introduction immune checkpoint inhibitors. Immune checkpoint inhibitors have now become the standard of care for the treatment of cancers. These immune agents including programmed death receptor-1 inhibitors, programmed death-ligand 1 inhibitors and cytotoxic T-lymphocyte antigen-4 inhibitors have shown promising results but have been associated with numerous immune-related complications. Pembrolizumab, a programmed death receptor-1 inhibitor, has been associated with a number of immune-related adverse events affecting multiple organ systems including integument, ocular, endocrine, cardiovascular, pulmonary, renal, gastrointestinal, and musculoskeletal system. Case report We present a case of an 88-year-old Caucasian male with metastatic melanoma of the face with metastasis to the right fifth cranial nerve and into the right cavernous sinus. He underwent resection of the melanoma and was placed on pembrolizumab at 2 mg/kg every three weeks. Interestingly, 24 months on pembrolizumab therapy, he developed corneal erosions, oral and genital ulcerations. Management and outcome Patient completed his 24 months of pembrolizumab and was started on prednisone and colchicine with improvement in his symptoms. At his follow-up eight months, he had recurrence of an oral ulcer. Discussion Here we present a rare case of an elderly male on pembrolizumab who suffered from corneal erosions, oral and genital ulcers, a syndrome similar to Behcet’s disease. Given that pembrolizumab and other immune checkpoint inhibitors are being utilized in the treatment of cancers, physicians should be aware of the wide range immune-related adverse events including the possible Behcet’s-like syndrome presentation.

Prognostic relevance of neutrophil to lymphocyte ratio (NLR) before anti-PD1 therapy in metastatic melanoma patients.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e21045-e21045
Author(s):  
Daniel Vilarim Araujo ◽  
Rafael Vanin de Moraes ◽  
Victor Aurelio Ramos Sousa ◽  
Mauro Daniel Spina Donadio ◽  
Aline Fusco Fares ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Metastatic Melanoma ◽  
Proportional Hazards ◽  
Checkpoint Inhibitors ◽  
Prognostic Significance ◽  
Multivariable Analysis ◽  
Continuous Variable ◽  
Cox Proportional Hazards ◽  
Rank Test ◽  
Melanoma Patients

e21045 Background: Biomarkers to select the patients most likely to benefit from checkpoint inhibitors are urged. NLR is a simple way of measuring systemic inflammation and is an independent predictor of survival before Anti-CTLA4 therapy. We hypothesized if NLR is also a predictor of survival before Anti-PD1 therapy. Methods: We performed a retrospective review of the medical records of all consecutive metastatic melanoma patients who received Nivolumab treatment from January/2014 – February/2017, including 53 patients prospectively collected from an Expanded Access Program. Of 86 patients, 83 patients were included for demographic and efficacy analysis, and 74 had information about baseline pre-treatment NLR. We analyzed NLR as a continuous variable and categorised ≥ 5 vs. < 5. Kaplan-Meier method was used for survival analysis. Long-rank test compared categories and Cox proportional hazards regression model was used to assess the prognostic significance of baseline NLR in univariate and multivariable analysis. Results: Median PFS for the entire population was 6,407 months (3,28 – 9,52) and median OS was not reached (NR) with a median FU of 10,74 months. The median NLR ratio was 3,11 (0,87 – 19). 18 patients (24,3%) had a ≥ 5 NLR vs. 56 (75,7%) < 5. Median PFS for NLR ≥ 5 was: 2,3 (1,75 – 2,84) vs. 12,02 (5,11 – 18,93) for < 5 (HR = 3,11; IC95% 1,52 – 6,27; p = 0,001). Median OS ≥ 5: 3,05 (2,06 – 4,04) vs. NR for < 5 (HR = 5,88; IC95% 2,60 – 13,29; p = 0,001). NLR categorised remained statistically significant in multivariate analysis for PFS and NLR as a continuous variable remained statistically significant for both PFS and OS in multivariate analysis (Table 1). Conclusions: Baseline NLR is a rapid, simple, and cost-free predictor of survival before Anti-PD1 therapy. These results should be validated in a larger cohort of patients. [Table: see text]

Rates of immunosuppressive treatment and hospitalization after checkpoint inhibitor therapy in melanoma and lung cancer patients with autoimmune diseases.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14140-e14140
Author(s):  
David Andrew Bender ◽  
Catherine Spina ◽  
Samuel P. Heilbroner ◽  
Eric Xanthopoulos ◽  
Tony J. C. Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Adverse Events ◽  
Autoimmune Diseases ◽  
Cancer Patients ◽  
Checkpoint Inhibitors ◽  
Oral Prednisone ◽  
Immunosuppressive Treatment ◽  
Lung Cancer Patients ◽  
Pharmacy Claims ◽  
Increased Risk

e14140 Background: Immune checkpoint inhibitors (ICIs) are known to cause immune-related adverse events. Patients with autoimmune diseases (AID) were excluded from most ICI clinical trials due to the potentially high risk of adverse effects. Data on the safety of ICIs in patients with a diagnosis of AID is therefore limited. Methods: A retrospective cohort study was conducted using a de-identified large oncology health care and pharmacy claims database with data from March 2010 until April 2017. Patients analyzed had a diagnosis of either melanoma or lung cancer and were treated with either of the anti-PD-1 inhibitors nivolumab or pembrolizumab. We assessed whether patients with AID compared with no AID were more likely to require medical interventions within 180 days of ICI therapy. We determined the percentage of patients receiving oral prednisone, IV methylprednisolone, or were hospitalized, which may represent responses to ICI toxicity. Results: 16.7% (16/96) of patients with either melanoma or lung cancer and AID received oral prednisone treatment within 180 days of ICI treatment, while 8.3% (131/1573) of patients without AID received oral prednisone during the same period. 8.4% (16/190) of patients with AID received IV methylprednisolone compared to 3.6% (79/2190) of patients without AID. Among melanoma patients, 24.1% (13/54) of patients with AID were hospitalized following ICI treatment, compared to 5.8% (28/480) of patients without ICI. Among lung cancer patients, 38.2% (52/136) of patients with AID were hospitalized compared to 31.6% (541/1711) of patients without AID. All comparisons are significant at p < 0.05 except hospitalizations in lung cancer patients. Conclusions: Patients with AID were more likely to receive interventions after ICI treatment that may represent responses to immune-related adverse events, suggesting that patients with AID are at increased risk for toxicity when being treated with ICIs.

scholarly journals Melanoma: From Melanocyte to Genetic Alterations and Clinical Options

Scientifica ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-22 ◽  
Author(s):  
Corine Bertolotto
Keyword(s):  
Metastatic Melanoma ◽  
Recent Progress ◽  
Molecular Mechanisms ◽  
Disease Free Survival ◽  
Genetic Alterations ◽  
Cancer Resistance ◽  
Free Survival ◽  
Clinical Responses ◽  
Melanoma Patients ◽  
First Time

Metastatic melanoma remained for decades without any effective treatment and was thus considered as a paradigm of cancer resistance. Recent progress with understanding of the molecular mechanisms underlying melanoma initiation and progression revealed that melanomas are genetically and phenotypically heterogeneous tumors. This recent progress has allowed for the development of treatment able to improve for the first time the overall disease-free survival of metastatic melanoma patients. However, clinical responses are still either too transient or limited to restricted patient subsets. The complete cure of metastatic melanoma therefore remains a challenge in the clinic. This review aims to present the recent knowledge and discoveries of the molecular mechanisms involved in melanoma pathogenesis and their exploitation into clinic that have recently facilitated bench to bedside advances.

scholarly journals Clinical Categorization Algorithm (CLICAL) and Machine Learning Approach (SRF-CLICAL) to Predict Clinical Benefit to Immunotherapy in Metastatic Melanoma Patients: Real-World Evidence from the Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4164
Author(s):  
Gabriele Madonna ◽  
Giuseppe V. Masucci ◽  
Mariaelena Capone ◽  
Domenico Mallardo ◽  
Antonio Maria Grimaldi ◽  
...  
Keyword(s):  
Machine Learning ◽  
Metastatic Melanoma ◽  
Learning Algorithm ◽  
Checkpoint Inhibitors ◽  
Real Life ◽  
Previous Treatment ◽  
Clinical Decision ◽  
Neutrophil Lymphocyte Ratio ◽  
Real World Evidence ◽  
Melanoma Patients

The real-life application of immune checkpoint inhibitors (ICIs) may yield different outcomes compared to the benefit presented in clinical trials. For this reason, there is a need to define the group of patients that may benefit from treatment. We retrospectively investigated 578 metastatic melanoma patients treated with ICIs at the Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale” of Napoli, Italy (INT-NA). To compare patients’ clinical variables (i.e., age, lactate dehydrogenase (LDH), neutrophil–lymphocyte ratio (NLR), eosinophil, BRAF status, previous treatment) and their predictive and prognostic power in a comprehensive, non-hierarchical manner, a clinical categorization algorithm (CLICAL) was defined and validated by the application of a machine learning algorithm—survival random forest (SRF-CLICAL). The comprehensive analysis of the clinical parameters by log risk-based algorithms resulted in predictive signatures that could identify groups of patients with great benefit or not, regardless of the ICI received. From a real-life retrospective analysis of metastatic melanoma patients, we generated and validated an algorithm based on machine learning that could assist with the clinical decision of whether or not to apply ICI therapy by defining five signatures of predictability with 95% accuracy.

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