scholarly journals Endocrine Toxicity and Outcomes in Patients with Metastatic Malignancies treated with Immune Checkpoint Inhibitors

2021 ◽  
Author(s):  
Suleiman I Al Ashi ◽  
Bicky Thapa ◽  
Monica Flores ◽  
Ramsha Ahmed ◽  
Shab E Gul Rahim ◽  
...  
Keyword(s):  
Overall Survival ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Metastatic Cancer ◽  
Adult Population ◽  
Cleveland Clinic ◽  
Response To Treatment ◽  
Pituitary Insufficiency ◽  
Advanced Malignancies

Abstract Context Immune checkpoint inhibitors (ICIs) have gained a revolutionary role in management of many advanced malignancies. However, immune-related endocrine events (irEEs), have been associated with their use. irEEs have non-specific clinical presentations and variable timelines, making their early diagnosis challenging. Objective To identify risk factors, timelines, and prognosis associated with irEEs development. Design and setting Retrospective observational study within the Cleveland Clinic center. Patients Metastatic cancer adult patients who received ICIs were included. Methods 570 charts were reviewed to obtain information on demographics, ICIs used, endocrine toxicities, cancer response to treatment with ICI, and overall survival. Main Outcome Measures Incidence of irEEs, time to irEEs development, and overall survival of patients who develop irEEs. Results The final cohort included 551 patients. The median time for the diagnosis of irEEs was 11 weeks. Melanoma was associated with the highest risk for irEEs (31.3%). Ipilimumab appeared to have the highest percentage of irEEs (29.4%), including the highest risk of pituitary insufficiency (11.7%), the most severe (Grade 4 in 60%) and irreversible (100%) forms of irEEs. 45 % of patients with irEEs had adequate cancer response to ICI compared to 28.3 % of patients without irEEs (p= 0.002). Patients with irEEs had significantly better survival compared to patients without irEEs (P <0.001). Conclusions In the adult population with metastatic cancer receiving treatment with ICI, irEEs development may predict tumor response to immunotherapy and a favorable prognosis. Ipilimumab use, combination ICI therapy, and melanoma are associated with a higher incidence of irEEs.

190 Timing of steroid doses and response rates to immune-checkpoint inhibitors in metastatic cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A204-A204
Author(s):  
Karine Tawagi ◽  
Diana Maslov ◽  
Victoria Simenson ◽  
Helen Yuan ◽  
Cameron Parent ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Metastatic Cancer ◽  
Progression Free Survival ◽  
Response Rates ◽  
Free Survival ◽  
Treatment Type

BackgroundCorticosteroids (CS) are the mainstay of immune-related adverse effect (irAE) management, as well as for other indications in cancer treatment. Previous studies evaluating whether CS affect immune checkpoint inhibitor (CPI) efficacy compared patients receiving steroids vs. no steroids.1 This comparison may be confounded by different rates of irAEs, which are known to be associated with higher response rates to CPIs. Preclinically CS have been shown to diminish naïve T-cell proliferation and differentiation,2 though there is a paucity of clinical data evaluating how the timing of concomitant CS affects CPI efficacy.MethodsWe retrospectively collected data from patients treated with CPIs alone, who received CS during their CPI treatment at a single institution. Patients were allocated into two cohorts based on timing of initiation of CS (> 2 months vs. < 2 months after initiating CPI). Patient characteristics, irAEs, cancer type, treatment type, treatment response/progression per RECIST v1.1, and survival data were collected. Kaplan Meier and Cox proportional hazard regression methods were used to estimate hazard ratios (HR) for the primary endpoint of progression free survival (PFS) along with overall survival (OS).ResultsWe identified 247 patients with metastatic cancer who received CS concurrently with CPIs alone. The majority of patients had non-small cell lung cancer (n=98), followed by renal cell carcinoma (n=43), and melanoma (n=30). 242 patients were on PD-1 inhibitor monotherapy, while 45 patients received CPI in combination with anti-CTLA-4 ipilimumab (table 1). The median time on steroids for all patients was 1.8 months. After adjusting for differences in rates of treatment type, tumor type, brain metastases and irAEs, patients who were treated with CS > 2 months after starting CPI had a statistically significant longer progression free survival (PFS) [HR of 0.33, p≤0.0001], and overall survival (OS) [HR of 0.36, p≤0.0001] than those who received steroids < 2 months after starting CPI. Rates of irAEs in each group were not significantly different (p = 0.15). Objective response rate (ORR) for patients on CS > 2 months was 39.8%, vs. ORR for patients <2 months was 14.7% (p-value = <0.001).Abstract 190 Table 1Cancer subtypes and drug types in the study population (n=247)ConclusionsAfter adjusting for possible confounding factors such as rates of irAEs, our results suggest that early use of steroids during CPI treatment significantly hinders CPI efficacy. These data need to be validated prospectively. Future studies should focus on the immune mechanisms by which CS affect T-cell function early in CPI treatment course.ReferencesGarant A, Guilbault C, Ekmekjian T, Greenwald Z, Murgoi P, & Vuong T. ( 2017). Concomitant use of corticosteroids and immune checkpoint inhibitors in patients with hematologic or solid neoplasms: a systematic review. Critical reviews in oncology/hematology120, 86–92.Giles AJ, Hutchinson MKN, Sonnemann HM, Jung J, Fecci PE, Ratnam NM,. .. & Reid CM. Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy. Journal for immunotherapy of cancer 2018;6(1):1–13.

The Current Role of Immunotherapy in mCRPC: A Systematic Review

2021 ◽  
Vol 8 (7) ◽  
Author(s):  
Dalibey H ◽  
◽  
Hansen TF ◽  
Zedan AH ◽  
◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Systematic Review ◽  
Overall Survival ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Specific Antigen ◽  
Treatment Modalities ◽  
Significant Difference

Background: The development of immunotherapy has shown promising results in several malignant diseases, including prostate cancer, calling for a systematic review of the current literature. This review aims to evaluate the present data and prospects of immune checkpoint inhibitors in metastatic Castration Resistant Prostate Cancer (mCRPC). Methods: Articles were identified via a systematic search of the electronic database Pubmed, in accordance with the PICO process and following the PRISMA guidelines. Articles in English studying immune checkpoint inhibitors in patients with mCRPC published between March 2010 and March 2020 were eligible for inclusion. Endpoints of interest were Overall Survival (OS), Progression-Free Survival (PFS), clinical Overall Response Rate (ORR), and Prostate-Specific Antigen (PSA) response rate. Results: Ten articles were identified as eligible for inclusion. The studies primarily explored the use of Ipilimumab, a CTLA-4 inhibitor, and Pembrolizumab, a PD-1 inhibitor. These drugs were both used either as monotherapy or in combination with other treatment modalities. The largest trial included in the review demonstrated no significant difference in overall survival between the intervention and placebo. However, two studies presented promising data combing immunotherapy and immune vaccines. Grade 3 and 4 adverse events ranging from 10.1% to 82.3%, whit diarrhea, rash, and fatigue were the most frequently reported. Forty relevant ongoing trials were identified exploring immunotherapy with or without a parallel treatment modality. Conclusion: Overall, the current data shows that the effect of immune checkpoint inhibitors as monotherapy may have limited impact on mCRPC, and the results from ongoing combinational trials are eagerly awaited.

scholarly journals 803 Immune-related adverse events correlate with improved outcomes in patients with advanced non-small cell lung cancer treated with combinations of immune-checkpoint inhibitors and chemotherapy

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A840-A840
Author(s):  
Lindsey Shantzer ◽  
Sean Dougherty ◽  
Wendy Novicoff ◽  
John Melson ◽  
Daniel Reed ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Adverse Events ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Small Cell Lung

BackgroundImmune checkpoint inhibitors (ICIs) have become the backbone of treatment for most driver-mutation negative, advanced non-small cell lung cancers. ICIs have been approved both as monotherapy and in combination with chemotherapy for front line management. While ICIs are generally regarded as well-tolerated, an unintended activation of the immune system can result in a variety of immune-related adverse events (irAEs), which can limit their use in severe cases. In patients with NSCLC treated with ICI monotherapy, the occurrence of an irAE and the development of multisystem irAEs have been associated with improved clinical outcomes, suggesting irAE occurrence could have prognostic implications.1–4 However, in patients treated with combination immunotherapy plus chemotherapy, the correlation between irAEs and survival has not been completely elucidated.MethodsWe conducted a retrospective chart review of 94 patients with advanced NSCLC treated with a combination of ICI plus chemotherapy between 2015 and 2021 to evaluate for a correlation between irAE occurrence and overall survival (OS). Patients were divided into two groups: those who experienced at least one irAE and those who did not experience an irAE. To account for immortal time bias, we conducted landmark analyses at 12 and 24 weeks. We additionally investigated the impact of multisystem irAEs on clinical outcomes and described the profile of irAEs observed at our institution.ResultsAmong the 94 evaluable patients identified in our population, 43.6% experienced at least one irAE. Of those patients who experienced an irAE, 26 (63.4%) experienced a single irAE, 9 (22.0%) experienced 2 irAEs, and 6 (14.6%) experienced 3 or more irAEs. The most commonly observed irAEs were dermatitis followed by pneumonitis and colitis. In our cohort, patients with at least one irAE had significantly longer median OS (16.8 mos vs 9.8 mos) compared to those who did not experience an irAE (HR 0.51, 95% CI 0.43–0.76, p=0.011) (figure 1). Landmark survival analyses at 12 and 24 weeks continued to support significant differences in median OS based on presence or absence of an irAE (HR 0.49, 95% CI 0.24–0.46, and HR 0.45, 95% CI 0.21–0.60 respectively). Among patients with at least one irAE, the subset of patients who experienced multiple irAEs had further improved median OS compared to those with a single irAE.ConclusionsIn patients with advanced NSCLC treated with combination ICI plus chemotherapy, the occurrence of an irAE is associated with improved overall survival.ReferencesTeraoka S, Fujimoto D, Morimoto T, et al. Early Immune-related adverse events and association with outcome in advanced non-small cell lung cancer patients treated with Nivolumab: a prospective cohort study. Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer 2017;12(12):1798–1805. doi:10.1016/j.jtho.2017.08.022.Ricciuti B, Genova C, De Giglio A, et al. Impact of immune-related adverse events on survival in patients with advanced non-small cell lung cancer treated with nivolumab: long-term outcomes from a multi-institutional analysis. Journal of Cancer Research and Clinical Oncology 2019;145(2):479–485. doi:10.1007/s00432-018-2805-3.Toi Y, Sugawara S, Kawashima Y, et al. Association of immune-related adverse events with clinical benefit in patients with advanced non-small-cell lung cancer treated with nivolumab. The Oncologist. 2018;23(11):1358–1365. doi:10.1634/theoncologist.2017-0384.Shankar B, Zhang J, Naqash AR, et al. Multisystem immune-related adverse events associated with immune checkpoint inhibitors for treatment of non-small cell lung cancer. JAMA Oncol 2020;6(12):1952–1956. doi:10.1001/jamaoncol.2020.5012Ethics ApprovalThis research study obtained ethics approval by the institutional review board at the University of Virginia, IRB# 19083.Abstract 803 Figure 1Overall Survival by presence or absence of an irAE in patients with advanced lung cancer treated with immune checkpoint inhibitors plus chemotherapy

The effect of concomitant cannabinoids during immune checkpoint inhibitor treatment of advanced stage malignancy.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15064-e15064
Author(s):  
Adam Biedny ◽  
Susan Szpunar ◽  
Ahmed Abdalla ◽  
Zyad Kafri ◽  
Tarik H. Hadid
Keyword(s):  
Overall Survival ◽  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Advanced Stage ◽  
Anti Inflammatory ◽  
Inflammatory Effect

e15064 Background: Immune checkpoint inhibitors are used in treatment of advanced neoplasms. Immunotherapy agents create a potent pro-inflammatory effect in cancer. The efficacy of immunotherapy may negatively be impacted by the use of anti-inflammatory agents. An anti-inflammatory effect of cannabinoids has been described in literature in several models. Recent data suggests a negative impact of cannabis on tumor response to immunotherapy. Methods: We retrospectively reviewed medical records of all patients with metastatic cancer who received at least 2 months of immune checkpoint inhibitors between August 2014 and August 2018. The patients were stratified by use of cannabis (cannabis vs non-cannabis users). Baseline patients’ characteristics were compared. Overall survival was estimated and compared between the two groups. An analysis was performed using analysis of variance, Student's t-test, correlation, chi-squared test, and logrank test. All data were analyzed with SPSS v. 26.0 and a p-value less than 0.05 was set to indicate statistical significance. Results: A total of 104 patients with advanced-stage malignancy met the inclusion criteria. The median age was 63.9±10.5 years, 48.1% males and 81.7% Caucasians. 41.3% of patients has lung adenocarcinoma, 20.3% has squamous cell carcinoma of the lung, 11.5% has squamous cell carcinoma of the head and neck and 26.9% have other tumor types. Twenty patients (19.2%) had brain metastasis and twenty-three patients (22.1%) had bone metastasis. Seventy patients (66.8%) received Nivolumab, and twenty-seven patients (26%) received Pembrolizumab. The mean duration of immunotherapy use was 10.2 months. Characteristics of patients were similar between the groups except for a higher prevalence of tobacco use in the cannabis group. Twenty-eight patients (26.9%) reported concomitant cannabis use during immunotherapy treatment, 23 were prescribed (dronabinol) and 5 used it recreationally (smoking marijuana/cannabis oil). Non-cannabis users had significantly longer overall survival (OS) compared to cannabis users (40 months vs 16 months, p = 0.004). Conclusions: This study shows significant association between the use of cannabis during immunotherapy treatment and worse OS. This can be explained by an anti-inflammatory effect of cannabis, which may decrease response to immune checkpoint inhibitors. This observation should be further investigated in randomized trials. Health care professionals should be aware of the potentially harmful effect of cannabis on cancer care.

Association of antibiotic exposure with overall survival and colitis in patients with stage III and IV melanoma receiving immune checkpoint inhibitors.

2020 ◽  
Vol 38 (5_suppl) ◽  
pp. 56-56
Author(s):  
Brian Chu ◽  
Jahan J. Mohiuddin ◽  
Andrea Facciabene ◽  
Xingmei Wang ◽  
Abigail Doucette ◽  
...  
Keyword(s):  
Overall Survival ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Stage Iii ◽  
Secondary Outcome ◽  
Future Research ◽  
Antibiotic Exposure ◽  
Primary Analysis ◽  
Immune Mediated

56 Background: Recent studies suggest that changes in the gut microbiome modulate response to cancer treatment, including immune checkpoint inhibitors (ICI). Broad-spectrum antibiotics (Abx) are known to cause significant dysbiosis. We hypothesize that recent Abx exposure worsens outcomes in patients (pts) with stage III/IV melanoma (MM) receiving ICI. Methods: We identified MM pts treated with ICI from our institutional database. All received their first ICI between 2004-2019. Antibiotic exposure was defined as receipt of Abx within 3 months prior to the first infusion of ICI. The primary outcome was overall survival (OS) and the secondary outcome was immune-mediated colitis requiring intravenous (IV) steroids. Stage III and IV pts were analyzed separately for the primary analysis. Results: Of 568 pts in our database, 20% received Abx within the 3 months prior to ICI. 36% of pts had stage III disease and 26% of pts were treated with either adjuvant or neoadjuvant ICI. 1.6% of pts died of causes other than MM. The Abx+ and Abx- groups were balanced in terms of stage, race, age, sex, BRAF status, LDH, prior systemic therapies, and class of ICI received. Only 4 pts were hospitalized due to the infection prompting the Abx, and no pts died due to the infection. In the Stage IV group, Abx+ pts had worse OS on MV analysis (HR 1.6, 95% CI 1.1-2.2). Stage III Abx+ also had worse OS (HR 2.8, 95% CI 1.3-5.9). In a sensitivity analysis excluding pts who received IV Abx or were admitted due to infection, survival was still worse for Abx+ pts (HR 1.7, 95% CI 1.2-2.4). In a Fine-Grey competing risk MV model, Abx+ had a higher rate of immune-mediated colitis requiring IV steroids (HR 2.1, 95% CI 1.02-4.5). Conclusions: In MM pts treated with ICI, receipt of Abx within 3 months prior to ICI initiation was associated with decreased OS and increased colitis. Future research should include prospective studies to better define the risk/benefit profile of antibiotics in close proximity to ICI. [Table: see text]

scholarly journals Association Between FSIP2 Mutation and an Improved Efficacy of Immune Checkpoint Inhibitors in Patients With Skin Cutaneous Melanoma

2021 ◽  
Vol 8 ◽  
Author(s):  
Haoxuan Ying ◽  
Anqi Lin ◽  
Junyi Liang ◽  
Jian Zhang ◽  
Peng Luo
Keyword(s):  
Immune Checkpoint ◽  
Cutaneous Melanoma ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Response To Treatment ◽  
Interacting Protein ◽  
Tumor Immunogenicity

BackgroundImmune checkpoint inhibitors (ICIs) have shown remarkable success in treating skin cutaneous melanoma (SKCM); however, the response to treatment varies greatly between patients. Considering that the efficacy of ICI treatment is influenced by many factors, we selected the Fibrosheath interacting protein 2 (FSIP2) gene and systematically analyzed its potential to predict the efficacy of ICI treatment.MethodsPatient data were collected from an ICI treatment cohort (n = 120) and a The Cancer Genome Atlas (TCGA)-SKCM cohort (n = 467). The data were divided into an FSIP2-mutant (MT) group and FSIP2-wild-type (WT) group according to FSIP2 mutation status. In this study, we analyzed the patients’ overall survival rate, tumor mutational burden (TMB), neoantigen load (NAL), copy number variation (CNV), cell infiltration data and immune-related genes. We used gene set enrichment analysis (GSEA) to delineate biological pathways and processes associated with the efficacy of immunotherapy.ResultsThe efficacy of ICI treatment of SKCM patients with FSIP2 mutation was significantly better than that of patients without FSIP2 mutation. The patients in the FSIP2-MT group had higher tumor immunogenicity and lower regulatory T cell (Treg) infiltration. Results of GSEA showed that pathways related to tumor progression (MAPK and FGFR), immunomodulation, and IL-2 synthesis inhibition were significantly downregulated in the FSIP2-MT group.ConclusionOur research suggests that the FSIP2 gene has the potential to predict the efficacy of ICI treatment. The high tumor immunogenicity and low Treg levels observed may be closely related to the fact that patients with FSIP2-MT can benefit from ICI treatment.

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