scholarly journals Therapeutic and Systemic Adverse Events of Immune Checkpoint Inhibitors Targeting the PD-1/PD-L1 axis for Clinical Management of NSCLC

2021 ◽  
Vol 30 ◽  
pp. 096368972110415
Author(s):  
Jing Chen ◽  
Yaser Alduais ◽  
Baoan Chen
Keyword(s):  
Monoclonal Antibodies ◽  
Adverse Effects ◽  
Adverse Events ◽  
Immune Evasion ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Critical Parameters ◽  
Small Cell Lung ◽  
Randomized Controlled ◽  
Google Search

Non-small-cell lung cancer takes up the majority of lung carcinoma-caused deaths. It is reported that targeting PD-1/PD-L1, a well-known immune evasion checkpoint, can eradicate tumor. Checkpoint inhibitors, such as monoclonal antibodies, are actively employed in cancer treatment. Thus, this review aimed to assess the therapeutic and toxic effects of PD-1/PD-L1 inhibitors in treatment of NSCLC. So far, 6 monoclonal antibodies blocking PD-1/PD-L1 interaction are identified and used in clinical trials and randomized controlled trials for NSCLC therapy. These antibody-based therapies for NSCLC were collected by using search engine PubMed, and articles about the assessment of adverse events were collected by using Google search. Route of administration and dosage are critical parameters for efficient immunotherapy. Although antibodies can improve overall survival and are expected to be target-specific, they can cause systemic adverse effects in the host. Targeting certain biomarkers can limit the toxicity of adverse effects of the antibody-mediated therapy. Clinical experts with knowledge of adverse effects (AEs) of checkpoint inhibitors can help manage and reduce mortalities associated with antibody-based therapy of NSCLC.

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

Potential role of serum proteome in predicting immune-related adverse events from immune checkpoint inhibitors in non-small cell lung cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21218-e21218
Author(s):  
Leeseul Kim ◽  
Young Kwang Chae ◽  
Chan Mi Jung ◽  
Emma Yu ◽  
Alice Daeun Lee ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Adverse Events ◽  
Small Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
Significant Difference ◽  
Nsclc Patients

e21218 Background: Early recognition of immune-related adverse events (irAEs) of immune checkpoint inhibitors(ICI) is important. Circulating proteome reflects host response to diseases and is being explored as a marker for response to immunotherapy. We previously have reported that a serum-based proteomics test, Primary Immune Response (PIR) demonstrated a trend that PIR-sensitive patients are more likely to tolerate ICI treatment longer without developing irAEs in non-small cell lung cancer (NSCLC) patients. The VeriStrat test is another serum-based proteomic assay, which was reported to be predictive of survival outcomes for all treatment regimens and lines of therapy including ICI in NSCLC. We explored the associations between the VeriStrat test and developing irAEs in NSCLC patients treated with ICI. Methods: Data of 70 consented NSCLC patients treated with any regimens and lines of therapy including ICI were collected. Samples were grouped into either VeriStrat ‘Good’(VS-G) or VeriStrat ‘Poor’(VS-P). We analyzed the durations from the immunotherapy initiation to each episode of irAE and each irAE above grade 2 using log-rank test. IrAEs were graded according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Results: Among the 70 patients, 18 patients (25%) experienced one or more irAEs. There was no significant difference in ‘Time to first irAE’ between VS-G and VS-P (p = 0.72, HR = 0.82, 95% CI = 0.29-2.32). Among 48 VS-G patients, 12(25%) had one or more irAE and 5(10%)had irAE graded over 2. Among 22 VS-P patients, 6(27%) had one or more irAE and 2(9%) had irAE graded over 2. There was no significant difference between VS-G and VS-P groups in the development of irAE and irAE graded over 2. Conclusions: There was no statistically significant association between the VeriStrat test and the development of irAEs. Further studies are warranted to investigate proper serum based proteomic assay to predict the development of irAE.

scholarly journals Systematic Review and Network Meta-Analysis of Immune Checkpoint Inhibitors in Combination with Chemotherapy as a First-Line Therapy for Extensive-Stage Small Cell Carcinoma

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3629
Author(s):  
Hsiao-Ling Chen ◽  
Yu-Kang Tu ◽  
Hsiu-Mei Chang ◽  
Tai-Huang Lee ◽  
Kuan-Li Wu ◽  
...  
Keyword(s):  
Systematic Review ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Small Cell ◽  
Randomized Controlled ◽  
Extensive Stage ◽  
Grade 3

Patients with extensive-stage small cell lung cancer (ED-SCLC) have a very short survival time even if they receive standard cytotoxic chemotherapy with etoposide and platinum (EP). Several randomized controlled trials have shown that patients with ED-SCLC who received a combination of EP plus immune checkpoint inhibitors (ICIs) had superior survival compared with those who received EP alone. We conducted a systematic review and network meta-analysis to provide a ranking of ICIs for our primary endpoints in terms of overall survival (OS), progression free survival (PFS), and objective response rate (ORR), as well as our secondary endpoint in terms of adverse events. The fractional polynomial model was used to evaluate the adjusted hazard ratios for the survival indicators (OS and PFS). Treatment rank was estimated using the surface under the cumulative ranking curve (SUCRA), as well as the probability of being best (Prbest) reference. EP plus nivolumab, atezolizumab or durvalumab had significant benefits compared with EP alone in terms of OS (Hazard Ratio HR = 0.67, 95% Confidence Interval CI = 0.46–0.98 for nivolumab, HR = 0.70, 95% CI = 0.54–0.91 for atezolizumab, HR = 0.73, 95% CI = 0.59–0.90 for durvalumab) but no significant differences were observed for pembrolizumab or ipilimumab. The probability of nivolumab being ranked first among all treatment arms was highest (SCURA = 78.7%, Prbest = 46.7%). All EP plus ICI combinations had a longer PFS compared with EP alone (HR = 0.65, 95% CI = 0.46–0.92 for nivolumab, HR = 0.77, 95% CI = 0.61–0.96 for atezolizumab, HR = 0.78, 95% CI = 0.65–0.94 for durvalumab, HR = 0.75, 95% CI = 0.61–0.92 for pembrolizumab), and nivolumab was ranked first in terms of PFS (SCURA = 85.0%, Prbest = 66.8%). In addition, nivolumab had the highest probability of grade 3–4 adverse events (SUCRA = 84.8%) in our study. We found that nivolumab had the best PFS and OS in all combinations of ICIs and EP, but nivolumab also had the highest probability of grade 3–4 adverse events in our network meta-analysis. Further head-to head large-scale phase III randomized controlled studies are needed to verify our conclusions.

scholarly journals Checkpoint inhibitors plus chemotherapy for first-line treatment of advanced non-small cell lung cancer: a systematic review and meta-analysis of randomized controlled trials

2019 ◽  
Vol 5 (9) ◽  
pp. FSO421 ◽  
Author(s):  
Aung Myint Tun ◽  
Kyaw Zin Thein ◽  
Wai Lin Thein ◽  
Elizabeth Guevara
Keyword(s):  
Adverse Events ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Objective Response ◽  
Small Cell ◽  
High Grade ◽  
Line Treatment ◽  
Small Cell Lung ◽  
First Line ◽  
First Line Treatment

Background: We conducted a meta-analysis to evaluate the efficacy and safety of upfront add-on immunotherapy for advanced non-small cell lung cancers (NSCLC). Methods: We performed a literature search on first-line chemotherapy ± immunotherapy in NSCLC. We utilized Revman version 5.3 to calculate the estimated pooled hazard ratio for overall survival (OS) and progression-free survival (PFS) and pooled risk ratio for objective response rate (ORR), all-grade and high-grade adverse events with 95% CI. Results: We analyzed 4322 patients. The pooled hazard ratios for OS, PFS and ORR were 0.74 (95% CI: 0.62–0.88; p = 0.0007), 0.62 (95% CI: 0.57–0.68; p = 0.00001) and 1.51 (95% CI: 1.3–1.74; p = 0.00001), respectively. The pooled risk ratios for all-grade and high-grade adverse events were 1.01 (95% CI: 0.99–1.03; p = 0.27) and 1.17 (95% CI: 1.07–1.28; p = 0.0006), respectively. Conclusion: Add-on immunotherapy significantly improves PFS, OS and ORR for the first-line treatment of advanced NSCLC with a reasonable safety profile.

Panuveitis in patient on ipilimumab/nivolumab combination for small-cell lung cancer treated with an intravitreal dexamethasone implant

2020 ◽  
pp. 107815522096979
Author(s):  
Jade L Hefler ◽  
Lauren M Bailey ◽  
Cynthia El Rahi ◽  
Amy C Schefler ◽  
Eric H Bernicker
Keyword(s):  
Lung Cancer ◽  
Adverse Events ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Checkpoint Inhibitors ◽  
Early Recognition ◽  
Small Cell ◽  
Small Cell Lung ◽  
Antitumor Effects ◽  
Serious Adverse Events

Background Immunotherapy with checkpoint inhibitors has demonstrated durable responses and remarkable antitumor effects in a variety of cancers. Although these agents are generally well-tolerated, patients can experience immune-related adverse events (irAEs) that require prompt recognition by healthcare providers. Immune-related ocular toxicities are rare, but serious adverse events have been reported with the use of checkpoint inhibitors. Case presentation: Here, we describe a rare case of panuveitis during Nivolumab and Ipilimumab combination treatment in a patient being treated for recurrent Small Cell Lung Cancer (SCLC). The patient was managed with an injection of Ozurdex (Allergan, Madison, NJ), a dexamethasone intravitreal implant. The patient had a resolution of inflammation and an improvement in her vision and was able to resume nivolumab monotherapy without recurrence of the panuveitis. Conclusion This case highlights the importance of early recognition of ocular irAEs by ocular oncologists and the successful approach to treatment of immunotherapy-induced panuveitis in order to avoid permanent cessation of therapy.

Real-world comparison of immune checkpoint inhibitors in non-small cell lung cancer following platinum-based chemotherapy

2019 ◽  
Vol 26 (3) ◽  
pp. 564-571 ◽  
Author(s):  
Taylor M Weis ◽  
Shannon Hough ◽  
Haritha G Reddy ◽  
Stephanie Daignault-Newton ◽  
Gregory P Kalemkerian
Keyword(s):  
Lung Cancer ◽  
Adverse Events ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Response Rates ◽  
Small Cell ◽  
Controlled Trials ◽  
Small Cell Lung ◽  
Randomized Controlled ◽  
Platinum Based Chemotherapy

Purpose Immunotherapy is a relatively new treatment modality for advanced non-small cell lung cancer following platinum-based chemotherapy. Nivolumab, pembrolizumab, and atezolizumab demonstrated superior outcomes and improved tolerability compared to standard treatment in randomized controlled trials; however, these studies vary significantly in inclusion criteria and study design. To our knowledge, the efficacy and safety of nivolumab and atezolizumab following platinum-based chemotherapy have not been directly compared to one another in a real-world clinic setting. Methods We retrospectively compared immunotherapy response rates and toxicity in patients with stage IV or recurrent non-small cell lung cancer following progression during or after platinum-based chemotherapy. Results Among 124 eligible patients, the objective response rate was 14.8% in the nivolumab group (n = 81) vs. 13.9% in the atezolizumab group (n = 43) (p = 0.897). Median overall survival was 8.4 months with nivolumab (95% confidence interval (CI), 6.3 to 11.2) vs. 6.5 months with atezolizumab (95% CI, 4.7 to not reached). Median progression free survival was 2.2 months (95% CI, 1.7 to 2.8) and 2.0 months (95% CI, 1.8 to 2.7) in the nivolumab and atezolizumab groups, respectively. Treatment-related adverse events occurred in 70.4% of patients in the nivolumab group and 65.1% in the atezolizumab group. Conclusions There was no statistically significant difference in efficacy outcomes in patients with non-small cell lung cancer who received atezolizumab or nivolumab after progression during or after platinum-based chemotherapy. Response rates in this study were numerically lower than response rates observed in the landmark randomized controlled trials leading to approval of immunotherapy in this setting. Rates of treatment-related adverse events were similar between groups.

Dermatologic adverse events with immune checkpoint blockade: Systematic review and meta-analysis.

2020 ◽  
Vol 38 (5_suppl) ◽  
pp. 84-84
Author(s):  
Kushal Naha ◽  
Lakshmi Manogna Chintalacheruvu ◽  
Donald C. Doll ◽  
Sowjanya Naha
Keyword(s):  
Adverse Effects ◽  
Adverse Events ◽  
Confidence Interval ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Randomized Controlled ◽  
Dermatologic Adverse Events

84 Background: Immune checkpoint blockade is known to be associated with various dermatologic adverse events. However, these adverse effects have not been studied in a systematic manner. This is especially relevant considering the rapidly increasing number of immune checkpoint inhibitors that are now available. Methods: We searched for eligible studies in PubMed and Google scholar. We reviewed randomized controlled trials involving cancer patients treated with immune checkpoint inhibitors - PD1 inhibitors, PDL1 inhibitors and CTLA4 inhibitors and for dermatologic adverse effects. A total of 47 randomized controlled trials involving 11875 patients met eligibility criteria for our study. Results: Incidence rate of all grade dermatologic adverse effects was 40.6% (95% confidence interval [CI], 39.4-41.7%). Most common adverse effects included pruritus (17.3%) (95% confidence interval [CI] 16.6-18.1%), undifferentiated rash (15.1%) (95% confidence interval [CI] 14.4-15.9%), vitiligo (3.6%) (95% confidence interval [CI] 3.2-3.9%), maculopapular rash (2.3%) (95% confidence interval [CI] 2.1-2.6%), stomatitis (0.7%) (95% confidence interval [CI] 0.55-0.92%) and dry skin (0.7%) (95% confidence interval [CI] 0.5-0.8%). Less common adverse events include palmoplantar erythrodysesthesia, pemphigoid skin reactions, lichen planus and hyperhidrosis. Grade 3 and higher adverse effects were seen in 1.3% of patients (95% confidence interval [CI] 1.1-1.6%). Conclusions: A wide range of dermatologic adverse effects can be seen with immune checkpoint blockade. While the majority of these events are of grade 1-2, they can occasionally be severe and even life threatening. Patients receiving immune checkpoint blockade should be closely monitored for dermatologic adverse effects.

scholarly journals Treatment- and immune-related adverse events of immune checkpoint inhibitors in advanced lung cancer

2020 ◽  
Vol 40 (5) ◽  
Author(s):  
Jun Shao ◽  
Chengdi Wang ◽  
Pengwei Ren ◽  
Yuting Jiang ◽  
Panwen Tian ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Adverse Events ◽  
Small Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Advanced Lung Cancer ◽  
Small Cell Lung ◽  
Organ Specific

Abstract Background: Immune checkpoint inhibitors (ICIs) emerged as the preferred therapy in advanced lung cancer, understanding the treatment- and immune-related adverse events of these drugs is of great significance for clinical practice. Materials and methods: PubMed, Embase, Cochrane library and major conference proceedings were systematically searched for all randomized controlled trials (RCTs) in lung cancer using PD-1/PD-L1/CTLA-4 inhibitors. The outcomes included treatment-related adverse events (TRAEs) and several organ specific immune-related adverse events (IRAEs). Results: 24 RCTs involving 14,256 patients were included. There was a significant difference for ICI therapy in the incidence of any grade of TRAEs (RR: 0.90; 95%CI: 0.84–0.95; P=0.001) and a lower frequency of grade 3-5 of TRAEs (RR: 0.65; 95%CI: 0.51–0.82; P<0.001). Patients treated with ICI therapy in non–small-cell lung cancer (NSCLC) were less reported TRAEs than in small cell lung cancer (SCLC). A lower risk of TRAEs was favored by anti-PD-1 inhibitors over anti-PD-L1 antibodies and anti-CTLA-4 drugs. The most common organ specific IRAE was hypothyroidism that occurred 8.7%. The incidence of pneumonitis and hepatitis reached 4.5% and 4.0% respectively. Compared with patients treated in control arms, those treated with ICI drugs were at higher risk for each organ specific adverse event including colitis, hepatitis, pneumonitis, hypothyroidism and hypophysitis. Conclusions: ICI therapy was safer than chemotherapy, especially ICI monotherapy such as anti-PD-1 antibodies in NSCLC. Compared with standard treatments, ICI drugs increased the risk of organ-specific IRAEs, although the overall incidence remained low.

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