Immune-related adverse events (irAEs) affect all organs and are associated with various symptoms. The identification of biomarkers that can predict irAEs may be particularly clinically useful. This ...study aimed to investigate whether the prognostic nutritional index (PNI) before the initiation of immune checkpoint inhibitor (ICI) treatment can predict the occurrence of irAEs. We conducted a survey of 111 patients with cancer who were receiving ICI fixed-dose monotherapy at Saga University Hospital from the time each ICI became available until January 2020. We compared the PNI between the patients with and without irAE expression, established a cutoff value for PNI associated with the development of irAEs, and investigated the incidence of irAEs and progression-free survival (PFS) in groups divided by the cutoff value. Patients with irAEs had significantly higher PNI than did those without, and there was a significant association between PNI and irAEs after adjusting for potential factors (odds ratio, 1.12; 95% confidence interval, 1.03–1.21). In addition, PNI ≥44.2 was associated with a significantly higher incidence of irAEs (75.0% vs. 35.2%, p = 0.0001) and significantly longer PFS than PNI <44.2 (p = 0.025). In conclusion, pretreatment PNI may be associated with the risk of developing irAEs in patients with advanced recurrent solid tumors. When the PNI is ≥44.2, patient management is important for avoiding serious AEs because while the treatment may be effective, the occurrence of irAEs is a concern.
Introduction
Immune‐related adverse event (IRAE) onset may represent a clinical biomarker for anti‐programmed cell death protein 1 (PD‐1) antibody response based on emerging evidence from patients ...with various advanced malignancies. This phenomenon has not been previously reported in a multidisease cohort of patients with gastrointestinal (GI) cancer with Food and Drug Administration (FDA)‐approved indications to receive immune checkpoint inhibitor therapy.
Materials and Methods
The study was a multicenter retrospective cohort analysis of 76 patients with GI cancer who had received anti‐PD‐1 antibodies for FDA‐approved indications. The primary and secondary outcomes of the study were progression‐free survival (PFS) and overall survival (OS) in patients based upon IRAE presence, respectively. PFS and OS were estimated by the Kaplan‐Meier method; a Cox proportional‐hazards model adjusted for IRAE onset, patient age, and enrolling institution was used to analyze outcomes.
Results
Median PFS and OS were prolonged in patients who experienced IRAEs compared with those who did not experience them (PFS: not reached NR vs. 3.9 months hazard ratio (HR) 0.13, 95% confidence interval (CI) 0.05–0.3, p < .001; OS: NR vs. 7.4 months HR 0.11, 95% CI 0.03–0.36, p < .001). Among patients who experienced IRAEs, there were no significant differences in PFS and OS by either initial IRAE severity, management, or time to onset.
Conclusion
Patients with gastrointestinal cancer who experienced IRAEs while on anti‐PD‐1 antibodies demonstrated significant improvements in PFS and OS compared with their counterparts who did not develop IRAEs. Although these findings add to results from studies in other tumor types, larger prospective studies are needed prior to clinical adoption of IRAE onset as a biomarker for immune checkpoint inhibitor response.
Implications for Practice
Predictive clinical biomarkers for immune checkpoint inhibitor response have been understudied in the field of immuno‐oncology. Immune‐related adverse event onset appears to be one such biomarker. Across tumor types, immune‐related adverse event onset has been associated with response to anti‐programmed cell death protein 1 (PD‐1) antibodies. The results of this study demonstrate this for the first time in patients with gastrointestinal cancer receiving anti‐PD‐1 antibodies. Before immune‐related adverse event onset can be adopted clinically as a predictive biomarker for immune checkpoint inhibitor response, however, larger prospective studies are needed to better understand the nuances between immune‐related adverse event characteristics (severity, site, management, timing of onset) and immune checkpoint inhibitor effectiveness.
Despite the potential of immune checkpoint inhibitors, few patients with gastrointestinal cancer are eligible to receive these therapeutic agents. The search for biomarkers to better select patients who might respond is ongoing. This article assesses immune‐related adverse events as a possible biomarker in gastrointestinal cancer.
Long-term safety of pembrolizumab in melanoma was analyzed in KEYNOTE-001, KEYNOTE-002, and KEYNOTE-006.
Analysis involved patients who received ≥1 pembrolizumab dose. Lead-time bias was addressed ...via landmark analyses in patients who were progression-free before day 147.
Adverse events (AEs) were analyzed for 1567 patients (median follow-up, 42.4 months). Most AEs were mild/moderate; grade 3/4 treatment-related AEs occurred in 17.7% of patients. Two pembrolizumab-related deaths occurred. Any-grade immune-mediated AEs (imAEs) occurred in 23.0%, most commonly hypothyroidism (9.1%), pneumonitis (3.3%), and hyperthyroidism (3.0%); grade 3/4 imAEs occurred in 6.9% of patients. Most imAEs occurred within 16 weeks of treatment. In landmark analysis, patients who did (n = 79) versus did not (n = 384) develop imAEs had similar objective response rates (ORRs) (64.6% versus 63.0%); median time to response (TTR), 5.6 months for both; median duration of response (DOR), 20.0 versus 25.3 months; median progression-free survival (PFS), 17.0 versus 17.7 months; median overall survival (OS), not reached (NR) versus 43 months (p = 0.1104). Patients who did (n = 17) versus did not (n = 62) receive systemic corticosteroids had similar ORRs (70.6% vs. 62.9%) and median TTR (6.4 vs. 5.6 months) but numerically shorter median PFS (9.9 vs. 17.0 months); median DOR, 14.2 months versus NR; median OS, NR for both.
These results enhance the knowledge base for pembrolizumab in advanced melanoma, with no new toxicity signals after lengthy follow-up of a large population. In landmark analyses, pembrolizumab efficacy was similar regardless of imAEs or systemic corticosteroid use.
NCT01295827, NCT01704287, NCT01866319.
•Long-term (3.5 years) safety analysis of pembrolizumab monotherapy in melanoma.•Data were pooled from KEYNOTE-001, KEYNOTE-002, and KEYNOTE-006 trials (N = 1567).•Treatment-related AEs and immune-mediated AEs (imAE) were generally mild/moderate.•In landmark analysis, efficacy was similar regardless of imAEs or corticosteroid use.•With no new toxicity signals, results support pembrolizumab use in advanced melanoma.
Immune checkpoint inhibitors (ICIs) may cause potentially life-threatening adverse events (AEs), but the risk of cardiotoxicity has not been fully investigated. It is also unknown whether ICI ...combinations increase cardiotoxicity compared with single ICI. We aimed to assess the cardiotoxicity of ICI in a range of tumour types.
This systematic review and meta-analysis was conducted according to PRISMA guidelines (PROSPERO registration number: CRD42020183524). A systematic search of PubMed, MEDLINE, Embase databases, and conference proceedings was performed up to 30 June 2020. All randomised clinical trials comparing ICI with other treatments (primary objective) or dual-agent ICI versus single-agent ICI (secondary objective) in any solid tumour were included. Pooled risk ratios (RRs) with 95% confidence intervals (95% CIs) for cardiotoxicity events were calculated using random effect models.
Eighty studies including 35,337 patients were included in the analysis (66 studies with 34,664 patients for the primary endpoint and 14 studies with 673 patients for the secondary endpoint). No significant differences in terms of cardiac AEs were observed between ICI and non-ICI groups (RR 1.14, 95% CI 0.88–1.48, p = 0.326) nor between dual ICI and single ICI groups (RR 1.91, 95% CI 0.52–7.01, p = 0.329). Myocarditis incidence did not significantly differ between ICI and non-ICI groups (RR 1.11, 95% CI 0.64–1.92, p = 0.701) nor between dual ICI and single ICI groups (RR 1.10, 95% CI 0.31–3.87, p = 0.881). No differences were observed in subgroup analyses according to tumour type, setting of disease, treatment line, and type of treatment.
The use of ICI as single or combination regimens is not associated with increased risk of cardiotoxicity.
•Immune checkpoint inhibitors (ICIs) may cause life-threatening adverse events (AEs).•The risk of cardiotoxicity of ICIs has been poorly investigated.•In our meta-analysis, ICIs were not associated with increased cardiotoxicity risk.•Cardiac AEs in clinical trials should be reported as completely as possible.
The functions of, and interactions between, the innate and adaptive immune systems are vital for anticancer immunity. Cytotoxic T cells expressing cell-surface CD8 are the most powerful effectors in ...the anticancer immune response and form the backbone of current successful cancer immunotherapies. Immune-checkpoint inhibitors are designed to target immune-inhibitory receptors that function to regulate the immune response, whereas adoptive cell-transfer therapies use CD8
T cells with genetically modified receptors-chimaeric antigen receptors-to specify and enhance CD8
T-cell functionality. New generations of cytotoxic T cells with genetically modified or synthetic receptors are being developed and evaluated in clinical trials. Furthermore, combinatory regimens might optimise treatment effects and reduce adverse events. This review summarises advances in research on the most prominent immune effectors in cancer and cancer immunotherapy, cytotoxic T cells, and discusses possible implications for future cancer treatment.
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Recently, concerns regarding the safety of red yeast rice (RYR) have been raised after the publication of some case reports claiming toxicity. Since the previous meta-analyses on the ...effects of RYR were mainly focused on its efficacy to improve lipid profile and other cardiovascular parameters, we carried out a meta-analysis on safety data derived from the available randomized controlled clinical trials (RCTs).
Primary outcomes were musculoskeletal disorders (MuD). Secondary outcomes were non-musculoskeletal adverse events (Non-MuD) and serious adverse events (SAE). Subgroups analyses were carried out considering the intervention (RYR alone or in association with other nutraceutical compounds), monacolin K administered daily dose (≤3, 3.1–5 or >5 mg/day), follow-up (>12 or ≤12 weeks), with statin therapy or statin-intolerance and type of control treatment (placebo or statin treatment).
Data were pooled from 53 RCTs comprising 112 treatment arms, which included 8535 subjects, with 4437 in the RYR arm and 4303 in the control one. Monacolin K administration was not associated with increased risk of MuD (odds ratio (OR) = 0.94, 95% confidence interval (CI) 0.53,1.65). Moreover, we showed reduced risk of Non-MuD (OR = 0.59, 95%CI 0.50, 0.69) and SAE (OR = 0.54, 95%CI 0.46, 0.64) vs. control. Subgroups analyses confirmed the high tolerability profile of RYR. Furthermore, increasing daily doses of monacolin K were negatively associated with increasing risk of Non-MuD (slope: -0.10; 95%CI: -0.17, -0.03; two-tailed p < 0.01).
Based on our data, RYR use as lipid-lowering dietary supplement seems to be overall tolerable and safe in a large kind of moderately hypercolesterolaemic subjects.
To investigate the association between the onset, severity, and type of immune‐related adverse events (irAEs) and the efficacy of pembrolizumab in patients with platinum‐pretreated advanced ...urothelial carcinoma (UC), we retrospectively collected clinical datasets of 755 patients and conducted landmark analysis. Patients who survived for fewer than 3 months were excluded from the evaluation to reduce the immortal time bias. In total, 620 patients were evaluated, of whom 220 patients (35.5%) experienced grade ≥2 irAEs, including 134 patients with grade 2 irAEs and 86 with grade ≥3 irAEs. Propensity score matching extracted 198 patients with and without grade ≥2 irAEs. The onset of grade ≥2 irAEs was associated with longer median progression‐free survival (PFS) (8.3 months vs. 4.5 months, p = 0.003) and overall survival (OS) (20.4 months vs. 14.3 months, p = 0.031) and a higher objective response rate (ORR) (44.8% vs. 30.2%, p = 0.004). Patients with grade 2 irAEs had significantly better oncological outcomes (PFS, OS, and ORR) than grade ≤1 and ≥3 irAEs. Patients with grade ≥3 irAEs had worse outcomes than grade 2 irAEs. Endocrine and skin irAEs were related with better survival outcomes, and the rate of severities was lower in these categories. In conclusion, the occurrence of irAEs, particularly low‐grade irAEs, was predictive of pembrolizumab efficacy in patients with platinum‐pretreated advanced UC.
Kaplan‐Meier plots analysis showing OS for 396 patients with grade ≥2 irAEs and with grade 1 or no irAEs who survived longer than 3 months after propensity score matching. The onset of grade ≥2 irAEs was associated with longer median OS (20.4 months vs. 14.3 months, p = 0.031).
Background
Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but may also trigger autoimmune adverse drug reactions (ADRs) referred to as immune‐related adverse events (irAEs). ...Although endocrinopathies are among the most common form of irAEs, primary adrenal insufficiency (PAI) is infrequent and has only been published in case reports. The aim of this study was to identify and characterize the main features of PAI‐irAE.
Materials and Methods
Suspected PAI‐irAE cases were identified using VigiBase, the World Health Organization's pharmacovigilance database of individual case safety reports.
Results
From September 2, 2008, through October 5, 2018, a total of 50,108 ICI‐associated ADRs were reported. Since 2008, there were 451 cases of PAI‐irAE identified of which 45 were “definite PAI” and 406 “possible PAI.” Patients were mainly male (58.1%) with a median age of 66 years (range, 30–95). Indications of ICI were predominantly for melanoma (41.2%) and lung cancer (28.6%). The majority of patients were treated with ICI monotherapy (nivolumab: 44.3%, pembrolizumab: 11.7%, ipilimumab: 23.6%), and 17.9% were treated with ICI combination therapy. These events occurred with a median time to onset of 120 days (range, 6–576). ICI‐associated PAI was associated with significant morbidity (≥90% severe) and mortality (7.3%). Fatality rates were similar in the subgroups of combination therapy versus monotherapy. There were no relevant differences in clinical or demographical characteristics and outcomes between “definite” versus “possible” PAI group.
Conclusion
Our study represents the largest clinical description and characterization of PAI‐irAE. Although ICI‐associated PAI is a rare adverse event, early recognition is important to implement corticosteroid treatment. Further studies are required to elucidate risk factors and reversibility of this rare but severe irAE. Clinical trial identification number. NCT03492242
Implications for Practice
Immune checkpoint inhibitor (ICI)‐associated primary adrenal insufficiency (PAI) is a rare adverse event that is important to recognize because it may be severe and life‐threatening, requiring emergent and often lifelong hormonal replacement therapy. Awareness regarding this ICI‐related endocrinopathy is strongly encouraged among clinicians in addition to patient education about common PAI symptoms that should prompt urgent medical evaluation. In clinical practice, close monitoring and investigation for PAI is crucial to allow for early management and to further define the pathophysiology and prognosis of ICI‐PAI. Corticotrophin (adrenocorticotrophic hormone) circulating level evaluation may be often lacking but should be considered as part of the diagnostic workup to differentiate PAI from secondary (central) adrenal insufficiency.
Limited data are available for immune‐related adverse events related to primary adrenal insufficiency. This article characterizes such events using Vigibase, the WHO's global database of individual case safety reports.
Summary
Background
Tralokinumab is a fully human monoclonal antibody that specifically neutralizes interleukin‐13, a key driver of atopic dermatitis (AD).
Objectives
To evaluate the efficacy and ...safety of tralokinumab in combination with topical corticosteroids (TCS) in patients with moderate‐to‐severe AD who were candidates for systemic therapy.
Methods
This was a double‐blind, placebo plus TCS controlled phase III trial. Patients were randomized 2 : 1 to subcutaneous tralokinumab 300 mg or placebo every 2 weeks (Q2W) with TCS as needed over 16 weeks. Patients who achieved an Investigator’s Global Assessment (IGA) score of 0/1 and/or 75% improvement in Eczema Area and Severity Index (EASI 75) at week 16 with tralokinumab were rerandomized 1 : 1 to tralokinumab Q2W or every 4 weeks (Q4W), with TCS as needed, for another 16 weeks.
Results
At week 16, more patients treated with tralokinumab than with placebo achieved IGA 0/1: 38·9% vs. 26·2% difference (95% confidence interval): 12·4% (2·9–21·9); P = 0·015 and EASI 75: 56·0% vs. 35·7% 20·2% (9·8–30·6); P < 0·001. Of the patients who were tralokinumab responders at week 16, 89·6% and 92·5% of those treated with tralokinumab Q2W and 77·6% and 90·8% treated with tralokinumab Q4W maintained an IGA 0/1 and EASI 75 response at week 32, respectively. Among patients who did not achieve IGA 0/1 and EASI 75 with tralokinumab Q2W at 16 weeks, 30·5% and 55·8% achieved these endpoints, respectively, at week 32. The overall incidence of adverse events was similar across treatment groups.
Conclusions
Tralokinumab 300 mg in combination with TCS as needed was effective and well tolerated in patients with moderate‐to‐severe AD.
What is already known about this topic?
Atopic dermatitis (AD) is a chronic interleukin (IL)‐13‐mediated disease.
In clinical practice, biologics are commonly initiated as add‐on therapy to topical corticosteroids (TCS).
Tralokinumab is a fully human monoclonal antibody that binds specifically to the IL‐13 cytokine with high affinity, thereby preventing receptor interaction and subsequent downstream signalling.
Tralokinumab combined with TCS showed early and sustained efficacy and safety in a 12‐week, phase IIb trial in moderate‐to‐severe AD.
What does this study add?
This is the first phase III trial evaluating a targeted anti‐IL‐13 biologic in combination with TCS.
These data demonstrate that tralokinumab plus TCS can achieve significant improvements in AD signs and symptoms and quality of life, as well as exert a steroid‐sparing effect.
Response with tralokinumab in combination with TCS was maintained over 32 weeks.
Tralokinumab may be considered a targeted biological treatment option for patients with moderate‐to‐severe AD.
Linked Comment: Morra and Drucker. Br J Dermatol 2021; 184:386–387.
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