Analysis of Toxicity Profile and Predictors of Immune Checkpoint Inhibitor-Related Adverse Events

doi:10.21203/rs.3.rs-95117/v1

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Analysis of Toxicity Profile and Predictors of Immune Checkpoint Inhibitor-Related Adverse Events

https://doi.org/10.21203/rs.3.rs-95117/v1

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posted 23 Oct, 2020

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Background and objective

In recent years, a wide variety of immune checkpoint inhibitors (ICIs) is emerging and has shown long-lasting and significant efficacy in the treatment of various malignant tumors. However, about 10% of patients experience serious and even life-threatening immune-related adverse events (irAEs). Fully understanding the characteristics of toxic effects and biomarkers to predict irAEs is, therefore, of great interest. We aimed to retrospectively analyze the toxicity profile and predictors of irAEs, as well as the correlation between irAEs and clinical efficacy in patients with advanced pan-cancer who were treated with multi-type ICIs in real-world.

Methods

We retrospectively analyzed data from 105 patients with advanced pan-cancer who were treated with multi-type ICIs in the First Hospital of Jilin University from Jan 1, 2016 to Aug 1, 2020. We used logistic regression analyses to investigate associations between irAEs and clinical baseline characteristics, blood count parameters, and biochemical indicators during the treatment. Receiver-operating characteristic (ROC) curve was used to determine a cutoff value for parameters and area under the curve (AUC). Kaplan–Meier and cox multivariate regression analysis were performed to estimate the relationship of baseline characteristics and irAEs with progression-free survival (PFS) and overall survival (OS).

Results

We found that lower relative lymphocyte count (RLC) (cutoff=0.285*10^9/L), higher albumin (ALB) (cutoff=39.05g/L) and higher absolute eosinophil count (AEC) (cutoff=0.175*10^9/L) were significantly associated with the occurrence of any irAEs, of which a higher AEC (cutoff=0.205*10^9/L) was strongly associated with skin-related irAEs (HR=0.163, p=0.004); And a higher lactate dehydrogenase (LDH) level (cutoff=237.5U/L) was an independent predictor of serious irAEs (HR=0.199, p=0.022). In the analysis of immune cell subgroup, lower absolute CD8⁺CD28^- T cell count (HR=0.806; 95%CI: 0.643-1.011; p=0.062), a regulatory T lymphocytes, was associated with the occurrence of irAEs, although the difference was not statistically significant; And a higher percentage of CD19⁺ B cells were associated with the occurrence of serious irAEs and irAEs of grade ≥2 (p＜0.05). In addition, our study showed that patients with any grade irAE had a significantly better PFS (8.37 vs.3.77 months, HR=2.02, p=0.0038) and OS (24.77 vs.13.83 months, HR=1.78, p=0.029).

Conclusions

This retrospective study reported the clinical profile data of irAEs of unselected patients in the real world, and explored some parameters that may all be conventional, potentially predictable markers of the occurrence, type, or grade of irAEs in clinical practice. Evidence of a correlation between safety and efficacy may contribute to fully assess the risk-benefit ratio for patients treated with ICIs.

Translational Medicine

Neoplasm

Immune checkpoint inhibitors

Immune-related adverse events

Predictor

Efficacy

Immune checkpoint inhibitors (ICIs), as a novel class of anti-tumor drugs, have shown long-lasting and significant efficacy in the treatment of a variety of malignant tumors by inhibiting immune checkpoint-negatively regulated signaling pathways and activating T lymphocytes to clear tumor cells^[1-4]. At present, ICIs that have been approved for clinical application include anti-CTLA-4 drug, ipilimumab, anti-PD-1, nivolumab, pembrolizumab, and anti-PD-L1,atezolizumab; in addition, a variety of anti-PD-(L)1 drugs are continuously developed and gradually approved for marketing in China, such as Toripalimab(JS001), Sintilimab(IBI308) and Camrelizumab(SHR-1210). However, due to the specific targets and mechanisms of action, ICIs may attack normal tissues and organs of the human body while activating the immune system, causing autoimmune and inflammatory effects at the corresponding sites, known as immune-related adverse events (irAEs) ^[5]. IrAEs can affect almost all organs of the human body, most commonly involving the endocrine, skin, digestive and respiratory systems ^[6]. Although irAEs appear insidious, variable, and mostly tend to be mild and self-limiting, serious and even life-threatening irAEs can occur in less than 10% of patients^[7], and in particular, the incidence of severe irAEs is as high as 50% with combination immunotherapy^[8]. Therefore, with the wide application of ICIs in clinical practice, physicians need to fully identify the possible adverse events and effective treatment strategies, weigh the benefit-risk ratio and use drugs rationally to improve the survival outcomes of patients receiving immunotherapy. Although several studies have investigated biomarkers that may predict an increased incidence of irAEs, including increased T cell repertoire, cytokines and related gene expression, those are not extensive, definitive, and poorly popularized in clinical practice. Therefore, there are currently no convenient and effective clinical biomarkers that can be used to predict irAEs in patients with advanced tumors. Routine blood test may be easy and cost-effective method to detect irAEs. Based on this, this retrospective cohort study aims to comprehensively analyze the toxicity profile of irAEs, explore convenient and available markers that can predict irAEs, and explore the correlation between irAEs and the clinical efficacy in patients with advanced pan-cancer who were treated with multi-type ICIs in real-world.

This study is a retrospective analysis that was approved by the Institutional Review Board (IRB) of the First Hospital of Jilin University to collect information of all patients with advanced pan-cancer receiving ICIs therapy in our hospital from Jan 1, 2016 to Aug 1, 2020, recording until disease progression or unacceptable toxicity, and patients who withdrew from treatment for other reasons with only 1-2 courses of treatment without adverse event evaluation were excluded. A detailed manual chart review was performed for each patient to record any adverse events related to ICIs that started on medication, and all patients were followed for progression and survival until death, loss to follow-up, or withdrawal of consent. According to previous studies, irAEs are defined as adverse events that are considered by the investigator to be related to immunotherapeutic agents, have a potential immunological basis, and require frequent monitoring or potential intervention. To reduce bias, this study focused only on irAEs objectively identifiable by medical professionals, and infusion reactions were not included. IrAEs include skin reactions, endocrine, pulmonary events, gastrointestinal, hepatic, nervous system, hematological, and other rare adverse events. Occurring only one of these events is defined as "single-site" irAE, and two or more events are defined as "multi-site" irAEs. Clinical severity of irAEs was graded according to Common Terminology Criteria Adverse Events (CTCAE) V4.0. Serious irAEs were defined as grade 3-4 irAEs or any grade irAEs leading to discontinuation of medication. Statistical data including age, gender, ECOG PS score, body mass index (BMI), smoking status, tumor type and stage, distant metastasis, previous treatment, number of treatment lines, immunotherapy regimens, available laboratory tests [including blood count and related ratio parameters, baseline lactate dehydrogenase (LDH) level, thyroid function indicators and partially available venous immune cell count] and imaging examination, all were obtained through individual medical record review. The primary endpoint of study was the occurrence of irAEs, and the secondary endpoints were the occurrence of two or more irAEs, and serious irAEs with drug discontinuation. Attending physicians and nurses performed physical examinations, assessed and recorded irAEs every 4 weeks throughout treatment. Patients were divided into two groups according to the occurrence of irAEs, irAE group and non-irAE group. Overall survival (OS) was defined as the time from treatment initiation to death from any cause, censoring patients who are still alive at the date of follow-up. Progression-free survival (PFS) was defined as the time from treatment initiation to progressive disease or death from any cause, whichever came first. Patients who survived without disease progression were censored at the follow-up date.

Data were summarized using basic descriptive statistics. The association between categorical variables and events was analyzed by logistic regression: univariate logistic regression analysis was first applied to identify the variable factors that were significantly associated with irAEs; and to explain the sample size when deriving the model, all variables that were significant at an alpha level less than 0.1 were entered into the multiple logistic regression model to finalize independent correlates of events. Receiver-Operating Characteristic (ROC) curve was applied to calculate cutoff values for the laboratory parameters and area under the curves (AUC)^[9]. The cutoff point was determined using Youden’s index. OR for each of the cutoff points was calculated using the results from each of the corresponding logistic regression analyses. The cut-off date for survival analysis was Aug 1, 2020. Survival probabilities were estimated using Kaplan-Meier curves and log-rank tests, and based on that, all covariates with p-values less than 0.1 were included in a multivariate Cox proportional hazards model to estimate hazard ratios (HRs) and 95% confidence interval (CI). Throughout the analyses, all P values were based on a 2-sided hypothesis, and those less than 0.05 were considered statistically significant. When assessing the predictor model, the Hosmer-Lemeshow goodness-of-fit test was used to assess the completeness and predictive accuracy of the model. We performed all statistical analyses using GraphPad Prism version 6.0 for Mac and SPSS 22.0 software.

Patient characteristics and treatment

In this retrospective study, 119 patients with advanced tumors (stage IV or stage III tumors that progressed after treatment) who received ICIs were examined, 14 patients who refused treatment for various reasons rather than disease progression after 1-2 courses of treatment without adverse event evaluation were excluded, and finally 105 patients were included in the final analysis. Of all patients, 77.14% were male and 22.86% were female, aged 61 years (24-84 years). All patients had an ECOG score of 0 or 1.The study included 52 cases of lung cancer, 15 cases of melanoma, 9 cases of liver cancer, 11 cases of esophageal cancer, 8 cases of urothelial cancer, 5 cases of gastric cancer, and 5 cases of other types of tumors (including hypopharyngeal cancer, nasopharyngeal cancer, colon cancer, pancreatic cancer, and orbital malignancy).Of these, 40 had metastatic cancer to at least one distant organ, 16 patients had two or more distant metastases. 13 patients had bone metastases, and 16 had liver metastases. In terms of previous treatment, 63.81% had received previous chemotherapy, 20.95% had received radiotherapy, 7.62% had received targeted therapy, 2.86% had received previous immunotherapy, and 8.57% had received other treatment regimens (including interferon therapy, intervention/radiofrequency ablation therapy, etc.). (Table 1) Of the 105 patients, 82 (78.10%) received anti-PD-1 therapy, including 16 patients treated with nivolumab, 14 patients treated with pembrolizumab, and 52 patients treated with anti-PD-1 drugs made in China, including Toripalimab (JS001), Sintilimab (IBI308), Tislelizumab (BGB-A317) and Camrelizumab (SHR-1210); 13 patients (12.38%) received anti-PD-L1 therapy (atezolizizumab); and 10 patients (9.52%) received anti-PD-1 combined with anti-CTLA-4 therapy (nivolumab combined with ipilimumab). Of all patients, 28 patients (26.67%) were treated with first-line therapy and 77 patients (73.33%) with non-first-line therapy.

Characteristics and management of irAEs

Of the 105 patients with advanced tumors, 41 (39.05%) had irAEs of any grade, 23 (21.9%) had irAEs of grade 2 or higher, 10 (9.5%) had irAEs of grade 3 or higher, and 14 (13.33%) had serious irAEs. Each irAE occurred at a different time for each patient. The study statistics showed that the time to the first occurrence of irAE was 1.4 months, and the majority (85.37%) of patients had the first occurrence of irAE within 3 months after administration. The specific details of irAEs were as follows: 19 cases (18.10%) had endocrine adverse events, all of which were grade 1-2 except 2 cases with grade 3 diabetes mellitus, mainly hypothyroidism/hyperthyroidism; 13 cases (12.38%) had skin responses, all of which were grade 1-2, with rash being the most common; 13 cases (12.38%) had immune-related liver injury, of which 7 cases (6.67%) had grade 3-4 or discontinued due to liver injury, which was considered to be related to anti-PD-1 plus anti-CTLA4 therapy; 6 cases (5.71%) had hematological adverse events, and one discontinued drug due to coagulation factor deficiency; 4 cases (3.81%) had pancreatic-related adverse events, of which 3 cases were serious irAE events; the rest were 3 cases (2.86%) with grade 2 immune-related pneumonia, 3 cases (2.86%) with grade 1 nerve injury, 2 cases (1.90%) with grade 1 gastrointestinal symptom, and 11 cases (10.48%) of other adverse events, including LDH increased, creatine kinase and creatine kinase isoenzyme increased, as well as myalgia, back pain, etc., but all were low grade. (Table 2) There were no irAE-related deaths during the study. Of the 41 patients with irAEs of any grade, 20 had "multi-site" irAEs (number: 2; range, 2-7) and 21 had "single-site" irAEs. The time to onset of the first irAE was 1.37 (0.43-4.87) months for "single-site" irAEs and 1.43 (0.2-10.1) months for "multi-site" irAEs. The most common symptoms of "multi-site "irAEs were 65% (13/20) endocrine adverse events, 45% (9/20) hepatic events, 40% (8/20) cutaneous events, 30% (6/20) hematologic events. The most commonly observed combination was 25% (5/20) endocrine and cutaneous events, 20% (4/20) endocrine and hematologic events, and endocrine and hepatic adverse events. The most common "single-site" irAEs were 28.57% (6/21) endocrine events and 23.81% (5/21) cutaneous events.

Some differences in the incidence of irAEs between different tumor types and different therapeutic drugs were found, but they were not statistically significant. The highest incidence of irAEs was 81.8% (9/11) in esophageal cancer, which may be closely related to the fact that most patients chose combination immunotherapy, and the rest were 40.4% (21/52) in lung cancer, 37.5% (3/8) in urothelial cancer, 33.3% (3/9) in liver cancer, 20% in melanoma (3/15), gastric cancer (1/5), and other types of tumors each (1/5). Of the 41 patients with irAEs, 51.2% (21 patients) had lung cancer, 22.0% (9 patients) esophageal cancer, 7.32% (3 patients) melanoma, liver cancer, and urothelial cancer, and the remaining 2 patients had gastric cancer and pancreatic cancer, respectively. In terms of safety of different drugs, anti-PD-L1 had the best safety, with the incidence of irAEs of 7.69% (1/13 cases), and no serious irAEs occurred; in contrast, the incidence of irAEs of anti-PD-1 drugs was relatively high (39.02%, 32/82), although most were grade 1-2, still 10.98% (9/82) had grade 3-4 irAEs or led to drug withdrawal; the incidence of irAEs and serious irAEs was high in the combination of double ICIs therapy, 80% (8/10) and 50% (5/10), respectively.

All patients in our study were managed for irAEs according to the American Society of Clinical Oncology (ASCO) Clinical Practice Guideline^[10]. For mild irAEs, drug interruption, symptomatic treatment and close monitoring may be performed as appropriate; For grade 3-4 immune-related liver injury, all patients were improved after intravenous steroid therapy combined with hepatoprotective, enzyme reduction, and symptomatic and supportive treatment. Patients with grade 4 events permanently discontinued the drug, and some patients chose to continue drug treatment for grade 3 events after liver function recovered; For patients with grade 2 pancreatitis and grade 4 lipase elevation, the drug was permanently discontinued and gradually improved after intravenous methylprednisolone treatment; One patient developed factor VIII deficiency, which improved after discontinuation of the drug and supplementation of coagulation factors, transfusion of plasma or cryoprecipitate; Grade 2 interstitial pneumonia was improved after steroid therapy and immunotherapy was continued; Patients with grade 1-2 rash and pruritus were treated with loratadine for anti-allergic therapy; For endocrine events of grade 2-3, such as diabetes and hypothyroidism, the drug is still applied after hypoglycemic therapy and hormone replacement therapy are used to maintain stable condition. No serious irAEs was found to develop into refractory or refractory events.

Analysis of predictors of irAEs

3.1 Analysis of predictors in the total patients

All patients were divided into irAE group and non-irAE group. There was no significant difference in baseline characteristics (age, gender, ECOG PS, BMI, distant metastasis and number of treatment lines) between the two groups (p >0.05). Next, the association between test variables and irAEs was analyzed by univariate and multivariate logistic regression. Univariate analysis showed that relative lymphocyte count (RLC), albumin (ALB), absolute eosinophil count (AEC) and platelet (PLT) were significant factors associated with irAE. Multivariate analysis confirmed that lower RLC (cutoff=0.285*10^9/L), higher ALB (cutoff=39.05g/L) and higher AEC (cutoff=0.175*10^9/L) were independent factors associated with the occurrence of irAEs. (Table 3) In addition, in this study, 87 patients with LHD data were analyzed separately, and LDH levels were significantly higher in the group with any grade irAEs (HR=0.341, 95%CI: 0.13-0.92, p=0.034), and in the group with irAEs of grade ≥2 (HR=3.9, 95%CI: 1.04-14.57, p=0.043), and in the group with "multi-site" irAEs (HR=4.95, 95%CI: 1.05-23.31, p=0.043) than in the non-irAE group, the group with only grade 1 or non-irAE, and the group with "single-site" or non-irAE, respectively. In a separate analysis of 89 patients with thyroid function parameters, T3 level was significantly lower in the irAE group (HR=4.4, 95%CI: 1.17-16.69, p=0.029), and TSH level was higher in the group with irAEs of grade ≥2 (HR=3.2, 95%CI: 1.13-8.80, p=0.028).

3.2 Analysis of predictors in ICI monotherapy group

In view of the possible impact of immune combination therapy regimen on the results of irAEs analysis, we analyzed the ICI monotherapy group (95 cases) separately. Univariate analysis showed that RLC, ALB, AEC and PLT were significantly different in irAE group (p <0.05), and other factors, such as age, gender, ECOG PS, BMI, smoking status, distant metastasis and number of treatment lines, were not significantly correlated with irAE. Multivariate analysis was consistent with the analysis results in the total population, also showed that lower RLC, higher ALB, and higher AEC were independent factors associated with irAEs. For different treatment regimens (PD-1 or PD-L1), both univariate (p=0.056) and multivariate analysis (p=0.052) analyses showed that the incidence of irAEs in the PD-1 treatment group tended to be higher than that in the PD-L1 group, but there was no statistical difference. (Table 4) Similarly, 84 patients with LHD data in ICI monotherapy group were analyzed separately in our study, but no correlation was found. In a separate analysis of 79 patients with available thyroid function parameters, T3 level was significantly lower in the irAE group (p=0.031, HR=5.6, 95%CI: 1.17-26.72), and TSH tended to be higher in the group with irAEs of grade ≥2 (p=0.058).

3.3 Analysis of predictors of irAEs in immune cell subgroup

Data of the immune cell in venous blood were available for only 40 of 105 patients in this study, and only 15 patients were tested for special subtypes of T cells, such as CD8⁺CD28^- T cell and CD8⁺CD28⁺ T cell. The correlation between multiple factors including immune cell index and irAEs was analyzed by logistic regression. The results only showed that lower absolute CD8⁺CD28^- T cell count (HR=0.806; 95%CI: 0.643-1.011; p=0.062) was associated with the occurrence of irAEs, although the difference was not statistically significant, and none of the other parameters were correlated, including blood counts. (Table 5) It should be pointed out that due to the limitation of the number of patients, the results of blood factors may not be consistent with those in the overall population.

3.4 Analysis of predictors of organ-specific irAEs

In this study, the predictors of organ-specific irAEs were analyzed separately, but no factors related to endocrine events, liver- and lung-related irAEs were found. Only higher AEC (>0.205*10^9/L) was found to be an independent factor related to skin-related irAEs (HR=0.163, 95%CI: 0.048-0.554, p=0.004).

3.5 Analysis of predictors of serious irAEs and irAEs of grade ≥2

Of the 105 patients, 14 (13.3%) had serious irAEs. Univariate analysis of blood count parameters showed that only higher LDH (cutoff=237.5U/L) was an independent factor associated with the occurrence of serious irAEs (HR=0.199, 95%CI: 0.05-0.79, p=0.022). Among the 40 patients with immune cell parameters, 7 had serious irAEs. The analysis results showed that only a higher percentage of CD19⁺ B cells (cutoff=6.625%) (HR=10.5, 95%CI: 1.12-97.91, p=0.039) was associated with the occurrence of serious irAEs. Of the 105 patients, 23 (21.9%) experienced irAEs of grade ≥2. No relevant factors were found after analysis of blood count parameters in the overall patients. The analysis of immune cell parameters in 40 patients also showed that only a high percentage of CD19⁺ B cell (cutoff=6.605%) (HR=11.67, 95%CI: 1.28-106.80, p=0.030) was significantly associated with irAEs of grade 2 and higher.

Correlation analysis between irAEs and survival outcomes

OS data were available for 103 of the 105 total patients, and PFS was available for 87 patients due to disease progression. We examined the impact of baseline characteristics (age, gender, ECOG PS, BMI, smoking status, distant metastases, and number of treatment lines) and irAEs on PFS and OS, and performed multivariate analysis when necessary. We found that there were no significant differences in baseline characteristics and efficacy, and only irAEs were independent factors associated with survival outcomes. (Table 6) There was a significant difference in PFS between the group with any grade irAE and non-irAE group [mPFS: 8.37 mo (95%CI 4.37-22.9) vs. 3.77 mo (95%CI 2.1-4.27), HR=2.02, 95%CI: 1.25 – 3.26, p=0.0038); 12-month PFS: 42.86% vs. 11.86%, HR=0.18, 95%CI: 0.06 – 0.53, p=0.002] (Figure 1A). And there also a significant difference in OS between irAE group and non-irAE group [mOS: 24.77 mo (95%CI 10.68-38.86) vs. 13.83mo (95%CI 8.16-19.51), HR=1.78, 95%CI: 1.07-2.97, p=0.029; 18-month OS rate: 36.59% vs.16.13% , HR=0.33, 95%CI: 0.13-0.84, p=0.020] (Figure 1B).

With the widespread use of ICIs in anti-cancer treatment, irAEs have also been paid more and more attention by clinicians and researchers. Although most of the reported common irAEs (e.g., rash, thyroid dysfunction, colitis, diarrhea) are easy to manage and treat, some serious or rare irAEs still significantly affect the efficacy and course of immunotherapy in patients, and the occurrence of irAEs in clinical practice is personalized, complex, and unpredictable. It is noted that the incidence data and characteristics spectrum of irAEs published for several classes of ICIs (mainly PD-1/PD-L1 antibodies) that have been marketed in different cancer types are basically similar^[11-16], reflecting the commonality of the occurrence mechanism of irAEs, that is, irAEs were mainly associated with abnormal activation of autoimmune T lymphocytes. Therefore, how to predict the occurrence of irAEs during treatment of pan-cancer with different ICIs is an urgent problem to be solved at present, and no study has conducted in-depth exploration of the overall occurrence and predictive markers of this event in the real world. Based on this, this study conducted a retrospective analysis in patients with advanced pan-cancer who were treated with different ICIs to fully assess the incidence and toxicity profile of irAEs in real clinical practice, and identify the predictors of irAEs among multiple factors involving clinical baseline characteristics, blood count parameters and biochemical indicators, as well as explore the correlation between irAEs and clinical outcomes.

First, the incidence of irAEs of any grade observed in this study was 39.05%, mild and transient, with 21.9% of irAEs of grade ≥2. The incidence of irAEs and the overall toxicity profile were consistent with previous studies of treatment with ICIs ^[11-13], which showed that the incidence of irAEs was up to 70% in patients treated with anti-CTLA4 compared with 50% in patients treated with anti-PD-1/PD-L1 antibodies ^[14-17]. A meta-analysis published in 2015 including 1265 patients from 22 clinical trials^[18] showed that the overall incidence of any grade irAEs was 61% and high-grade irAEs was 17% in patients receiving 3 mg/kg ipilimumab. Previous randomized clinical trials showed that ICIs were generally well tolerated, and the incidence of irAEs of grade ≥3 with anti-PD- (L)1 therapy was less than 15%. Our study showed that the incidence of serious irAEs was 13.33% and irAEs of grade ≥3 was 9.5%, indicating that ICIs were relatively safe. All patients with high-grade irAEs in the study improved after discontinuation and/or treatment with steroids, with none developing into refractory or refractory adverse events, and there were no treatment-related toxicity deaths. Overall, the first median time of the occurrence of irAEs was 1.4 months after the start of ICIs, with 1.37 (0.43-4.87) months for "single-site" irAEs and 1.43 (0.2-10.1) months for "multi-site" irAEs. The time (kinetics) of appearance of irAEs is usually determined by the affected organ system^[19], from early onset (one week) to delayed events (up to 26 weeks for acute kidney injury), with a main onset window of 4-12 weeks, while the vast majority of events occur in the first 2 months, known as the " critical pharmacovigilance window ". Of note, the first occurrence of irAEs of a patient in our study was the 10th treatment course after treatment, reflecting the delayed response to immunotherapy. A study including 70 patients with advanced NSCLC treated with nivolumab showed that 28 patients (40%) appeared irAEs, of which 21 patients (75%) had irAEs within 8 weeks, and the median onset time was 5.0 weeks ^[20]. The latest study by Maillet et al. ^[21] counted 435 patients with irAEs of grade ≥2 using ICIs and found that 126 patients (29%) had irAEs of grade ≥2, 49 patients (11%) had irAEs of grade ≥3, and the median time to the first occurrence of irAEs of grade ≥2 and 3 was 0.8 months (95%CI: 0.5-1.8) and 0.6 months (95%CI: 0.2-1.4), respectively.

As for the incidence of different type of irAEs, a recent systematic review and meta-analysis^[22] including 125 clinical trials involving 20,128 patients showed that among immune-related endocrine disorders, the most common all-grade adverse events were hypothyroidism (6.07%) and hyperthyroidism (2.82%), followed by hyperglycemia (1.20%), thyroiditis (0.75%) and adrenal insufficiency (0.69%). The most common other irAEs of all grades were diarrhea (9.47%), AST increased (3.39%), vitiligo (3.26%), ALT increased (3.14%), pneumonitis (2.79%), and colitis (1.24%). In this study, the most common adverse events were endocrine disorders, thyroid disorders. One condition is transient enhancement of thyroid function as acute thyroiditis, followed by conversion to hypothyroidism; the other condition is hypothyroidism on regular blood tests, and similar results were reported by Peiro et al. ^[23]. Patients with endocrine diseases can basically remain stable after the use of hormone replacement and symptomatic treatment. Although some studies have reported that anti-thyroid autoantibodies before ICI treatment are predictors of the occurrence of hypothyroidism ^{[20, 24]}, and other studies have also explored the correlation between autoantibodies before treatment and irAEs, in this study, only basic thyroid function indicators (TSH, FT3, FT4) were measured due to the inability to obtain a sufficient number of patients with baseline autoantibody levels. We confirmed that low T3 levels before immunotherapy were significantly associated with the occurrence of irAEs of any grade, and high TSH levels were significantly associated with the occurrence of irAEs of grade≥2. The next is immune-mediated skin-related disorders, mainly rash with dry and itchy skin, which were treated with moisturizers, oral antihistamines, and topical creams, and no events of severe grade were observed. In this study, the proportion of immune-related liver injury (12.38%, 13 cases) was relatively large, which was considered to be related to the combination of anti-PD-1 and anti-CTLA4 drugs. Although 7 of them were serious events, all of them were improved after intravenous corticosteroid therapy, and some patients could continue to use the drug. In addition, we found some rare types of irAEs. Neurologic events include mild numbness of both feet, toes and facial neuritis, 1 case for each; Hematological events include 1 case of prolonged APTT and coagulation factor deficiency, leading to drug withdrawal and reporting SAE; It should be noted that a patient with stage IV gastric differentiated adenocarcinoma successively developed systemic serious adverse events one week after the administration of nivolumab combined with ipilimumab, including dry mouth/dry eyes, pneumonia of grade 2, hypothyroidism of grade 1, lipase increased of grade 4, pancreatitis of grade 2, hepatic injury of grade 4, facial neuritis of grade 1 and myalgia of grade 2. The patient discontinued treatment after 4 courses of treatment due to intolerable severe adverse reactions although SD was evaluated after 2 courses, which fully reflected the individual uniqueness and unpredictability of the immune response. Although our study differed from the previous study in the occurrence of irAEs in each category due to the limitation of the number of patients, the overall incidence and toxicity profile of irAEs were similar. Patient inclusion criteria in clinical trials are stringent and may ignore some rare and unique cases, while we report clinical data characteristics of patients in real world, albeit with limited sample sizes. Larger retrospective surveys are expected to be conducted in the real world in the future to comprehensively characterize the toxicity profile of irAEs in patients treated with ICIs.

Given that multiple irAEs occur before or near routine response evaluation, early identification of irAEs is important to optimize the therapeutic benefit of ICIs. As mentioned previously, the published data and spectrum of irAEs of these ICIs have been marketed in different cancer types are basically similar. However, given that the number of patients using each ICI in our study varied significantly and some of them were very small, a detailed comparison of the incidence of irAEs between different drugs could not be made, and we only found that there was no statistical difference in the occurrence of irAEs between anti-PD-1 and anti-PD-L1 drugs. Although several studies have reported biomarkers that may predict the occurrence of irAEs, such as T cell repertoire, IL-6, IL-17, etc., in recent years, it has been found that complete blood counts may be markers of cancer inflammation and adaptive immune response. The most accessible routine blood test may be easy and cost-effective method to detect irAEs, but the predictability of which has not been elucidated. Thus, this study examined the predictive ability of baseline peripheral blood count for irAEs. It was found that lower RLC (cutoff=0.285*10^9/L), higher ALB (cutoff=39.05g/L) and higher AEC (cutoff=0.175*10^9/L) were significantly associated with the occurrence of any grade irAEs, and no significant association was found between clinical characteristics and irAEs. A number of previous studies have shown that cells in peripheral blood can not only predict tumor response, but also are associated with the occurrence of irAEs mediated by ICIs. The results of multivariate analysis by Diehi et al. ^[25] showed that the absolute number of lymphocytes and eosinophils at baseline and 1 month after initial treatment were independent factors that were significantly associated with a higher incidence of irAEs of grade ≥2 in patients with solid tumors (including melanoma, renal cell carcinoma, and urothelial carcinoma) treated with anti-PD-1 antibodies. Schindler et al. ^[26] reported a higher incidence of irAEs in patients with higher eosinophil counts at weeks 4 and 7 and in patients with a change in eosinophil count from baseline in melanoma patients treated with ipilimumab. Univariate analysis in melanoma patients treated with nivolumab showed that both increased total WBC count and decreased RLC compared to baseline were associated with serious irAEs of grade ≥3, although multivariate analysis failed to show independence^[27]. Increased neutrophils may represent a response to systemic inflammatory response, while decreased lymphocytes may reflect an impaired cell-mediated specific immunity response^[28]. The observations in our study may be partially explained by the decreased lymphocytes and expansion of neutrophils, which significantly infiltrated within the involved organs.

Secondly, the correlation between blood cells and irAEs in various organs is poorly understood. In this study, the predictors of irAEs at different sites were analyzed separately, and only a higher baseline AEC was found to have a strong association with the occurrence of skin-related irAEs (HR=0.163, p=0.004), and the cut-off value of AEC was determined to be 0.205*10^9/L by ROC curve. It was considered that a higher baseline AEC in blood tests may be a potential predictor of skin-related adverse events. Previous studies have shown increased circulating eosinophil and infiltration of eosinophils in the dermis in patients who develop cutaneous irAEs while receiving anti-CTLA-4 therapy^[29]. In addition, a significant correlation was observed between baseline absolute and relative eosinophil counts and the occurrence of endocrine irAEs at 1 month in melanoma patients treated with anti-PD-1 antibodies^[30].Therefore, eosinophils may play an important role in the pathogenesis of anti-PD-1-induced irAEs and may be organ-specific. In addition, the predictive role of LDH in the occurrence of irAEs was also confirmed in this study, founding that LDH levels were significantly higher in patients in the irAE group, especially in the group of grade≥2 irAE and the group of "multi-site" irAEs.

In the immune cell subgroup, we confirmed that thelower absolute CD28^-CD8⁺T cell count (p=0.062) was associated with the occurrence of irAEs, although the difference was not statistically significant. CD8⁺CD28^- T-suppressor cells are derived from the monoclonal expansion of T cells^[31], which can act directly on APCs, resulting in the down-regulation of the expression of costimulatory molecules and the induction of the up-regulation of inhibitory receptors^[32]. In in vitro experiments, CD8⁺CD28^-T cells inhibited the proliferation of effector CD4⁺T cells and their secretion of IFN-γ. CD8⁺CD28^-T cells can negatively modulate immune responses through multiple mechanisms, such as directly negatively regulating adaptive immune responses or limiting the diversity of adaptive immune responses by competing for limited space. CD8⁺CD28^-T regulatory lymphocytes are almost persistent and functional in human tumors and are able to inhibit both T cell proliferation and cytotoxicity, with pathogenic relevance and significance for immunotherapy of cancer^[33]. A study showed that the elevated peripheral blood CD8⁺CD28^-T cells was associated with poorer prognosis for metastatic breast cancer, especially in patients with higher risk of progression in patients with first-line chemotherapy and higher risk of death more than second-line chemotherapy^[34]. In addition, CD8⁺CD28^-T cells have the ability to suppress experimental inflammatory bowel disease in mice; repeated stimulation of human peripheral blood lymphocytes with allogeneic APCs in vitro can cause a loss of lymphocyte proliferative activity, a phenomenon caused by CD8⁺CD28^-regulatory T cells^[35]. However, the role of immunosuppressive function of CD8⁺regulatory T cells in immune responses and immune-mediated adverse effects has not been studied. This study showed that patients with relatively higher CD8⁺CD28^-T-suppressor cells were less likely to have irAEs, considering that it may be due to the inhibitory effect of CD8⁺CD28^-T-suppressor cells on effector T cells. After the application of ICIs, it is not easy to activate systemic immune system to produce response and immune-mediated autoimmune and inflammatory effects in normal tissues and organs of the human body. However, unfortunately, our study had a small sample of patients, and the difference was not statistically significant between the two groups. Nevertheless, to our knowledge, our study is the first report to discover the role of CD8⁺CD28^-T cells in immune responses and adverse events, and these data with suggestive significance are available only from a simple peripheral blood examination. Moreover, previous studies have only detected and analyzed CD8⁺T cells, and our study suggests whether they can be further divided into CD28⁺ and CD28⁺T cells in the future to more accurately understand their role in the body's immune response and irAEs. In the future, the sample size needs to be expanded to test the role of CD8⁺CD28^-T cells in large-scale prospective studies.

Serious irAEs can significantly affect the treatment response or lead to discontinuation, thus, the identification of predictors of serious irAEs is essential for clinical management and patient survival outcomes. This study found that a higher LDH level (cutoff=237.5U/L) was significantly higher in the group with serious irAEs (HR=0.199, p=0.022). Therefore, the detection and analysis of LDH levels in clinical practice may provide some reference for the occurrence, grade, and site number of irAEs. In addition, our study analyzed peripheral blood immune cell counts in patients with different grades of irAEs. In fact, drugs targeting PD-(L)1 axis can not only trigger potential autoimmune responses by enhancing T cell-mediated mechanisms, but also induce autoantibody production by B cell-mediated mechanisms, which further enhances humoral immune responses and disrupts self-tolerance, ultimately produces autoimmune diseases by attacking autoantigens ^[24]. For example, the study has shown that in patients treated with anti-PD-1, the presence of anti-thyroid antibodies at baseline or after the start of treatment may trigger immune-related thyroid disease ^[36]. Due to limited data, the autoantibody data of our patients were not obtained. But we considered the essence of irAEs is that immunotherapy activates B cells and makes the body more sensitive to antigen recognition, finally results in the damage by immune response with autoantibodies that are themselves insidious or provoked. Therefore, in this study, small samples of peripheral blood immune cells were analyzed. It was found that a higher percentage of CD19⁺ B cells (≥6.625%) was associated with the occurrence of serious irAEs (HR=10.5, p=0.039) and irAEs of grade ≥2 (HR=11.67, p=0.030). Our study further confirmed the cellular and humoral immune mechanisms underlying the development of irAEs, providing important insights into immunobiology of ICIs drug and autoimmunity in general. Overall, in the exploration of predictors of irAEs, although some indicators , have been shown to be closely related to the occurrence of irAEs, it should always be kept in mind that the occurrence of immune-related toxicities may be difficult to predict and diagnose and may be fatal, which is particularly important with the widespread use of immunotherapy.

Finally, given the similar immunological basis between immune-related toxicity and the clinical benefit of ICIs, a number of recent retrospective studies have investigated the correlation between irAEs and the ICIs-efficacy, especially in lung cancer and melanoma that have shown positive results^{[20, 37-39]}. A meta-analysis of four prospective studies in different cancers showed that any grade irAEs were associated with a higher overall response rate, but no effect on PFS was detected ^[11]. However, Rogado et al. ^[39] found that PFS was significantly shorter (3 vs.10 months, HR=2.2, p=0.016)in patients without any grade irAEs in a study of 153 patients treated with anti-PD- (L) 1, but the reduction in mOS was not significant. Therefore, it remains unknown whether the occurrence of irAEs can reflect treatment response and translates into better survival outcomes in clinical practice. Based on this, this study conducted a retrospective analysis of 105 real-world patients, further emphasizing the importance of irAEs in predicting survival outcomes. The overall results of our study showed that patients with any grade irAE had a significantly better PFS (8.37 vs.3.77 months, HR=2.02, p=0.0038) and OS (24.77 vs.13.83 months, HR=1.78, p=0.029), indicating a strong association between the occurrence of irAEs and better treatment efficacy. Our study initially confirmed that the occurrence of irAEs may translate into a better clinical survival benefit, emphasizing that maintenance of ICIs should be a priority in patients with irAEs, and that careful management of treatment-related toxicities can maximize the clinical benefit of immunotherapy patients.

This study is a small, retrospective, non-randomized study in a single center with certain limitations, the results, therefore, should be interpreted with caution. First, the sample size of observed patients is small and may affect by the intrinsic selection bias caused by the retrospective study itself. Second, the definition criteria for irAEs vary in different studies, and the determination of irAEs in clinical practice also has some subjectivity, some of which are only diagnosed by exclusion. Therefore, in the absence of specific descriptions in the medical records, irAEs of grade 1-2 may be underestimated or overlooked, but the detection of most severe irAEs is not considered missed. Third, as patients with longer exposure to immunotherapy are more likely to develop immunotoxicity, duration/observation time of immunotherapy may also be a potential confounding factor. However, 30 of the 41 patients (73.17%) with irAEs in this study developed symptoms 8 weeks after treatment, indicating that the occurrence risk of adverse events is unlikely to be increased due to the longer treatment period, but is more likely to be caused by abnormal activation of immune system. Fourth, the patients in this study had multiple different tumor types, and in the context of multiple different types and dosage regimens of ICI drugs, although we mentioned that the occurrence spectrum of different ICIs in different cancers is basically similar, confounding factors are still inevitable. Fifth, other studies have reported some biomarkers related to irAEs based on germline genetic factors, indicators of immune repertoire and cytokines, such as clonality of T cell repertoire, IL-6, IL-17, HLA typing and gene polymorphisms, which may more accurately predict adverse events and guide clinical decisions. However, due to the lack of tissue samples in most patients, these biomarkers cannot be assessed in our study, and we mainly explored the clinical characteristics and baseline blood biochemical indicators of the patients. Nevertheless, these simple and easily available markers we found may be faster and more convenient to guide clinical practice, which need to be further validated and promoted the development of this field.

Overall, this retrospective study reported the clinical profile data of irAEs of unselected patients in the real world, and explored some parameters that may all be conventional, cost-effective, potentially predictable markers of the occurrence, type, or grade of irAEs in clinical practice, being of great clinical value. Evidence of a correlation between safety and efficacy may ultimately be integrated into treatment decisions to fully assess the risk-benefit ratio for patients based on the type, severity of irAEs and response. Although these findings need to be further validated in larger retrospective or prospective, randomized controlled studies, our study provides important information and reference value for future studies on predictors of irAEs and its correlation with clinical outcomes.

Ethics approval and consent to participate

This study was approved by the Institutional Review Board (IRB) of the First Hospital of Jilin University.

Consent for publication

All the authors have read and approved the final version of manuscript and give consent.

Availability of data and materials

All pertinent data generated for this exploratory analysis are included in this published article; further information is available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

The authors are supported by the National Key R&D Program of China (No. 2016YFC1303800), the 13th Five-Year Science and Technology Project of Jilin Provincial Education Department (No.JJKH20190020KJ), Jilin Provincial Science and Technology Department Science and Technology Development Plan Project Jilin Provincial Key Laboratory Project(No.20180101009JC), the Key Laboratory Construction Project of Department of Science and Technology of Jilin Province(No.20170622011JC).

Authors’ contributions

Rilan Bai participated in the collection of data, data interpretation, literature review and manuscript writing. All authors contributed to the collection of data, the revision of the manuscript and approved the final draft for submission.

Acknowledgements

Not applicable

Authors' information

Jiuwei Cui, Tel: +86-15843073215, Fax: 0431-88786134, Email: [email protected]

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Table 1. Baseline characteristics of the patients

Variable		Number of cases/value	Percent
Gender	Male	81	77.14%
Gender	Female	24	22.86%
Age	Median	61	NA
Age	Scope	24-84	NA
ECOG PS	0	17	16.19%
ECOG PS	1	88	83.81%
BMI	Mean value	23.55±0.36 (95%CI: 22.83-24.27)	NA
BMI	Scope	15.8-31.2	NA
Tumor type	Lung cancer	52	49.52%
	Melanoma	15	14.29%
	Esophageal cancer	11	10.48%
	Liver cancer	9	8.57%
	Urothelial carcinoma	8	7.62%
	Gastric Cancer	5	4.76%
	Other types of tumors	5	4.76%
Distant metastasis	No distant organ metastasis	65	61.90%
Distant metastasis	One or more distant metastatic cancers	40	38.10%
Prior Therapy	Chemotherapy	67	63.81%
	Radiotherapy	22	20.95%
	Targeted therapy	8	7.62%
	Immunotherapy	3	2.86%
	Other therapies (interferon therapy, interventional/radiofrequency ablation therapy)	9	8.57%
Treatment lines	First-line	28	26.67%
Treatment lines	Non first-line	77	73.33%
Treatment Regimen	Anti-PD-1	82	78.10%
	Anti-PD-L1	13	12.38%
	Anti-PD-1 + anti-CTLA-4	10	9.52%

Table 2. Summary of specific irAEs

Types of irAEs	Grade	Number of cases	Percent	Number(Percent) of serious irAEs
Endocrine adverse events	1-3	19	18.10%	2(1.90%)
Skin response	1-2	13	12.38%	0
Immune-related liver injury	1-4	13	12.38%	7(6.67%)
Hematologic adverse events	1-2	6	5.71%	1(0.95%)
Pancreatic-related adverse events	2-4	4	3.81%	3(3.86%)
Immune-related pneumonitis	2	3	2.86%	1(0.95%)
Nervous system injury	1	3	2.86%	0
Gastrointestinal reaponse	1	2	1.90%	0
Immune-related Kidney injury	1	1	0.95%	0
Immune-related Cardiac injury	1	1	0.95%	0
Other irAEs	1-2	11	10.48%	0

Table3. Predictors of irAEs in the total patients

Variable	Univariate analysis			Multivariate analysis
Variable	HR	95%CI	p	HR	95%CI	p
Age	NA	NA	0.262	NA	NA	NA
Gender	NA	NA	0.119	NA	NA	NA
ECOG PS	NA	NA	0.160	NA	NA	NA
BMI	NA	NA	0.313	NA	NA	NA
Distant metastasis	NA	NA	0.06	NA	NA	NA
Treatment lines	NA	NA	0.117	NA	NA	NA
*RLC (cutoff=0.28510^9/L)**	3.32	1.28-8.63	0.014*	5.43	1.55-18.99	0.008*
*AEC (cutoff=0.17510^9/L)**	0.32	0.14-0.76	0.010*	0.28	0.10-0.84	0.023*
*PLT(cutoff=232.510^9/L)**	2.77	1.14-6.73	0.025*	-	-	0.080
ALB (cutoff=39.05g/L)	0.25	0.10-0.66	0.005*	0.26	0.09-0.80	0.019*

Table4. Predictors of irAEs in ICI monotherapy group

Variable	Univariate analysis			Multivariate analysis
Variable	HR	95%CI	p	HR	95%CI	p
Age	NA	NA	0.116	NA	NA	NA
Gender	NA	NA	0.162	NA	NA	NA
ECOG PS	NA	NA	0.152	NA	NA	NA
BMI	NA	NA	0.566	NA	NA	NA
Distant metastasis	NA	NA	0.123	NA	NA	NA
Treatment lines	NA	NA	0.452	NA	NA	NA
Treatment Regimen (PD-1/PD-L1)	7.68	0.95-61.95	0.056	NA	NA	0.052
*RLC (cutoff=0.28510^9/L)**	3.78	1.29-11.12	0.016*	5.43	1.55-18.99	0.008*
*AEC (cutoff=0.17510^9/L)**	0.32	0.13-0.80	0.015*	0.28	0.10-0.84	0.023*
*PLT(cutoff=232.510^9/L)**	2.68	1.01-7.11	0.047*	NA	NA	0.080
ALB(cutoff=39.05g/L)	0.29	0.10-0.81	0.019*	0.26	0.09-0.80	0.019*

Table 5. Predictors of irAEs in immune cell group

Variable	Logistics regression analysis
Variable	HR	95%CI	p
CD4+T cell			0.182
CD28-CD8+T cell			0.407
CD28-CD8+T cell	0.806	0.643-1.011	0.062
CD19+B cell			0.604
NK cell			0.413
Treg cell			0.12

Table 6. Correlation analysis between irAEs and survival outcomes

Survival outcomes	Variable		Kaplan–Meier analysis			Cox multivariate regression analysis
			HR	95%CI	p	HR	95%CI		p
PFS	Age		0.80	0.49-1.29	0.34	NA	NA		NA
	Gender		0.66	0.38-1.13	0.16	NA	NA		NA
	ECOG PS		0.80	0.41-1.58	0.49	NA	NA		NA
	BMI		0.59	0.36-0.96	0.030*	0.67	0.40-1.13		0.1371
	Smoking		0.91	0.571.48	0.71	NA	NA		NA
	Distant metastasis		0.82	0.49-1.36	0.42	NA	NA		NA
	Treatment lines		1.05	0.58-1.91	0.86	NA	NA		NA
	irAEs		2.02	1.25-3.26	0.0038*	2.18	1.22-3.90		0.0087*
OS	Age	0.86		0.51-1.44	0.56	NA		NA		NA
	Gender	0.78		0.41-1.46	0.46	NA		NA		NA
	ECOG PS	1.04		0.51-2.09	0.92	NA		NA		NA
	BMI	0.91		0.54-1.54	0.73	NA		NA		NA
	Smoking	1.21		0.72-2.02	0.47	NA		NA		NA
	Distant metastasis	0.69		0.40-1.19	0.16	NA		NA		NA
	Treatment lines	0.97		0.53-1.79	0.86	NA		NA		NA
	irAEs	1.78		1.07-2.97	0.029*	NA		NA		NA

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posted 23 Oct, 2020

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Analysis of Toxicity Profile and Predictors of Immune Checkpoint Inhibitor-Related Adverse Events

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Abstract

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Background

Patients And Methods

Results

Discussion

Conclusion

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References

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