irAEs Of Grade Research Articles

Analysis and evaluation of factors contributing to the occurrence of immune-related adverse events with immune checkpoint inhibitors.

In recent years, there has been a growing trend in the use of immune checkpoint inhibitors (ICIs) for treating a larger patient population. However, it is important to note that immune-related adverse events (irAEs) frequently arise as a result. Therefore, precise patient monitoring becomes essential. We present the findings of a retrospective study conducted at the International University of Health and Welfare Narita Hospital (referred to as "our hospital") that aimed to identify risk factors linked to the occurrence of irAEs. The study focused on analyzing various factors, including therapeutic and lifestyle backgrounds, as well as laboratory values of patients who received ICI treatment and were subsequently diagnosed with irAE. The study included patients who met the eligibility criteria for ICIs (both single agent and combination therapy) as well as ICI in combination with anticancer drugs. The inclusion period for the study encompassed April 2020 to May 2022 at our hospital. The fifty patients were divided into two groups based on the severity of irAEs: the first group consisted of patients with irAE Grade 2 or lower (referred to as irAE Grade under 2), while the second group included patients with irAE Grade 3 or higher (referred to as irAE Grade over 3). Statistical analysis revealed significant differences in age (p=0.027) and CRP (C-reactive protein) levels (p=0.008) among the background factors when comparing the two groups. Additionally, statistically significant differences were observed among different ICI treatment groups in the occurrence of irAEs (p=0.035). however, it was indicated to be a relatively weak correlation. Moving forward, we shifted our focus to examine the frequency of irAEs in relation to exposure. However, we did not observe any significant correlation between exposure and irAE grade. Additionally, even when exposure was doubled through the use of ipilimumab in combination with ICIs (referred to as "Mod exposure"), no correlation was found. Exposure was further categorized into three groups: the PD-1 group, PD-L1 group, and PD-1 + CTLA-4 group. However, no significant correlation was observed between exposure in any of these groups and the grade of irAEs. Similarly, no significant correlation was observed between the dosage of ICI in the fixed-dose group and the weight-based dosage group with exposure and irAE Grade. Based on our study findings, there is a suggestive relationship between age and CRP levels and the occurrence of irAEs of Grade 3 or higher. These factors may play a role in contributing to the development of more severe irAEs.

Neoadjuvant docetaxel-cisplatin followed by concurrent chemoradiotherapy and adjuvant tislelizumab for locally advanced nasopharyngeal carcinoma: A multicenter, single-arm, phase II trial.

e18047 Background: Patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) have a high risk of distant metastasis or recurrence despite the current standard of neoadjuvant chemotherapy and concurrent chemoradiation (CCRT), indicating the need of more comprehensive treatment. Due to good compliance and convenient adverse event management, the TP (docetaxel and cisplatin) regimen is more widely accepted and commonly used as a neoadjuvant chemotherapy for LA-NPC in the real world. Immune checkpoint blockade therapy plus chemotherapy has been shown to improve the survival in recurrent or metastatic NPC. We investigated the efficacy and safety of tislelizumab, an anti-PD-1 monoclonal antibody, as adjuvant treatment in patients with LA-NPC that had the neoadjuvant TP chemotherapy and CCRT. Methods: This multicenter, open label, single arm, phase II clinical trial was done at four hospitals in China. Patients (aged 18-65 years) with histologically confirmed, LA-NPC (T4N1 and T1-4N2-3) were enrolled and treated with neoadjuvant chemotherapy for 3 cycles (docetaxel 75 mg/m2 D1, cisplatin 75 mg/m2 D1) followed by concurrent cisplatin (100mg/m2, D1 and D22) during intensity-modulated radiation (IMRT). Four weeks post-RT, tislelizumab (200 mg) was given intravenously once every 3 weeks for up to 12 cycles. By Fleming one-stage design (type I error 0.05, power 0.80, 10% drop out), planned sample size is 100. Primary endpoint is 3-year (yr) progression free survival (PFS). Secondary endpoints include safety and tolerability. Results: From June 2021 to January 2024, a total of 100 patients (median age 53y, 73.0% male) were recruited at four study sites. This protocol specified analysis included 78 subjects with >12 months post-treatment follow up (median 26.2 months, 95% CI 21.3-30.1). Overall compliance rate: neoadjuvant cisplatin + docetaxel 97.5%, concurrent cisplatin 80.8%, adjuvant tislelizumab 78.2%, IMRT 99.7% (69.96 Gy). Treatment related adverse events (AEs, ≥grade 3, >10%): dysphagia (30.5%), mucositis (26.2%), neutropenia(26.7%), radiation dermatitis (23.7%), anemia (16.2%). No ≥grade 4 mucositis/dermatitis. In addition, the incidence of immune-related adverse events (irAEs) of grade 3 or 4 was 5.2%, and all were thyroid toxicity and skin rash. The 2-yr PFS and 2-yr overall survival were 89.6% (95% CI 53.8 - 88.5%) and 100%, respectively. 3-yr PFS and long-term efficacy are awaited. Conclusions: Tislelizumab adjuvant therapy after neoadjuvant docetaxel -cisplatin followed by CCRT is safe with promising results for LA-NPC. However, further follow-up is needed to confirm the long-term efficacy. Clinical trial information: NCT04870905 .

Emergence of immune-related adverse events correlates with pathological complete response in patients receiving pembrolizumab for early triple-negative breast cancer

ABSTRACT Based upon results of the KEYNOTE-522 trial and following approval by regulatory authorities, the addition of pembrolizumab to chemotherapy is now the standard-of-care for the treatment of early triple-negative breast cancer (eTNBC) (Clinical stage II-III). Pembrolizumab is a programmed cell death protein 1 monoclonal antibody, known to cause immune-related adverse events (irAEs) in a significant subset of patients. Real-world data on incidence, type and treatment strategies of irAEs in the setting of eTNBC treatment are sparse. In this multicenterretrospective analysis, we characterized real-world incidence of irAEs and treatment outcomes such as pathological complete response (pCR) from the combination of pembrolizumab and chemotherapy as neoadjuvant treatment for eTNBC. We found a rate of irAEs of all grades of 63.9% and of 20% for irAEs of grade 3 or higher. In the overall population, a pCR rate of 57.1% was observed. The emergence of irAEs correlated significantly with pCR (72.2% versus 30.8%; p =.03). Discontinuation of neoadjuvant chemotherapy before week 12 correlated significantly with a lower pCR rate. To our knowledge, this is the first study evaluating the real-world efficacy and safety of a neoadjuvant combination of chemotherapy and pembrolizumab in eTNBC, demonstrating a significant correlation between irAEs and pCR. Early discontinuation of neoadjuvant therapy due to AEs resulted in a lower pCR rate.

Autoimmune PaneLs as PrEdictors of Toxicity in Patients TReated with Immune Checkpoint InhibiTors (ALERT)

BackgroundImmune-checkpoint inhibitors (ICI) can lead to immune-related adverse events (irAEs) in a significant proportion of patients. The mechanisms underlying irAEs development are mostly unknown and might involve multiple immune effectors, such as T cells, B cells and autoantibodies (AutoAb).MethodsWe used custom autoantigen (AutoAg) microarrays to profile AutoAb related to irAEs in patients receiving ICI. Plasma was collected before and after ICI from cancer patients participating in two clinical trials (NCT03686202, NCT02644369). A one-time collection was obtained from healthy controls for comparison. Custom arrays with 162 autoAg were used to detect IgG and IgM reactivities. Differences of median fluorescent intensity (MFI) were analyzed with Wilcoxon sign rank test and Kruskal–Wallis test. MFI 500 was used as threshold to define autoAb reactivity.ResultsA total of 114 patients and 14 healthy controls were included in this study. irAEs of grade (G) ≥ 2 occurred in 37/114 patients (32%). We observed a greater number of IgG and IgM reactivities in pre-ICI collections from patients versus healthy controls (62 vs 32 p < 0.001). Patients experiencing irAEs G ≥ 2 demonstrated pre-ICI IgG reactivity to a greater number of AutoAg than patients who did not develop irAEs (39 vs 33 p = 0.040). We observed post-treatment increase of IgM reactivities in subjects experiencing irAEs G ≥ 2 (29 vs 35, p = 0.021) and a decrease of IgG levels after steroids (38 vs 28, p = 0.009).ConclusionsOverall, these results support the potential role of autoAb in irAEs etiology and evolution. A prospective study is ongoing to validate our findings (NCT04107311).

Tislelizumab (Tisle) combined with/without gemcitabine and cisplatin (GC) as adjuvant therapy in patients at high risk after upper urothelial carcinoma (UTUC) surgery: A real-world study.

e16592 Background: In China, UTUC affects 9.3% - 19.9% of urothelial carcinoma(UC) patients(Pts), comparing to 5%-10% in western countries. Radical nephroureterectomy (RNU) is the standard of care for locally advanced UTUC; however, patient prognosis remains suboptimal, and previous studies have shown a controversial survival benefit of postoperative adjuvant chemotherapy in pts with UTUC. Immune checkpoint inhibitors(ICI) have been demonstrated to improve disease-free survival (DFS) in pts after adjuvant therapy for UC, but the data from UTUC studies is limited. This study is intended to evaluate real-world study data on whether Tisle with/without GC is able to achieve better survival benefit in pts with UTUC. Methods: UTUC pts with clinical diagnosis of T1N1 or T2-T4aN0-1M0, ECOG ps of 0-1, could tolerate surgery and had adequate renal functional reserve after surgery. Enrolled pts underwent RNU surgery and adjuvant therapy was started within 90 days after surgery. ICI: 200 mg in day1(D1), Q3w regimen, when to discontinue the drug was assessed by clinicians, and the reasons for disease progression and intolerable toxicity; GC chemotherapy: gemcitabine 1000 mg/m2 D1, D8, cisplatin 70 mg/m2 D2, up to 6 (0-6) cycles. Primary endpoint: 3-year Overall survival (OS) rate; secondary endpoints included 5-year OS rate, tumor-related survival (CSS) and safety. Results: A total of 60 pts received the above treatment from Jan 2020 to Dec 2022, of whom 5 pts were considered to have metastases at initial diagnosis at further evaluation and were finally evaluated for safety only. Fifty-five pts were evaluable for response, with a median follow-up time of 21.5 (3-33) months, and 70.91% (39/55) of pts were followed up for more than 12 months. The OS rate was 93.14% at 1 year and 76.21% at 2 years. Tisle was administered for a median of 6 (1-14) cycles, with a 7.19% and 24.79% lower risk of death at 1 and 2 years in pts with Tisle ≥ 3 cycles compared with pts with Tisle &lt; 3 cycles (HR: 0.368, 95% CI (0.076-1.781); p = 0.162). GC was administered for a median of 3 (0-6) cycles, with a 3.7% and 24.8% lower risk of death at 1 and 2 years in pts with GC＞2 cycles compared with pts with GC≤2 cycles (HR: 0.218, 95% CI (0.045-0.970); p = 0.110). The incidence of treatment-related adverse reactions (trAEs) of any grade was 91.64%; the incidence of trAEs of grade 3-4 was 18.33%, mainly manifested as leukopenic, gastrointestinal reaction and thrombocytopenia. The incidence of immune-related adverse reactions (irAEs) was 25%, and no irAEs of grade 3 or higher were found. The enrollment and follow-up of the present study are currently ongoing. Conclusions: Encouraging efficacy data and safety have been preliminarily observed with adjuvant Tisle with/without GC chemotherapy in high-risk pts after UTUC surgery. Final results also need to be observed in further studies.

First-in-human phase I/Ib study of QL1706 (PSB205), a bifunctional PD1/CTLA4 dual blocker, in patients with advanced solid tumors

BackgroundQL1706 (PSB205) is a single bifunctional MabPair (a novel technical platform) product consisting of two engineered monoclonal antibodies (anti-PD-1 IgG4 and anti-CTLA-4 IgG1), with a shorter elimination half-life (t1/2) for CTLA-4. We report results from a phase I/Ib study of QL1706 in patients with advanced solid tumors who failed standard therapies.MethodsIn the phase I study, QL1706 was administered intravenously once every 3 weeks at one of five doses ranging from 0.3 to 10 mg/kg, and the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of QL1706 were investigated. In the phase Ib study, QL1706 was administered at the RP2D intravenously every 3 weeks, and the preliminary efficacies in non-small cell lung cancer (NSCLC), nasopharyngeal carcinoma (NPC), cervical cancer (CC), and other solid tumors were evaluated.ResultsBetween March 2020 and July 2021, 518 patients with advanced solid tumors were enrolled (phase I, n = 99; phase Ib, n = 419). For all patients, the three most common treatment-related adverse events (TRAEs) were rash (19.7%), hypothyroidism (13.5%), and pruritus (13.3%). The TRAEs and immune-related adverse events (irAEs) of grade ≥ 3 occurred in 16.0% and 8.1% of patients, respectively. In phase I, 2 of 6 patients in the 10mg/kg group experienced dose-limiting toxicities (DLTs) (grade 3 thrombocytopenia and grade 4 immune-mediated nephritis), so the maximum tolerated dose (MTD) was reached at 10 mg/kg. The RP2D was determined to be 5 mg/kg based on comprehensive analysis of tolerability, PK/PD, and efficacy. For all patients who received QL1706 at the RP2D, the objective response rate (ORR) and median duration of response were 16.9% (79/468) and 11.7 months (8.3—not reached [NR]), respectively; and the ORRs were 14.0% (17/121) in NSCLC, 24.5% (27/110) in NPC, 27.3% (15/55) in CC, 7.4% (2/27) in colorectal cancer, 23.1% (6/26) in small cell lung cancer. For immunotherapy-naive patients, QL1706 exhibited promising antitumor activities, especially in NSCLC, NPC, and CC, with ORRs of 24.2%, 38.7%, and 28.3%, respectively.ConclusionsQL1706 was well tolerated and demonstrated promising antitumor activity in solid tumors, especially in NSCLC, NPC, and CC patients. It is currently being evaluated in randomized phase II (NCT05576272, NCT05179317) and phase III (NCT05446883, NCT05487391) trials.Trial Registration ClinicalTrials.gov Identifier: NCT04296994 and NCT05171790.

Peripheral CD8+CD28+ T lymphocytes predict the efficacy and safety of PD-1/PD-L1 inhibitors in cancer patients.

Programmed cell death protein-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors works by reactivating immune cells. Considering the accessibility of noninvasive liquid biopsies, it is advisable to employ peripheral blood lymphocyte subsets to predict immunotherapy outcomes. We retrospectively enrolled 87 patients with available baseline circulating lymphocyte subset data who received first-line PD-1/PD-L1 inhibitors at Peking Union Medical College Hospital between May 2018 and April 2022. Immune cell counts were determined by flow cytometry. Patients who responded to PD-1/PD-L1 inhibitors had significantly higher circulating CD8+CD28+ T-cell counts (median [range] count: 236 [30-536] versus 138 [36-460]/μL, p < 0.001). Using 190/μL as the cutoff value, the sensitivity and specificity of CD8+CD28+ T cells for predicting immunotherapy response were 0.689 and 0.714, respectively. Furthermore, the median progression-free survival (PFS, not reached versus 8.7 months, p < 0.001) and overall survival (OS, not reached versus 16.2 months, p < 0.001) were significantly longer in the patients with higher CD8+CD28+ T-cell counts. However, the CD8+CD28+ T-cell level was also associated with the incidence of grade 3-4 immune-related adverse events (irAEs). The sensitivity and specificity of CD8+CD28+ T cells for predicting irAEs of grade 3-4 were 0.846 and 0.667, respectively, at the threshold of CD8+CD28+ T cells ≥ 309/μL. High circulating CD8+CD28+ T-cell levels is a potential biomarker for immunotherapy response and better prognosis, while excessive CD8+CD28+ T cells (≥ 309/μL) may also indicate the emergence of severe irAEs.

Association between PD-1 inhibitor-related adverse events and frailty assessed by frailty index in lung cancer patients.

The programmed cell death protein 1 (PD-1) inhibitor, as one of the immune checkpoint inhibitors (ICIs), is the standard treatment for advanced lung cancer. However, immune-related adverse events (irAEs) remain poorly understood toxicities. It is unclear whether frailty plays a role in the occurrence of irAEs. Thus, we assess whether irAEs occur more often in frail patients than in non-frail patients according to the Frailty Index (FI). A retrospective study was conducted. Medical records from lung cancer patients treated with PD-1 inhibitors (Sintilimab, Camrelizumab, Tislelizumab, and Pembrolizumab) at Peking University First Hospital (May 2018-June 2022). Patients were categorized into non-frail and frail groups according to a cut-point of 0.25 by FI. The FI calculation included 28 baseline variables, all of which were health deficits measured by questionnaires and body measurements. The statistical analysis included 114 advanced lung cancer patients. The median age was 66 years, and the male/female ratio was 4.7:1 (94/20). Approximately 39 (34%) were classified as frail. PD-1 inhibitor-related adverse events occurred in 17.5% of patients, and 6.1% experienced irAEs of grade ≥3. There was no significant difference in the occurrence of irAEs (14.7% vs. 23.1%, p= 0.26), grade ≥ 3 irAEs (5.3% vs. 7.7%, p= 0.93), and treatment discontinuation due to irAEs (12.0% vs. 17.9%, p= 0.39) between non-frail and frail patients. However, frail patients are more likely to have more than one type of irAEs and are more possibly to have checkpoint inhibitor pneumonitis (CIP) than non-frail patients when they use PD-1 inhibitors (p< 0.05). Frail patients had a longer hospital stay (6 vs. 3 days, p= 0.01). Frailty is not associated with severe irAEs, but is related to CIP. Meanwhile, it predicts more than one type of irAEs and a longer hospital stay. Frailty screening has added value to the decision-making process for frail patients eligible for PD-1 inhibitors.

Neoadjuvant chemotherapy plus tislelizumab followed by concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma: A single-arm, phase II trial.

6068 Background: Neoadjuvant treatment with gemcitabine plus cisplatin (GP) prior to concurrent chemoradiotherapy (CCRT) has favorable survival outcomes with acceptable toxicity in patients with locoregionally advanced nasopharyngeal carcinoma (LANPC), 10% of whom achieved complete response (CR) after neoadjuvant treatment. Immune checkpoint blockade therapy plus GP regimen has been shown to improve the survival in recurrent or metastatic NPC. We investigated the efficacy and safety of neoadjuvant treatment with GP plus tislelizumab, an anti-PD-1 monoclonal antibody, in previously untreated LANPC. Methods: In this phase II, single-armed Simon two-stage study, eligible patients are of age 18-70, with adequate haematological, renal, and hepatic function, diagnosed with staged III-IVa（AJCC 8th） non-keratinizing LANPC. Enrolled patients received intravenous gemcitabine (1000 mg/m2) on days 1 and 8, cisplatin (80 mg/m2) on day 1, and tislelizumab (200mg) on day 1 every 3 weeks for 3 cycles followed by standard CCRT. The primary endpoint was CR rate after neoadjuvant treatment, using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by investigator. The secondary endpoints included pathology complete response (pCR) rate, 2-year progress-free survival (PFS), overall survival (OS), locoregional failure-free survival (LRRFS), distant metastasis-free survival (DMFS), and toxicity. This study is registered with ClinicalTrials.gov, NCT04833257, all enrolled patients have finished their treatment and the follow-up is ongoing. Results: From April 14th 2021 to August 5th, 2021, a total of 63 patients (median age 46y, 74.6% male) were enrolled at Sun Yat-sen University Cancer Center. As of January 31st, 2022, the median follow-up is 7.37 months, no patients had disease progression. The CR rate after neoadjuvant treatment was 41.3% (95% CI, 28.8% to 53.8%). The ORR and pCR rate were 88.9% (95% CI, 80.9% to 96.9%) and 75.8% (95% CI, 64.8% to 86.8%), respectively. The incidence of acute treatment-related AEs (trAEs) and immune-related adverse events (irAEs) of grade 3 or 4 was 69.8% and 3.2%, respectively. All of irAEs for grade 3 or 4 were hepatotoxicity and skin rash. Long-term efficacy is awaited. Conclusions: Neoadjuvant treatment with GP plus tislelizumab achieved impressive CR rate and pCR rate with manageable toxicities. Further follow-up is needed to confirm the long-term efficacy. Clinical trial information: NCT04833257.

A phase Ib study of SHR-1701, a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC).

6024 Background: Immune checkpoint inhibitors (ICIs) demonstrated favorable antitumor activity in RM-NPC. However, only a subset of patients derived benefits. Combining ICIs with agents blocking immunosuppressive pathway may expand the clinical benefit of ICIs to more patients. Transforming growth factor β (TGF-β) participates in tumor immune escape. SHR-1701 is a bifunctional fusion protein composed of a mAb against PD-L1 fused to the extracellular domain of TGF-β receptor II. Here, we report the safety and efficacy of SHR-1701 in RM-NPC patients. Methods: This is an ongoing, multicenter, open-label, phase Ib study (NCT04282070). Patients with confirmed RM-NPC who failed prior platinum-based chemotherapy (Arm 1) or both platinum-based chemotherapy and anti-PD-1/PD-L1 antibody treatment (Arm 2) were enrolled to receive SHR-1701 30 mg/kg intravenously once every three weeks until disease progression, unacceptable toxicity, or patient withdrawal. The primary endpoint was safety. The secondary endpoints were objective response rate (ORR), duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Results: 54 patients with RM-NPC were enrolled (Arm 1, n = 30; Arm 2, n = 24). All patients had stage IVb disease and 34 (63%) had received ≥2 lines prior therapies. At data cutoff on Nov 19, 2021, the median SHR-1701 exposure was 6.7 cycles (range 2-23) in Arm 1 and 2.1 cycles (range 1-17) in Arm 2. Grade ≥3 treatment-related adverse events (TRAEs) were observed in 10 patients (18.5%), with the most common being anemia (7.4%) and hemoptysis (3.7%). Two patients (3.7%) discontinued study treatment due to AEs (peripheral nerve injury and epistaxis, n = 1 each), and 10 patients (18.5%) had dose delay caused by AEs. Investigator reported immune related AEs (irAEs) of grade ≥3 occurred in five patients (9.3%). One death (1.9%) from unknown cause was observed, and the causality was deemed as not assessable. At data cutoff, the ORR was 33.3% (95% CI 17.3-52.8) in Arm 1 and 4.2% (95% CI 0.1-21.1) in Arm 2. Responses were ongoing in nine (90.0%) and no patients, respectively, and the median DoR was not reached in Arm 1 and 4.1 months in Arm 2. The DCR was 53.3% (95% CI 34.3-71.7) and 25.0% (95% CI 9.8-46.7), respectively. The median PFS was 5.3 months (95% CI 1.3-not reached) in Arm 1 and 1.4 months (95% CI 1.3-2.7) in Arm 2. At data cutoff, five patients (16.7%) in Arm 1 and eight patients (33.3%) in Arm 2 had died, and the median OS was not reached in both Arms. The 12-month OS rate was 79.9% (95% CI 53.2-92.3) and 71.9% (95% CI 47.6-86.4), respectively. Conclusions: SHR-1701 showed tolerable toxicity profile and promising antitumor activity in patients with RM-NPC who failed prior platinum-based chemotherapy. Clinical trial information: NCT04282070.

Construction of a near-term predictive model for irAEs induced by PD-1 inhibitors.

3147 Background: Immune checkpoint inhibitors have opened a new chapter in cancer therapy, but the incidence of irAEs caused by them is high, and severe irAEs can be fatal. The current research on irAEs is almost focused on early predictions, and there is a lack of near-term predictions (the cycle before the occurrence of irAEs). Absolute eosinophil count (EO#) has been reported to be associated with immune-related pneumonia, but its association with other systemic irAEs requires further exploration. The aim of this study was to explore the near-term predictive value of neutrophil/lymphocyte (NLR), platelet/lymphocyte (PLR), and EO# for PD-1 inhibitor-induced irAEs. Methods: The data are from tumor patients who received PD-1 inhibitor therapy in our department from July 2019 to May 2021. A total of 146 cases were included, of which 56 had irAEs. The data of NLR, PLR and EO# in the cycle before the occurrence of irAEs (the median number of cycles was the second cycle) were collected, and the data of the second cycle was used as the control for patients without irAEs group. Logistic method was used to analyze the correlation between NLR, PLR and EO# and irAEs, and a predictive model was constructed. The sensitivity and specificity of the model were evaluated by ROC curve. This study was registered on Chinese Clinical Trail Registry (ChiCTR2100049849). Results: A total of 146 tumor patients were included, of which 56 developed at least one irAEs. Grade 1-2 irAEs occurred in 39 cases, grade 3-4 in 12 cases (including cardiac, liver, lung and skin toxicity), grade 5 in 2 cases(including cardiac and lung toxicity), and ungraded in 3 cases. The data of the cycle before the occurrence of irAEs were analyzed. Univariate analysis showed that NLR (odds ratio [OR], 1.4, p&lt; 0.05) and EO# (OR, 12.6, p&lt; 0.05) were associated with irAEs, and multivariate analysis suggested NLR (OR, 1.7, p&lt; 0.001) and EO# (OR, 20.4, p&lt; 0.05) were independent risk factors for irAEs. The prediction model composed of NLR, PLR and EO# had a correct rate of 76.7% (AUC = 0.752) in predicting the occurrence of irAEs in the near-term cycle, with a sensitivity of 51.8% and a specificity of 92.2%; the correct rate of predicting irAEs of grade 3 and above was as high as 91.9% (AUC = 0.778), the sensitivity was 14.3% and the specificity was 99.2%. Conclusions: The model composed of NLR, PLR and EO# may predict the occurrence of irAEs in the near-term cycle, especially the prediction of irAEs above grade 3, which can provide early warning for the occurrence of irAEs. Clinical trial information: ChiCTR2100049849.

Effects of immune checkpoint inhibitor therapy resumption in patients with malignant tumors after moderate-to-severe immune-related adverse events.

Background and aimsImmune checkpoint inhibitors (ICIs) are used to treat several cancers, but they sometimes induce immune-related adverse events (irAEs). Patients with irAEs often have improved antitumor responses, but discontinuation of ICIs after irAEs is considered necessary. Resuming the use of ICIs after irAEs is preferable, but few studies have investigated the safety of ICI resumption after irAEs. Therefore, we evaluated the factors associated with the recurrence of irAEs after ICI resumption to investigate the safety of this approach.MethodsIn this observational study, we enrolled patients treated with ICIs from September 2014 to March 2020 at our institution. Patient characteristics, ICIs, grades of irAEs, ICI discontinuation or resumption rates, and recurrence rates of irAEs after ICI therapy were analysed.ResultsTwo-hundred eighty-seven patients were included in the present study, and 76 patients experienced grade 2 or higher irAEs. Forty-two patients underwent ICI resumption after recovering from irAEs, and 13 of them had a recurrence of irAEs. Among those 13 patients, six had a recurrence of the same irAE, and seven experienced other irAEs. Ten of the 13 patients had grade ≥2 irAEs, and none had fatal irAEs. In the grade 2 or higher irAE group, more patients had irAEs associated with multiple organs and of initial grade ≥2 than those in the grade 1 and no recurrent irAEs group.ConclusionsPatients with initial multisystemic irAEs and irAEs of grade ≥2 were more likely to experience relapse or develop new grade ≥2 irAEs after ICI resumption.

Randomized phase III study of sintilimab in combination with modified folfrinox versus folfrinox alone in patients with metastatic and recurrent pancreatic cancer in China: The CISPD3 trial.

560 Background: FOLFIRINOX or modified FOLFIRINOX (mFFX) is the standard of care for the first line treatment of metastatic pancreatic adenocarcinoma (PDAC). However, the prognosis still remains poor, novel treatment options are urgently need. Sintilimab, a human IgG4 monoclonal antibody that binds to programmed cell death receptor-1(PD-1), has shown remarkable efficacy in various cancers. We designed the CISPD3-trial in China, aimed to determine the efficacy and safety of the combination of Sintilimab and mFFX for metastatic or recurrent PDAC. Methods: In this single center, randomized, open-label, phase 3 trial, we enrolled patients with metastatic or recurrent PDAC to compare the efficacy and safety of Sintilimab combined with mFFX versus mFFX alone as first-line or second-line therapy. Patients eligible were randomly assigned (1:1) to Sintilimab (200 mg every 3 weeks) plus mFFX (irinotecan 85 mg/m2, oxaliplatin 68 mg/m2 followed by 5-FU 2400 mg/m2, every 2 weeks) or mFFX. The primary endpoint was overall survival (OS), secondary endpoints included progression free survival (PFS), objective response rate (ORR), disease control rate (DCR) and safety. This study is registered with ClinicalTrials.gov, NCT03977272. Results: From March 2019, to Dec 2020, 110 patients were enrolled and randomized to Sintilimab plus mFFX (n = 55) or mFFX (n = 55). 85.5% Patients had metastatic disease and 14.5% had recurrent disease, 7.3% Patients had previous first-line chemotherapy. The baseline characteristics of the subjects in these two arms were comparable. The median follow-up time for OS was 21.3 months (IQR 15.9-25.0) in Sintilimab plus mFFX group and 19.6 months (15.5-25.1) in mFFX group. The median OS was similar between Sintilimab plus mFFX (10.9 months) and mFFX arm (10.8 months) with HR = 1.083 (95% CI 0.6843 to 1.690). Median PFS was 5.9 months in Sintilimab plus mFFX arm and 5.73 months in mFFX arm (HR 0.9324, 95% CI, 0.6158 to 1.412). The ORR was 50% in the Sintilimab plus mFFX arm versus 23.9% in the mFFX arm (P = 0.010). The most common AE of Grade ≥ 3 are neutropenia (58.5% in the Sintilimab plus mFFX group vs. 44.4% in mFFX group), thrombocytopenia (17.0% vs. 11.1%), anemia (13.2% vs. 13.0%), vomiting (13.2% vs. 11.1%), increased aminotransferase (11.3% vs. 5.6%). 22.6% immune-related adverse events (irAEs) and 5.7% irAEs of grade ≥ 3 were observed in Sintilimab plus mFFX arm. The most common irAEs were pulmonary adverse event (13.2%) with 3 (5.7%) patients grade ≥ 3, among which 1 (1.8%) death was considered to be treatment-related. No new safety signals were identified. Conclusions: The addition of Sintilimab to mFFX improved ORR in advanced PDAC patients significantly, however no superior OS and PFS were observed. Toxicity was manageable. These data suggest that combined PD-1 blockade may expand the benefit of chemotherapy in PDAC. Clinical trial information: NCT03977272.

Analysis of characteristics and predictive factors of immune checkpoint inhibitor-related adverse events.

Objective:We aimed to retrospectively analyze the toxicity profiles and predictors of immune-related adverse events (irAEs) as well as the correlation between irAEs and the clinical efficacy of multi-type immune checkpoint inhibitors (ICIs) in patients with advanced pan-cancer in a real-world setting.Methods:We retrospectively analyzed data from 105 patients with advanced pan-cancer treated with multi-type ICIs at the First Hospital of Jilin University between January 1, 2016 and August 1, 2020. We used logistic regression analyses to investigate the associations of irAEs with clinical baseline characteristics, blood count parameters, and biochemical indicators during treatment. Receiver operating characteristic curves were used to determine cutoff values for parameters and area under the curve values. Kaplan–Meier and Cox multivariate regression analyses were performed to estimate the relationships of baseline characteristics and irAEs with progression-free survival (PFS) and overall survival (OS).Results:A lower relative lymphocyte count (cutoff = 28.5%), higher albumin level (cutoff = 39.05 g/L), and higher absolute eosinophil count (AEC) (cutoff = 0.175 × 109/L) were significantly associated with the occurrence of irAEs, among which a higher AEC (cutoff = 0.205 × 109/L) was strongly associated with skin-related irAEs [odds ratios (ORs) = 0.163, P = 0.004]. Moreover, a higher lactate dehydrogenase level (cutoff = 237.5 U/L) was an independent predictor of irAEs of grade ≥ 3 (OR = 0.083, P = 0.023). In immune cell subgroup analysis, a lower absolute count of CD8+CD28− suppressor T cells (OR = 0.806; 95% confidence interval: 0.643–1.011; P = 0.062), which are regulatory T lymphocytes, was associated with the occurrence of irAEs, although the difference was not statistically significant. Furthermore, a higher percentage of CD19+ B cells was associated with the occurrence of irAEs of grade ≥ 3 (P = 0.02) and grade ≥ 2 (P = 0.051). In addition, patients with any grade of irAE had a significantly high PFS (8.37 vs. 3.77 months, hazard ratios (HR) = 2.02, P = 0.0038) and OS (24.77 vs. 13.83 months, HR = 1.84; P = 0.024).Conclusions:This retrospective study reports clinical profile data for irAEs in unselected patients in a real-world setting and explored some parameters that may be potential predictive markers of the occurrence, type, or grade of irAEs in clinical practice. Evidence of a correlation between safety and efficacy may facilitate a complete assessment of the risk-benefit ratio for patients treated with ICIs.

Correlation of Peripheral Blood Parameters and Immune-Related Adverse Events with the Efficacy of Immune Checkpoint Inhibitors.

Objective We aimed to retrospectively analyze the predictors of immune checkpoint inhibitors (ICIs)-efficacy in patients with advanced pancancer who were treated with various ICIs in the real world and focused on the correlation between ICIs-efficacy and immune-related adverse events (irAEs). Methods We retrospectively analyzed data from 103 patients with advanced pancancer treated receiving various ICIs in the First Hospital of Jilin University from January 1, 2016 to August 1, 2020. Survival probabilities of progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan–Meier curves and log-rank tests and the multivariate Cox proportional hazards model. Receiver-operating characteristic curve was used to determine a cutoff value for parameters and area under the curve. Correlations between the two variables were analyzed by logistic regression. Results All patients were analyzed for survival predictors of OS, while 87 of 103 patients experienced evaluable disease progression of immunotherapy and were included in the analysis of predictors of PFS. First, we found that lower platelet (cutoff = 201.5 × 109/L) and lactate dehydrogenase (LDH) (cutoff = 227 U/L) were independently associated with significantly improved PFS, while lower platelet-lymphocyte ratio (cutoff = 206.5), absolute monocyte count (cutoff = 0.62 × 109/L), and LDH (cutoff = 194.5 U/L) were significantly and independently associated with better OS. In the analysis of the immune cell subgroup, a lower absolute countof CD8+CD28−suppressor T cells was an independent factor associated with better PFS (6.60 vs.4.13 months (mo), hazard ratios (HR) = 3.17, p = 0.0038), and OS (29.4 vs. 9.57 mo, HR = 3.05, p = 0.03). Second, the results of the analysis for irAEs showed that patients with any grade irAEs had higher objective response rate (30% vs. 10%, HR = 4.34, p = 0.009), disease control rate (69.7% vs. 50%, HR = 2.3, p = 0.028), PFS (8.37 vs. 3.77 mo, HR = 2.02, p = 0.0038), and OS (24.77 vs.13.83 mo, HR = 1.84, p = 0.024). Moreover, the groups with irAEs of grade ≥2 and with “multi-site” irAEs had significantly better PFS and OS (p < 0.05) compared with the other groups. We also proved that endocrine irAEs (usually thyroid dysfunction) were significantly associated with better mPFS (p = 0.01), and hepatic irAEs were significantly associated with better mOS (p = 0.023). Conclusions This retrospective study explored the availability and effectiveness of some cost-effective and readily available blood biochemical parameters in routine clinical practice to predict the ICIs-efficacy and demonstrated the predictive role of different categories of irAEs on efficacy.

Safety and Efficacy of Checkpoint Inhibition in Patients With Melanoma and Preexisting Autoimmune Disease : A Cohort Study.

Because immune checkpoint inhibition (ICI) can cause immune-related adverse events (irAEs) mimicking immunologic diseases, patients with preexisting autoimmune disease (AID) have been excluded from clinical trials. To evaluate the safety and efficacy of ICI in patients with advanced melanoma with and without AID. Nationwide cohort study. The Netherlands. 4367 patients with advanced melanoma enrolled in the Dutch Melanoma Treatment Registry (DMTR) between July 2013 and July 2018 and followed through February 2019. Patient, clinical, and treatment characteristics; irAEs of grade 3 or higher; treatment response; and survival. A total of 415 patients (9.5%) had AID, categorized as rheumatologic AID (n = 227), endocrine AID (n = 143), inflammatory bowel disease (IBD) (n = 55), or "other" (n = 8). Of these, 228 patients (55%) were treated with ICI (vs. 2546 [58%] without AID); 87 were treated with anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4), 187 with anti-programmed cell death 1 (PD-1), and 34 with the combination. The incidences of irAEs of grade 3 or higher in patients with AID were 30% (95% CI, 21% to 41%) with anti-CTLA-4, 17% (CI, 12% to 23%) with anti-PD-1, and 44% (CI, 27% to 62%) with combination therapy; for patients without AID, the incidences were 30% (CI, 27% to 33%) (n = 916), 13% (CI, 12% to 15%) (n = 1540), and 48% (CI, 43% to 53%) (n = 388), respectively. Patients with AID more often discontinued anti-PD-1 treatment because of toxicity than patients without AID (17% [CI, 12% to 23%] vs. 9% [CI, 8% to 11%]). Patients with IBD were more prone to anti-PD-1-induced colitis (6/31 = 19% [CI, 7% to 37%]) than patients with other AIDs (3% [CI, 0% to 6%]) and patients without AID (2% [CI, 2% to 3%]).The objective response rate was similar in patients with versus without AID who were treated with anti-CTLA-4 (10% [CI, 5% to 19%] vs. 16% [CI, 14% to 19%]), anti-PD-1 (40% [CI, 33% to 47%] vs. 44% [CI, 41% to 46%]), or the combination (39% [CI, 20% to 59%] vs. 43% [CI, 38% to 49%]). Survival did not differ between patients with and those without AID (median, 13 months [CI, 10 to 16 months] vs. 14 months [CI, 13 to 15 months]). Information was limited on AID severity and immunosuppressive treatment. Response to ICI with anti-CTLA-4, anti-PD-1, or their combination for advanced melanoma and overall incidence of any irAEs of grade 3 or higher were similar in patients with and without preexisting AID. However, severe colitis and toxicity requiring early discontinuation of treatment occurred more frequently among patients with preexisting IBD, warranting close follow-up. The Netherlands Organization for Health Research and Development.

Incidence of Skin and Respiratory Immune-Related Adverse Events Correlates With Specific Tumor Types in Patients Treated With Checkpoint Inhibitors

Checkpoint inhibitors (CPIs) increase antitumor activity by unblocking regulators of the immune response. This action can provoke a wide range of immunologic and inflammatory side effects, some of which can be fatal. Recent studies suggest that CPI-induced immune-related adverse events (irAEs) may predict survival and response. However, little is known about the mechanisms of this association. This study was undertaken to evaluate the influence of tumor diagnosis and preexisting clinical factors on the types of irAEs experienced by cancer patients treated with CPIs. The correlation between irAEs and overall survival (OS) was also assessed. All cancer patients treated with atezolizumab (ATEZO), ipilimumab (IPI), nivolumab (NIVO), or pembrolizumab (PEMBRO) at Virginia Mason Medical Center between 2011 and 2019 were evaluated. irAEs were graded according to the Common Terminology Criteria for Adverse Events (Version 5) and verified independently. Statistical analyses were performed to assess associations between irAEs, pre-treatment factors, and OS. Of the 288 patients evaluated, 59% developed irAEs of any grade, and 19% developed irAEs of grade 3 or 4. A time-dependent survival analysis demonstrated a clear association between the occurrence of irAEs and OS (P < 0.001). A 6-week landmark analysis adjusted for body mass index confirmed an association between irAEs and OS in non-Small Cell Lung Cancer (NSCLC) (P < 0.03). An association between melanoma and skin irAEs (P < 0.01) and between NSCLC and respiratory irAEs (P = 0.03) was observed, independent of CPI administered. Patients with preexisting autoimmune disease experienced a higher incidence of severe irAEs (P = 0.01), but not a higher overall incidence of irAEs (P = 0.6). A significant association between irAEs and OS was observed in this diverse patient population. No correlation was observed between preexisting comorbid conditions and the type of irAE observed. However, a correlation between skin-related irAEs and melanoma and between respiratory irAEs and NSCLC was observed, suggesting that many irAEs are driven by a specific response to the primary tumor. In patients with NSCLC, the respiratory irAEs were associated with a survival benefit.

Low-dose ipilimumab plus nivolumab combined with IL-2 and hyperthermia in cancer patients with advanced disease: exploratory findings of a case series of 131 stage IV cancers \u2013 a retrospective study of a single institution

The 3-year overall survival (OS) rate of patients with previously treated or untreated stage III or IV melanoma has by now reached 63% using ipilimumab and nivolumab therapy. However, immune-related adverse events (irAEs) of grade 3 or 4 occurred in 59% of patients leading to discontinuation of therapy in 24.5% of patients and one death. Therapy with checkpoint inhibitors could be safer and more effective in combination with hyperthermia and fever inducing therapies. We conducted a retrospective analysis to test the safety and efficacy of a new combination immune therapy in 131 unselected stage IV solid cancer patients with 23 different histological types of cancer who exhausted all conventional treatments. Treatment consisted of locoregional- and whole-body hyperthermia, individually dose adapted interleukin 2 (IL-2) combined with low-dose ipilimumab (0.3 mg/kg) plus nivolumab (0.5 mg/kg). The objective response rate (ORR) was 31.3%, progression-free survival (PFS) was 10 months, survival probabilities at 6 months was 86.7% (95% CI, 81.0–92.8%), at 9 months was 73.5% (95% CI, 66.2–81.7%), at 12 months was 66.5% (95% CI, 58.6–75.4%), while at 24 months survival was 36.6% (95% CI:28.2%; 47.3%). irAEs of World Health Organization (WHO) Toxicity Scale grade 1, 2, 3, and 4 were observed in 23.66%, 16.03%, 6.11%, and 2.29% of patients, respectively. Our results suggest that the irAEs profile of the combined treatment is safer than that of the established protocols without compromising efficacy.

Correlation between immune-related adverse events and prognosis in patients with various cancers treated with anti PD-1 antibody

BackgroundImmune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) are used for the treatment of various cancer types. However, immune-related adverse events (irAEs) occur in patients treated with ICIs. Several small-scale studies have reported the onset of irAEs and therapeutic effects of ICIs. Here we report a large-scale retrospective study covering a wide range of cancers. We evaluated irAEs and the therapeutic effects of ICIs and determined whether irAEs could be predicted.MethodsThis study included patients treated with the anti-PD-1 antibodies nivolumab or pembrolizumab at Fujita Health University Hospital between December 2015 and March 2019. We retrospectively reviewed the electronic medical records for age, cancer type, pre-treatment blood test data, presence or absence of irAE onset, type and severity of irAEs, outcome of irAE treatment, response rate, progression-free survival and overall survival.ResultsTwo hundred-eighty patients received ICIs. The overall incidence of irAEs was 41.1% (115 patients), and the incidence of severe irAEs of grade 3 and higher was 2.8% (eight patients). The most common irAEs were skin disorders, thyroid disorders and interstitial pneumonitis. Patients with irAEs were significantly older than those without irAEs (69.7 versus 66.0 years, P = 0.02). The objective response rate (ORR) in patients with irAEs was 30.4%, which was significantly higher than in patients without irAEs (12.7%; P < 0.01). Both the median overall and progression-free survival were significantly longer in patients with irAEs (P < 0.01, p < 0.01). Based on the blood test data obtained before ICI therapy, hypothyroidism, thyroid-stimulating hormone levels and thyroglobulin antibody levels were associated with the onset of irAEs. In many patients with irAEs of Common Terminology Criteria for Adverse Events Grade 3 or higher, re-administration of ICIs was difficult, and their outcomes were poor. In contrast, many patients with irAEs of a lower grade were able to resume ICI therapy.ConclusionAlthough the onset of irAEs was difficult to be predicted based on pre-treatment tests. It appeared that the continuation of ICI therapy, along with early detection and adequate control of irAEs, might contribute to the improved prognosis of patients.

Long-lasting, irreversible and late-onset immune-related adverse events (irAEs) from immune checkpoint inhibitors (ICIs): A real-world data analysis.

e15095 Background: ICIs are effective in many tumors, but can cause severe irAEs, with potential long-term impact. Description of irAEs in literature is often insufficient, especially in terms of irAEs duration, and in terms of incidence of late-onset events. Namely, duration of irAEs and proportion of patients (pts) with toxicity still ongoing at data cut-off were not specified in 52 (89.6%) of 58 publications of trials leading to ICIs approval by US FDA and/or EMA up to August 2019. Real-world data are urgently needed to integrate this information. Methods: We retrieved the medical charts of all pts affected by lung cancer (LC) and melanoma (Mel) treated consecutively with approved ICIs at the Centre Hospitalier Universitaire Vaudoise (CHUV) from Jan 2012 to Dec 2019. We collected the following data: treatment setting, ICIs received, duration of each treatment, incidence of any irAEs of grade (G) ≥ 2 (according to CTCAE v5.0), time to onset and duration of irAEs. Pts with follow-up (FU) ≤ 28 days were excluded. Results: 345 pts were included (166 LC, 179 Mel), for a total of 455 ICIs treatment lines. 33 pts (7%, all with Mel) were treated in the adjuvant setting, while all the others were treated for advanced disease. 228 pts (50%) received anti-PD1, 43 (9%) anti-PD-L1, 56 (12%) anti-CTLA-4, 100 (22%) ICI-ICI combinations and 28 (6%) ICI–chemotherapy combinations. Median FU was 369 days (range 29-2903). Median duration of treatment was 71 days (range 1-1625). 196 pts (57%) experienced at least 1 G≥2 irAE for a total of 277 irAEs (22% skin, 18% gastro-intentinal [GI], 13% pneumonitis, 12% thyroid disorders, 11% hyphophisitis and 8% hepatitis). With 122/277 (44%) irAEs still on-going at our data cut-off, median duration of irAEs was 98 days; 104/277 irAEs (37%) lasted more than 6 month, of them 89% were considered irreversible. Out of 76 pts still on ICIs treatment at 6 months, incidence of G≥2 irAE with onset after 6 months was 51% (26% pneumonitis, 26% endocrine disorders, 15% skin disorders, 8% hepatitis and GI). Out of 32 pts still on ICIs treatment at 12 months, incidence of G≥2 irAE with onset after 12 months was 41% (38% pneumonitis, 23% endocrine and 15% skin disorders, 8% hepatitis and GI). Conclusions: Our real-world analysis shows that long-lasting and late-onset irAEs represent an important issue during ICIs treatment. A better description of toxicities in clinical trials is needed to allow a proper evaluation of treatment value and the impact on patients' quality of life.