Incidence Of irAEs Research Articles

Impact of Antibiotic on Efficacy and Adverse Reactions of Chemoimmunotherapy in Non‐small Cell Lung Cancer Patients: A Retrospective Cohort Study

ABSTRACTBackgroundThis study aimed to evaluate the impact of antibiotic exposure on efficacy and adverse reactions in non‐small cell lung cancer (NSCLC) patients receiving chemoimmunotherapy, and to explore any specific associations on the basis of antibiotic class.MethodsA retrospective study was conducted on NSCLC patients who received chemoimmunotherapy in two Shandong hospitals between January 2018 and October 2023. The association between antibiotic exposure and progression‐free survival (PFS), overall survival (OS), objective response rate (ORR) and incidence of immune related adverse reactions (irAE) of patients were evaluated.ResultsOf the 316 patients, 134 (42.41%) received antibiotics (ATB group), and 182 (57.59%) did not (N‐ATB group). There was no significant difference in PFS (aHR = 1.009, 95% CI: 0.770–1.323; p = 0.946) or OS (aHR = 1.420, 95% CI: 0.986–2.047; p = 0.060) between ATB and N‐ATB groups. The impact on efficacy was related to the type of antibiotic. β‐Lactams (aHR = 1.737, 95% CI: 1.148–2.629; p = 0.009), in particular β‐lactam/β‐lactamase inhibitor combinations (BLBLIs) (aHR = 1.885, 95% CI: 1.207–2.944, p = 0.005) were associated with poorer OS. However, quinolones (aHR = 1.192, 95% CI: 0.861–1.650; p = 0.291) were not associated with OS. The incidence of irAEs was not significantly different between ATB and N‐ATB groups (p = 0.073), but was higher with BLBLIs (p = 0.013).ConclusionsIn NSCLC patients receiving chemoimmunotherapy, no significant difference was observed in efficacy and incidence of irAEs between the ATB and the n‐ATB groups. In antibiotic class analysis, β‐lactams and specifically BLBLIs were observed to be associated with worse OS.

Adverse events after nivolumab and ipilimumab combined immunotherapy in advanced renal cell carcinoma: a multicentre experience in Poland.

Immune checkpoint inhibitors (ICIs) have been employed in the adjuvant and metastatic setting of renal cell carcinoma (RCC) treatment. Among ICIs, combined immunotherapy has the highest risk for immune-related adverse events (irAEs). We aimed to document the incidence of irAEs in RCC patients treated with nivolumab and ipilimumab as data from the European population remain limited. We analysed data from 88 RCC patients treated with nivolumab + ipilimumab between May 2022 and June 2024 across six high-volume oncology units in Poland. We reviewed irAEs and estimated their impact on survival parameters via univariate and multivariate Cox proportional hazards regression models, along with log-rank tests. With a median follow-up of 11.3 months, the median overall survival (OS) was not reached, whereas the median progression-free survival (PFS) was 12.8 months (6.3-19.3). A total of 74 irAEs were recorded in 50 patients. The most frequent events were endocrine (n = 20, 27%), hepatic (n = 15, 17%), general (n = 12, 13.6%), and cutaneous (n = 11, 12.5%). The occurrence of irAEs was associated with a 60% lower risk of disease progression (hazard ratio 0.44, 95% confidence interval 0.2-0.87, p = 0.018) without impacting OS and higher disease control rate (n = 45, 90% vs. n = 24, 63.2%, p = 0.004). In contrast, patients with hepatotoxicity had poorer outcomes, with a 2.6-fold greater risk of death (p = 0.05). IrAEs may serve as a predictive factor for the efficacy of the nivolumab + ipilimumab regimen in RCC patients. Special attention is needed for hepatotoxicity, as it can significantly impact survival outcomes.

Analysis of the association between immune-related adverse events and the effectiveness in patients with advanced non-small-cell-lung cancer.

Immune checkpoint inhibitors (ICIs) have improved lung cancer treatment but are associated with immune-related adverse events (irAEs). This study analyzes the relationship between irAEs and treatment effectiveness in advanced non-small cell lung cancer (NSCLC) patients. We conducted a retrospective study of NSCLC patients treated with ICIs from March 2019 to October 2022 at Zhongshan Hospital (Xiamen). Patients were divided into irAE and non-irAE groups, and treatment outcomes were compared. A total of 154 patients were included, with 36.4% in the irAE group and 63.6% in the non-irAE group. Most irAEs were Grade 1-2 (86.4%), with 13.6% being Grade 3 or higher. The irAE group had higher disease control rates (DCR: 94.6% vs. 76.5%, P = 0.004) and objective response rates (ORR: 42.9% vs. 26.5%, P = 0.037). Median progression-free survival (PFS) was longer in the irAE group (18 vs. 9months, HR: 0.53, P = 0.001), as was overall survival (OS: 39.5 vs. 16months, HR: 0.46, P = 0.001). Landmark analysis at 6 and 12weeks confirmed that irAEs were associated with improved outcomes. Moreover, patients who experienced two or more adverse events during treatment had significantly longer OS compared to those who had only one or no adverse events (41.6months vs. 34.0 vs. 23.6, P = 0.003). Patients with irAEs demonstrated better outcomes, including ORR, DCR, PFS, and OS. Further studies on biomarkers and irAE incidence are warranted to improve lung cancer management.

Association between programmed death protein 1-related single-nucleotide polymorphisms and immune-related adverse events induced by programmed death protein 1 inhibitors—a pilot study

Programmed death protein 1 (PD-1) inhibitors have potent anti-tumor activities. However, they often result in immune-related adverse events (irAEs) of varying severity. Therefore, the factors affecting the incidence of irAEs warrant urgent investigation. This study aimed to identify specific and sensitive predictors of irAEs in a Chinese population. We conducted a genome-wide association study (GWAS) comprising 80 patients with malignant tumors to evaluate single-nucleotide polymorphism (SNP) loci associated with the incidence of irAEs. The SNP rs2157775 on the LOC339166 gene had the lowest P value but did not reach the significance threshold after Bonferroni correction. Therefore, potentially associated SNPs were further investigated through the mechanism-related PD-1 pathway using the ImmPort and PathCards Human Gene Databases. A binary logistic regression model revealed that CD3E (rs3782040) A/A was associated with a lower incidence of irAEs in patients with malignant tumors who received PD-1 inhibitors. In contrast, PTPN11 (rs143894582) C/CA was associated with a higher incidence of irAEs. These findings provide a basis for the verification and identification of new loci to provide insight into the etiology of irAEs.

Evaluation of the safety of PD-1/PD-L1 inhibitors for immunotherapy in patients with malignant tumors after COVID-19 infection: A single-center cohort study.

An increasing body of evidence suggests a close association between COVID-19 infection and the safety of PD-1/PD-L1 inhibitor therapy in cancer patients. However, the available data concerning these impacts remain limited and occasionally contradictory. We conducted a retrospective analysis of cancer patients who received PD-1/PD-L1 inhibitor therapy at the same institution from November 2022 to May 2023. After excluding patients with missing information, a total of 224 cases were included. In our study, immune-related adverse events (irAEs) that occurred during the hospitalization of patients were included in the analysis. Further analysis of inter-subgroup differences was conducted following a 1:2 propensity score matching. Statistical analyses were performed using the Fisher's exact, chi-squared, and Mann-Whitney U-tests. The results showed that no statistically significant differences between the two subgroups in the incidence of irAEs, changes in immune function before and after using PD-1/PD-L1 inhibitors, and alterations in hepatic and renal function (p > 0.05). Our findings suggest that infection with COVID-19 does not significantly impact the safety of PD-1/PD-L1 inhibitors in cancer patients. Most cancer patients used PD-1/PD-L1 inhibitors during COVID-19 infection (asymptomatic or mild infection) did not experience exacerbation of their underlying condition, nor did they exhibit a substantial increase in toxic side effects.

Immune-related adverse events in a nationwide cohort of real-world melanoma patients treated with adjuvant anti-PD1 – Seasonal variation and association with outcome

IntroductionImmune checkpoint inhibitors (ICIs) carry the risk of immune-related adverse events (irAEs), a significant concern as therapy has transitioned to the adjuvant setting. Balancing therapeutic benefits against potential risks is crucial, necessitating real-world data from an unselected patient population in addition to clinical trial data to ensure optimal clinical decision-making. MethodsThis nationwide real-world study assessed irAEs in patients receiving adjuvant anti-PD1 therapy, primarily nivolumab, for resected stage III-IV melanoma between 2018–2022. Data were retrieved from two national databases: the IMMUNOTOX database and the Danish Metastatic Melanoma Database (DAMMED). IrAEs were sub-grouped according to organ systems graded using CTCAE ver. 5.0 ranging from mild toxicities (grade 1–2) to severe (grade 3–4) and fatal (grade 5). ResultsAmong 792 included patients, (55 % male, median age 62 years (range 16–88)), 697 patients (88 %) experienced an irAE. Severe irAEs occurred in 116 patients (15 %) and five (0.6 %) died due to toxicity. A landmark analysis showed that patients who experienced at least one irAE before the 1st evaluation at 90 days had an increased progression free survival (PFS) (p = 0.032) and overall survival (OS) (p = 0.0071). Additionally, a seasonal pattern was noted with higher incidence of irAEs during summer. ConclusionThe prevalence of irAEs in real-world patients is comparable to the observed risk in clinical trials. Patients experiencing irAEs demonstrate a lower risk of melanoma relapse. Further, gender, age and seasonal variation may impact the incidence of irAEs.

Abstract C170: Unveiling sex differences in hospitalization rates for immune-related adverse events in older lung cancer patients treated with ICIs: A SEER-Medicare analysis

Abstract Introduction Immune checkpoint inhibitors (ICIs) offer substantial benefits for older adults with lung cancer (LCa) but they also pose risks of immune-related adverse events (irAEs), necessitating investigation into the demographic influences on hospitalization rates. Sex differences among older adults within this cohort are understudied. Our study aims to explore the gender differences in irAE-related hospitalizations among older adults. Methods We utilized Surveillance, Epidemiology, and End Results (SEER)-linked Medicare data to identify older adults diagnosed with primary LCa from 1999 to 2017 and treated with ICIs between 2011 and 2019. Patients were steroid-naïve and chemo-naïve for 3 and 12 months, respectively, prior to ICI initiation. ICD-9/10 diagnosis codes were used to identify irAEs post-ICI initiation and these diagnosis were flagged during the pre-ICI period for comparison. An adjusted negative binomial model compared irAE-hospitalization rates in the post-ICI period (0-6, 7-12, and 13-24 months) to those in the pre-ICI period (6 months prior), accounting for confounders. An interaction term between gender and treatment period was included to compare differences in rates between males and females. Results Of the 1,089 patients, 54% were female, 79.6% had Charlson Comorbidity Index (CCI) ≥1. Females had 59% higher rates of irAE-hospitalizations at baseline (95% CI: 1.18 – 2.14, p<0.001). Patients with CCI≥3 had a 141% higher rate for irAE- hospitalization compared to those with CCI=0. Specifically for males, compared to 6-months pre-ICI, the irAE-hospitalization rates were 187% higher 0-6 months post-ICI (IRR = 2.87, 95% CI: 1.20-3.74), 134% higher 7-12 months post-ICI (IRR = 2.34, 95% CI: 1.66-3.31), and 122% higher 13-24 months post-ICI (IRR = 2.22, 95% CI: 1.53-3.28). Similarly for females, compared to 6-months pre-ICI, the irAE-hospitalization rates were 123% higher 0-6 months post-ICI (IRR = 2.23, 95% CI: 1.27-3.75), 69% higher 7-12 months post-ICI (IRR = 1.69, 95% CI: 1.27-3.37), and 11% higher 13-24 months post-ICI (IRR = 1.11, 95% CI: 1.03-2.37). Age and race did not impact irAE-hospitalization rates among LCa patients. Conclusions The incidence of irAEs following ICI treatment is notably higher in the first six months post-ICI for both males and females, with males experiencing a higher rate of events across all post-treatment periods. Key factors influencing the rate of irAE-hospitalizations include the CCI and pre-treatment gender differences. These findings underscore the need for tailored post-ICI monitoring strategies to mitigate adverse events in vulnerable populations. Citation Format: Fnu Nikita, Swapnil Sharma, Amy Shaver, Krupa Gandhi, Scott W. Keith, Christina Steinbock- Malfer, Jennifer M. Johnson, Sarah Gordon, Grace Lu-Yao. Unveiling sex differences in hospitalization rates for immune-related adverse events in older lung cancer patients treated with ICIs: A SEER-Medicare analysis [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C170.

Long-term survival and post-hoc analysis of toripalimab plus definitive chemoradiotherapy for oesophageal squamous cell carcinoma: insights from the EC-CRT-001 phase II trial

In the EC-CRT-001 phase II study, the combination of toripalimab (an anti-programmed death-1 antibody) and definitive chemoradiotherapy (CRT) has shown promising efficacy in patients with locally advanced oesophageal squamous cell carcinoma (ESCC). Here, we reported the long-term outcomes and post-hoc exploratory analyses. This single-arm, phase II trial enrolled 42 patients diagnosed with unresectable stage I-IVA ESCC was conducted at Sun Yat-sen University Cancer Center between November 2019 and January 2021. Treatment consisted of chemotherapy (weekly 50mg/m2 of paclitaxel and 25mg/m2 of cisplatin for five cycles), concurrent radiotherapy (50.4Gy in 28 fractions), and toripalimab (240mg every 3 weeks for up to 1 year). The primary endpoint was clinical complete response (CR) rate at 3 months after CRT completion. The 3-year overall survival (OS) and progression-free survival (PFS) rates were evaluated. Additionally, the exploratory objectives included analysing recurrence patterns, assessing the associations between immune-related adverse events (irAEs) and efficacy, and identifying potential predictors for irAEs. The trial was registered with ClinicalTrials.gov (NCT04005170). With a median follow-up of 44.3 months (IQR 40.8-46.1), the 3-year OS and PFS rates were 44.8% (95% CI 31.9-62.8) and 35.7% (95% CI 23.8-53.6), respectively. Patients who failed to achieve a clinical complete response (CR) demonstrated significantly worse OS (hazard ratio [HR]=13.73, 95% CI 4.43-42.54, P<0.0001) and PFS (HR=32.08, 95% CI 8.57-120.10, P<0.0001). Disease recurrence occurred in 23 of 42 patients (55%), with recurrences being earlier and more frequent in the non-CR group compared to the CR group. Patients experiencing irAEs showed a significantly higher CR rate (72% vs. 39%, P=0.082) and better PFS (HR=0.43, 95% CI 0.19-0.93, P=0.027) than those without irAEs. GON4L mutation was associated with a lower incidence of irAEs (P=0.036). The updated survival outcomes confirmed the efficacy of toripalimab plus definitive CRT in locally advanced ESCC. Moreover, the development of irAEs may predict a more favourable prognosis. National Natural Science Foundation of China, Beijing Xisike Clinical Oncology Research Foundation, and Sci-Tech Project Foundation of Guangzhou.

Toxicity profile of camrelizumab-based immunotherapy in older adults with advanced cancer

Immune checkpoint inhibitors (ICIs) have become an important cornerstone of many tumour treatments. However, the toxicity profile of immune-chemotherapy combination treatment approaches among older adult cancer patients is still unclear. Patients with any cancer who received camrelizumab-based immunotherapy were eligible for inclusion. The primary endpoints were adverse events (AEs) and immune-related adverse events (irAEs), which were defined based on Naranjo's algorithm. Patients were stratified by age (≥ 70 years and < 70 years), and comparisons were made based on the type of camrelizumab-based therapy (monotherapy, combined chemotherapy, or combined anti-VEGF therapy). A total of 185 patients were administered camrelizumab-based immunotherapy, 55 (30%) of whom were ≥ 70 years old. A total of 146 (78.9%) patients received camrelizumab-based combination treatment. The incidence of all-grade AEs was 56.8% (105 patients), while that of irAEs was 36.8% (68 patients). There was no difference in the percentage of patients experiencing any grade or grade ≥ 3 AEs between age groups. However, the frequency of irAEs (both any grade and grade ≥ 3) significantly differed by age group (P = 0.001 and 0.009, respectively). The results of multivariable analysis revealed that age ≥ 70 years was the only independent risk factor for irAEs. The results of subgroup analysis revealed that the incidence of irAEs was higher in older patients treated with camrelizumab-chemotherapy, while the incidence rates were similar between age groups in the monotherapy and combination anti-VEGF treatment subgroups. Immune-related diabetes mellitus occurred more frequently among older adults. The spectrum of irAEs showed that combination immunotherapy had more widely effects on the organ system than monotherapy. In this study, older (≥ 70 years) patients had a higher risk of all-grade and high-grade irAEs when receiving camrelizumab chemotherapy combination treatment. Notably, long-term random glucose monitoring should be performed during ICI-based immunotherapy in older cancer patients.

Association between the occurrence of immune-related adverse events and survival outcomes in patients with cancer treated with perioperative immune checkpoint inhibitors: A systematic review and meta-analysis.

39 Background: Although multiple studies have revealed that the occurrence of immune-related adverse events (irAEs) is associated with better survival in patients with advanced cancer, the association in patients with early-stage disease in the perioperative setting remains unclear. We performed a systematic review and meta-analysis to evaluate this association in the neoadjuvant and adjuvant settings. Methods: We performed a database search in PubMed/MEDLINE and Embase to identify eligible articles up to March 2024. We included studies evaluating the association between the occurrence of irAEs and survival outcomes in patients with solid tumors receiving at least one ICI in the perioperative setting. Cancer type, ICI agent, the number of patients, and survival outcomes (hazard ratio [HR] with 95% confidence interval [CI]) were summarized. We performed a random-effect model meta-analysis of survival outcomes that contained HR and 95% CI information from more than two studies. Results: After screening 884 articles, we found 15 eligible articles of which four studies reporting only treatment-related adverse events without irAE information were excluded. Finally, 11 studies (Clinical trials: n=3, Cohort studies: n=8) analyzing the association between the incidence of irAEs and survival were identified. Melanoma, triple-negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), and urothelial carcinoma were evaluated in seven, two, one, and one study, respectively. While ten studies defined the irAE group as any-type and any-grade irAEs, one study defined the irAE group as any-type and grade 2-5 irAEs. OS was evaluated in five studies (four studies for melanoma), of which two studies suggested that the occurrence of irAEs was associated with longer OS. A meta-analysis of three studies showed a tendency of the association between the occurrence of any-type and any-grade irAEs and longer OS (Pooled HR=0.69, 95% CI 0.47-1.00, p = 0.05). RFS was evaluated in eight studies (seven for melanoma), of which seven studies indicated the association between the incidence of any-type irAEs (any-grade: 6 studies, grade 2-5: 1 study) and longer RFS. A meta-analysis of five studies revealed a significant association between the occurrence of any-type irAEs (any-grade: 4 studies, grade 2-5: 1 study) and longer RFS (Pooled HR=0.52, 95% CI 0.41 - 0.67, p &lt; 0.0001]); however, Funnel plot indicated a presence of publication bias. Conclusions: This study suggests an association between irAEs and longer survival from perioperative ICI therapy, particularly in patients with melanoma. The result should be cautiously interpreted given a possible presence of publication and immortal bias. Further prospective studies and individual patient data meta-analysis are needed to validate this result.

Detrimental Impact of Chemotherapy Dose Reduction or Discontinuation in Early Stage Triple-Negative Breast Cancer Treated With Pembrolizumab and Neoadjuvant Chemotherapy: A Multicenter Experience

BackgroundPembrolizumab combined with neoadjuvant chemotherapy (NAC) is the current standard of care in early stage triple-negative breast cancer (TNBC) based on higher event-free survival and pathological complete response (pCR) in Keynote-522 (KN-522) clinical trial. However, this aggressive five-drug regimen is associated with increased risks for immune-related adverse events (irAEs). We investigated real-world clinical outcomes and toxicity of this regimen as well as factors predictive of pCR and irAEs. MethodsWe identified and abstracted data from 153 early-stage TNBC patients treated with the KN-522 regimen between July 1, 2021, and December 31, 2023, at 4 academic institutions in the U.S. Descriptive analysis was conducted, univariate and multivariate analyses were performed to identify factors associated with pCR and irAEs. ResultsThe median age was 52 years (interquartile range, 42-60years), with 66% White and 24% Black patients with stage I/II (67%), node-negative disease (58%), grade 3 (86%) tumors, and ≥1 comorbidities (68%). Approximately 21% discontinued pembrolizumab, because of toxicity; ∼50% received a lower relative dose intensity (RDI) of chemotherapy (dose reduction or discontinuation). Of the 153 patients, 99 (64.7%) achieved pCR and 83 (54%) experienced an irAE, with 18 (12%) having ≥ grade 3 irAE. The majority (90%) of the irAEs were observed during neoadjuvant phase. Stage I/II versus stage III disease (OR 1.55, CI 1.04-2.33, P = .03), age (OR 0.96, CI 0.93-0.99, P = .01) and full versus reduced RDI of NAC (OR 1.53, CI 1.04-2.26, P = .03) were associated with higher pCR rates on multivariate analyses. Fewer cycles of pembrolizumab were associated with a higher likelihood of irAEs (OR 1.52, CI 1.07-2.16, P = .02), likely explained by the early discontinuation and receipt of less than 8 cycles of pembrolizumab in patients who experienced irAEs. ConclusionsOur study validates the clinical efficacy of KN-522 regimen; however, we observed a higher incidence of irAEs (54%) in this real-world population. Lower stage and younger age were associated with higher likelihood of achieving pCR. Toxicity-related chemotherapy dose reduction or discontinuation was observed to adversely impact the likelihood of achieving pCR.

Interleukin-7 Risk Allele, Lymphocyte Counts, and Autoantibodies for Prediction of Risk of Immune-Related Adverse Events in Patients Receiving Atezolizumab plus Bevacizumab Therapy for Unresectable Hepatocellular Carcinoma.

Atezolizumab plus bevacizumab (AB) therapy was the effective immune checkpoint inhibitor (ICI) for unresectable hepatocellular carcinoma (u-HCC). However, immune-related adverse events (irAEs) are common in patients receiving ICI therapies. Our research aimed to explore the risk factors for irAE development, with attention to interleukin-7 (IL-7) risk alleles, lymphocyte counts, and autoantibodies. Seventy-six patients receiving AB therapy for u-HCC were recruited. Single nucleotide polymorphism genotyping was done for the analysis of rs16906115 polymorphism near IL-7-expressing genes using 20 μL of stored buffy coat at baseline. The association between IL-7 risk alleles, lymphocyte counts, autoantibodies, and irAE development was investigated. irAEs were found in 14 (18%) patients. The incidence of irAEs did not differ significantly between the groups showing IL-7 AG/AA and the GG group (p = 0.72). The incidence in the group with a lymphocyte count of 1,130/µL or more at baseline was higher than in that with a value below 1,130/µL (p = 0.0093). The group showing IL-7 AG/AA or lymphocyte count &gt;1,130/μL had a higher irAE prevalence rate than the others (p = 0.019). IL-7 AG/AA or lymphocyte count &gt;1,130/μL and positivity for autoantibodies at baseline were the prognostic factors for irAE development. irAE incidence could be stratified using a combination of IL-7 AG/AA or lymphocyte counts ≥1,130/µL and positive autoantibodies (p = 0.016). Patients with IL-7 risk alleles, high lymphocyte counts, and autoantibodies at baseline may require careful monitoring for irAE development.

Evaluation of safety outcomes between nivolumab regimens with differing dosing patterns.

Real-world safety outcomes between the two flat-dose nivolumab regimens demonstrated to be similar in a study of adjuvant nivolumab recipients for melanoma. However, this study was limited by a single oncology patient population, a small sample size, and insufficient study power. The primary objective of this study was to evaluate the incidence of immunotherapy-related adverse effects (irAEs) between nivolumab regimens with differing dosing patterns in various solid tumor patient populations. Single-center retrospective cohort study of adult patients with solid tumor malignancies who received nivolumab 240 mg Q2W or 480 mg Q4W, or who were transitioned from 240 mg Q2W to 480 mg Q4W from March 1, 2018 to March 31, 2022 were selected for analysis from an electronic health record generated report. The primary endpoint evaluated was the incidence of irAEs. Secondary endpoints included the incidence of significant irAEs and reasons for treatment discontinuation. These endpoints were compared by univariate analysis between all three cohorts. A multivariate analysis was then conducted for the primary endpoint. Nivolumab 240 mg Q2W was associated with a statistically significant increase in the incidence of colitis whereas the 480 mg Q4W regimen was associated with a statistically significant increase in the incidence of pruritis. The incidence of irAEs was not different between the three cohorts, while the incidence of significant irAEs was higher in the 240 mg Q2W and 240 mg Q2W to 480 mg Q4W cohorts. Clinicians ought to be aware of differences in the irAE profiles between nivolumab regimens with differing dosing patterns.

Real-world experience of immune checkpoint inhibitors in patients with solid tumours in the Top End of the Northern Territory, Australia from 2016 to 2021: a retrospective observational cohort study.

Use of immune checkpoint inhibitors is growing, but clinical trial data may not apply to Indigenous patients or patients living in remote areas. To provide real-world incidence of immune-related adverse events (irAE) in the Top End of the Northern Territory and compare incidence between demographic subgroups. This retrospective, observational, cohort study collected data from electronic records of patients living in the Top End with solid organ cancer treated with immunotherapy between January 2016 and December 2021. The primary outcome was cumulative incidence of any-grade and severe irAE. Secondary outcomes were overall survival, treatment duration and reason for treatment discontinuation. Two hundred and twenty-six patients received immunotherapy. Forty-eight (21%) lived in a remote or very remote area, and 36 (16%) were Indigenous. Cumulative incidence of any-grade irAE was 54% (122/226 patients); incidence of severe irAE was 26% (59/226 patients). Rates were similar between Indigenous and non-Indigenous patients of any-grade (42% vs 56%, P = 0.11) and severe (11% vs 18%, P = 0.29) irAE. However, Indigenous patients had shorter treatment duration, more frequently discontinued treatment due to patient preference and appeared to have shorter median overall survival than non-Indigenous patients (17.1 vs 30.4 months; hazard ratio (HR) = 1.5, 95% confidence interval (CI) = 0.92-2.66). There was no difference in mortality between remote and urban patients (median overall survival 27.5 vs 30.2 months; HR = 1.1, 95% CI = 0.7-1.7). Rates of irAE in our cohort are comparable to those in the published literature. There was no significant difference in any-grade or severe irAE incidence observed between Indigenous and non-Indigenous patients.

Safety, efficacy, and survival outcomes of immune checkpoint inhibitors rechallenge in patients with cancer: a systematic review and meta-analysis.

There is little evidence on the safety, efficacy, and survival benefit of restarting immune checkpoint inhibitors (ICI) in patients with cancer after discontinuation due to immune-related adverse events (irAEs) or progressive disease (PD). Here, we performed a meta-analysis to elucidate the possible benefits of ICI rechallenge in patients with cancer. Systematic searches were conducted using PubMed, Embase, and Cochrane Library databases. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and incidence of irAEs were the outcomes of interest. Thirty-six studies involving 2026 patients were analyzed. ICI rechallenge was associated with a lower incidence of all-grade (OR, 0.05; 95%CI, 0.02-0.13, P < .05) and high-grade irAEs (OR, 0.37; 95%CI, 0.21-0.64, P < .05) when compared with initial ICI treatment. Though no significant difference was observed between rechallenge and initial treatment regarding ORR (OR, 0.69; 95%CI, 0.39-1.20, P = .29) and DCR (OR, 0.85; 95%CI, 0.51-1.40, P = 0.52), patients receiving rechallenge had improved PFS (HR, 0.56; 95%CI, 0.43-0.73, P < .05) and OS (HR, 0.55; 95%CI, 0.43-0.72, P < .05) than those who discontinued ICI therapy permanently. Subgroup analysis revealed that for patients who stopped initial ICI treatment because of irAEs, rechallenge showed similar safety and efficacy with initial treatment, while for patients who discontinued ICI treatment due to PD, rechallenge caused a significant increase in the incidence of high-grade irAEs (OR, 4.97; 95%CI, 1.98-12.5, P < .05) and a decrease in ORR (OR, 0.48; 95%CI, 0.24-0.95, P < .05). ICI rechallenge is generally an active and feasible strategy that is associated with relative safety, similar efficacy, and improved survival outcomes. Rechallenge should be considered individually with circumspection, and randomized controlled trials are required to confirm these findings.

Safety and efficacy of restarting immune checkpoint inhibitors in non-small cell lung cancer patients following immune-related adverse events: a systematic review and meta-analysis.

This meta-analysis aims to evaluate the safety and efficacy of restarting immune checkpoint inhibitors (ICIs) in patients with non-small cell lung cancer (NSCLC) after experiencing immune-related adverse events (irAEs). A comprehensive search of PubMed, Web of Science, Embase, and the Cochrane Library was conducted to identify studies investigating the safety and efficacy of restarting ICIs in NSCLC patients after irAEs. Outcome measures, including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) after ICI restarting, were extracted. Meta-analysis was performed using the R meta-package. Four studies involving a total of 326 subjects were included, comprising 137 patients who restarted ICI treatment after irAEs and 189 patients who did not restart ICI treatment. The results revealed that ICI restarting was associated with an increased ORR (OR = 2.36, 95% CI 1.49-3.84), prolonged PFS (HR = 0.60, 95% CI 0.42-0.86), and prolonged OS (HR = 0.65, 95% CI 0.43-0.99) compared to non-restarting. The incidence of irAEs after ICI restarting was 45% (95% CI 0.27-0.63). Restarting ICI treatment after discontinuation due to previous irAEs appears to be a reasonable option for NSCLC patients. However, a comprehensive assessment of the potential benefits and risks to individual patients is crucial, and close monitoring of irAEs is warranted.

Immunotherapy for endometrial cancer.

Advanced recurrent endometrial cancer (EC) has a poor prognosis and new treatment options are needed. In 2013, EC was classified by genomic analysis into four groups: the POLE ultra-mutated group, the MSI-high hypermutated group (MSI-H), the copy number low group, and the copy number high group. The prognosis differs based on the classification, which should enable the individualization of treatment. The MSI-H and POLE types can induce PD-L1 expression in cancer cells. Among the gynecological cancers, EC exhibits the highest levels of PD-1 and PD-L1 expression and has the highest proportion of MSI-H. Thus, an immune checkpoint inhibitor (ICI) is expected to be effective. The first ICI to show efficacy in recurrent EC was the anti-PD1 antibody pembrolizumab, which exhibited efficacy in MSI-H EC. The combination of pembrolizumab and the multi-kinase inhibitor lenvatinib significantly prolongs OS/PFS compared with single-agent chemotherapy in previously treated recurrent EC, regardless of MSI status. ICIs are now moving from second-line and beyond to first-line treatment regimens. The efficacy of paclitaxel plus carboplatin (TC) and ICI combinations compared with TC have been demonstrated, including an ongoing Phase III trial comparing chemotherapy with the combination of pembrolizumab and lenvatinib. Although ICIs are becoming the mainstay of EC, they cause systemic inflammatory side effects known as irAEs. The incidence of irAEs is higher for combination therapy with CT or lenvatinib compared with ICI therapy alone. Even though they are rarely fatal, irAEs should be addressed promptly.

Combination therapy with immune checkpoint inhibitors and denosumab improves clinical outcomes in non-small cell lung cancer with bone metastases

BackgroundThe concomitant use of denosumab and immune checkpoint inhibitor (ICI) treatment may have synergistic effects and enhance antitumor activity; however, this has not been fully evaluated. This study aimed to evaluate the clinical outcomes of non-small cell lung cancer (NSCLC) patients with bone metastases receiving combination therapy and to identify the best combination regimen. MethodsEighty-six NSCLC patients with bone metastases who received ICI treatment were enrolled in this study. The patients were divided into two groups; a denosumab combination group (D + ICI group; n = 47) and a non-combination group (non-D + ICI group; n = 39). The response rate (RR) for bone metastases, disease control rate (DCR), overall survival (OS), real world progression-free survival (rwPFS), and the incidence of immune-related adverse events (irAEs) were evaluated. Additionally, the time when denosumab treatment should commence and concomitant treatment duration were evaluated. ResultsThe D + ICI group showed significantly better RR (40.4 % vs. 20.5 %, p = 0.01), DCR (67.3 % vs. 38.7 %, p = 0.02), OS (14.2 vs. 8.6 months, p = 0.02), and rwPFS (7.4 vs. 3.6 months, p < 0.01) than the non-D + ICI group; however, incidence of irAEs showed no difference (29.7 % vs. 12.8 %, p = 0.07). Although clinical outcomes did not differ regardless of whether denosumab was initiated before or after ICI treatment, the group that received concomitant denosumab for more than four months had significantly better RR (46.2 % vs. 17.4 %, p = 0.03), OS (20.3 vs. 3.8 months, p < 0.01), and rwPFS (10.9 vs. 2.8 months, p < 0.01) than the group that received concomitant denosumab for less than four months. However, the landmark analysis showed no significant differences in OS (20.4 vs. 12.7 months, p = 0.11) and rwPFS (22.8 vs. 11.2 months, p = 0.21), and the results of denosumab duration were influenced by long-term survivors. ConclusionDenosumab showed favorable synergistic effects with ICI treatment and may significantly improve the response to bone metastasis and prognosis without increasing the incidence of irAEs.

Real-world efficacy and adverse events of neoadjuvant immunotherapy in patients with early-stage triple-negative breast cancer: A multi-center experience.

e23293 Background: Pembrolizumab (pembro) combined with neoadjuvant chemotherapy (NAC) consisting of carboplatin- paclitaxel and doxorubicin-cyclophosphamide is the current standard of care in early-stage triple negative breast cancer (TNBC) based on KEYNOTE 522, which demonstrated improvements in pathologic complete response (pCR) to 65% but associated with high incidence of immune related adverse events (irAEs). We investigated real-world clinical outcomes and toxicity of this regimen. Methods: We conducted a retrospective, multi-center observational study among TNBC patients (pts) treated with NAC and pembro at 4 academic institutions from July 2021-December 2023. Data on clinicodemographic variables, irAEs, and clinical outcomes were collected. Multivariable logistic regressions were used to evaluate the association between demographic/clinical characteristics and pathological response while controlling for confounders. Analyses were performed in R (v4.2.3) at a significance level of ≤ 0.05. Results: 145 pts were analyzed, all females, with median age 53.5 years (IQR 43.4-62.7), 66% White and 23.4 % Black, median body mass index 28.3 kg/m2 (IQR 23-32), 55.6% stage II and 34% stage III disease. Median follow up was 12.3 months from the date of diagnosis. 94 pts (64.8%) attained pathological complete response (pCR). The median number of Pembro cycles prior to surgery was 7. Receipt of &lt; 8 pembro cycles was associated with lower pCR rate compared to ≥ 8 cycles (37.2% vs 62.8%, p = 0.03). Pts in pCR group were younger than in non-pCR group (50.8 vs. 58.5 years, p = 0.002). The non-pCR group received lower relative dose intensity (RDI) of carboplatin (91.7% vs 96.6%, p = 0.001), paclitaxel (90% vs 92%, p = 0.03), cyclophosphamide (91% vs 96%, p = 0.04)compared to the pCR group. Median absolute eosinophil count (AEC) was higher in pCR group compared to non-pCR group (140/μl vs 110/μl). Higher baseline AEC was associated with higher pCR rate on multivariate analysis (OR 4.54, CI 2.08 - 50.0, p = 0.02) after adjusting for confounders such as age, number of pembro cycles, RDI, race and comorbidities. No other variables were predictive of pCR in multivariate analyses. 48.3% pts experienced irAE of any grade and 38% grade 3+ irAE. The most common irAEs were hypothyroidism (21.3%), transaminitis (20%), rash (17.5%), colitis (12.5%), adrenal insufficiency (10%), pneumonitis (8.8%), and infusion reactions (8.8%). No significant difference in pCR rate (57% vs 62%) and incidence of irAEs (42% vs 50%) were noted between Black and White pts respectively. Conclusions: The pCR rate in our study (64.8%) was comparable to KEYNOTE 522 but there was higher incidence of irAEs (48.3%). Higher AEC at baseline was associated with improved pathologic response to chemoimmunotherapy. More real world studies are needed to confirm the high incidence of irAEs that was observed in our study.

A bibliometric analysis of immune-related adverse events in cancer patients and a meta-analysis of immune-related adverse events in patients with hepatocellular carcinoma.

Immunotherapy has become the standard treatment for hepatocellular carcinoma (HCC), but it carries a risk of immune-related adverse events (irAEs) that can be life-threatening. This study employs bibliometric analysis to understand global scientific research on irAEs in cancer, focusing on characteristics and areas of interest. Additionally, a meta-analysis provides a comprehensive overview of irAEs in HCC patients receiving immune checkpoint inhibitor (ICI)-based therapies. We conducted a thorough search of Web of Science Core Collection (WoSCC) publications from 1999 to 2022. R and VOSviewer software were used for analysis. A meta-analysis was performed using data from PubMed, Embase, and the Cochrane Library databases up to March 22, 2022. Trials with HCC patients reporting irAE incidence were included. Quality assessment followed Cochrane risk of bias, Newcastle-Ottawa Scale (NOS), and Methodological Index for Non-Randomized Studies (MINORS). We used random-effects or fixed-effects models based on I2 values. Primary outcomes included any-grade irAEs and grade ≥ 3 irAEs. This review and meta-analysis are registered in PROSPERO as CRD42022318885. In bibliometric analysis, we included 2946 papers, showing a consistent rise in annual publications on irAEs in cancer research. Frequent keywords were "nivolumab", "immune checkpoint inhibitor", and "immune-related adverse event". "Hepatocellular carcinoma" emerged as a prominent research focus linked to irAEs. We conducted a comprehensive meta-analysis on irAE incidence in HCC patients, including 29 studies. The overall incidence of any-grade irAEs was 61.0% (95% CI 38.5%-81.3%), and grade ≥ 3 irAEs was 13.2% (95% CI 7.9%-19.6%). Treatment-related mortality occurred in 3.1% (95% CI 0.8%-6.3%), with treatment discontinuation at 10.7% (95% CI 6.3%-16.0%). Reactive cutaneous capillary endothelial proliferation (RCCEP) was the most common any-grade irAE, while elevated aspartate aminotransferase (AST) was the most common grade ≥ 3 irAE. Treatment strategies were independently associated with specific irAEs, as indicated by multivariable analysis. This study provides valuable insights into the current research landscape of irAEs in cancer and ofers a comprehensive overview of irAEs in HCC patients undergoing ICI-based therapy. The relatively high incidence of irAEs and their association with treatment strategies emphasize the need for careful management by clinicians when treating HCC patients. These findings offer significant guidance for optimizing care and treatment for HCC patients.