Pulmonary toxicity of immune checkpoint inhibitors.

Benefiting from the continuously clarifying underlying biology of immune checkpoints and ligand–receptor interactions, the emergence of new anticancer treatment strategy, immunotherapy has shown substantial benefits on several liquid and solid tumors. Immune checkpoint inhibitors (ICIs) can block the negative regulatory components and enhance the T cell function, thus leading to prominent anticancer activity. On account of their promising effect on various malignancies shown in clinical trials, ICIs have been considered to be the most potent anticancer agents in the near future. Head and neck cancer is the seventh most common neoplasm worldwide, and the gross 5-year survival rate was only 60%. Managing locoregionally advanced, recurrent, or metastatic head and neck tumors is still a challenging problem for both oncologists and surgeons. Recent clinical trials employing the immune-modulating antibodies that target cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death 1 (PD-1) herald a new era of anticancer therapy. However, like all other anticancer drugs, ICIs also have side effects while upregulating the immune system to enhance antitumor response, which were known as immune-related adverse events (irAEs). Generally, most irAEs were transient, but sometimes they can cause serious organ dysfunction, even fatal. In addition, due to the distinct anatomical feature, advanced head and neck tumors often affect the upper aerodigestive tract and cause serious dyspnea or dysphagia. Toxicities of ICIs may be more lethal for such patients. Thus, with the increasing application of anti-checkpoint agents in head and neck cancer, there is urgent need to ascertain the safety of this novel treatment strategy. Here, we compile this review of existing clinical trials on the toxicity of ICIs during cancer treatment. The particular clinical manifestation, characteristics of complication development in fatal cases, and the management strategies were discussed. This may provide vital information for future oncology trials and clinical practice.

https://www.crd.york.ac.uk/prospero/, identifier CRD42022367416.

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that target two key signalling pathways related to T cell activation and exhaustion, by binding to and inhibiting cytotoxic T lymphocyte antigen 4 (CTLA4) or PD1 and its ligand PDL1. ICIs, such as nivolumab, pembrolizumab and ipilimumab, are approved for the treatment of numerous and diverse cancer types, in various combination regimens, and are now an established cornerstone of cancer therapeutics. Toxicities induced by ICIs are autoimmune in nature and are referred to as immune-related adverse events (irAEs); these events can affect any organ system in an unpredictable fashion. Importantly, irAEs can manifest as endocrinopathies involving the thyroid (hypothyroidism or thyrotoxicosis), pituitary (hypophysitis), adrenal glands (adrenal insufficiency) and pancreas (diabetes mellitus). These events are a frequent source of acute and persistent morbidity in patients treated with ICIs and can even be fatal. Over the past few years, there has been a growing understanding of the underlying pathogenesis of irAEs that has led to the development of more effective management strategies. Herein, we review the current understanding of the pathobiology, clinical manifestations and treatment approaches to endocrine toxicities arising from ICIs.

2547 Background: Immune checkpoint inhibitors (ICIs) have ushered in a unique entity known as immune-related adverse events (IrAEs) that can be debilitating and challenging for physicians. Given that genomic variation underlies both disease susceptibility and drug response, there is reasonable cause to believe that genomic markers are predictive of IrAEs. We perform a pioneering pharmacogenomic study to uncover genomic biomarkers associated with IrAEs from ICIs. Methods: Since March 2018, we recruited cancer patients treated with ICIs from the National University Cancer Institute Singapore and Tan Tock Seng Hospital. IrAEs were clinical characterized and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5. DNA was extracted and genotyped by Infinium Global Screening Array (700K markers). Statistical analyses were performed using SVS/HelixTree. Genetic association was performed by logistic regression. Bonferroni corrected P < 7.1E-08 was considered statistically significant. Results: We conducted a pilot pharmacogenomic genome-wide association study (GWAS) on 307 patients of Asian Ancestry. Median age was 62. Majority were male (68.1%), Chinese (75.9%), ECOG PS 0-1 (91.6%), stage IV cancer at diagnosis (64.6%). Non-small cell lung cancer (36.2%), renal cell carcinoma (12.4%) and hepatocellular carcinoma (7.2%) were the three most common cancers. Top four ICIs used were pembrolizumab, nivolumab, atezolizumab and durvalumab, respectively (44.6%, 26.1%, 10.1% and 10.1% respectively). Nine percent of patients received dual ICIs concurrently. Median duration of treatment was 152 days and median follow up was 212 days. IrAEs were seen in 50.5% of patients. Skin (21.8%), endocrine (6.8%) and hepatotoxicity (5.9%) were the most common IrAEs. Eight percent of patients had CTCAEv5 grade ≥3 toxicity, of which hepatotoxicity (2.6%), skin (1.6%) and pulmonary toxicities (1.3%) were the most common. A preliminary pharmacogenomic investigation revealed one potential novel genetic locus associated with IrAEs: LOC105373202 rs5915369; Unadjusted P= 6.6E-08, OR (95%CI) = 27.8 (3.7-206.5), minor allele = A, 10.7% in cases vs 0.4% in controls. We also identified an additional 3 independent SNPs (rs167609, rs2341687, DMDrs5928214) with nominal significance (7.1E-0-8≤ P< 5.0E-7). Conclusions: This pilot pharmacogenomics GWAS uncovered 4 potential novel genetic loci predictive of IrAEs from ICIs amongst Asian patients. Further pharmacogenomic discovery/replication and functional validation studies are currently on-ongoing to identify specific genomic biomarkers that predispose individual patients to IrAEs.

297 Background: Immune checkpoint inhibitors (ICIs) have revolutionized treatment for melanoma and lung cancer and are in widespread use. This study aims to describe how patients and caregivers learn about ICI toxicities and their lived experiences of receiving an ICI. Methods: We conducted a qualitative study of patients with advanced cancer receiving ICIs from a single academic center and their caregivers. We purposively sampled patients with stage IV non-small cell lung cancer (n=16) or stage III (n=9) or IV (n=17) melanoma who were initiating or discontinuing an ICI. We conducted semi-structured interviews to explore patients' and caregivers' experiences learning about and living with ICI toxicity. We used a framework approach to analyze interview transcripts, which included developing a codebook, double-coding transcripts, and synthesizing codes into themes with a multidisciplinary research team. Results: The median age of patients was 68 years, 31% were female and 49% had at least a college degree. We identified the following themes: i) Patients initiating ICIs received exhaustive counseling about side effects (“everything from rash to death,” “like a drug ad on television”), yet some patients lost details in the deluge of information (“I'm sure I was told of the risk, I just can't specifically recall what”); ii) Patients and caregivers identified several factors that helped them feel comfortable to proceed with treatment, namely that the oncology team emphasized the infrequency of serious side effects and that the team was ready to manage whatever toxicity occurred. In addition, patients perceived that ICI benefits outweighed the risks or felt that they had no alternative; iii) Among patients who discontinued ICIs, the association between ICI toxicity and efficacy was a source of hope (“I hope every day to find vitiligo... that might say that the immunotherapy is working”); iv) Patients’ and caregivers’ impressions of ICIs depended on patients’ outcomes. Patients tolerating ICIs well and their caregivers were surprised at how easy their treatment was, whereas patients who discontinued ICIs after experiencing severe side effects felt frustrated and surprised by toxicity, or worried their cancer would progress. Conclusions: Patients receiving ICIs for advanced cancer and their caregivers felt they received comprehensive education about ICI toxicity. They appreciated when their oncology team provided reassurance that side effects were rare and manageable, as well as messages that framed toxicity as a sign of efficacy once they occurred. Even with excellent preparation for the possibility of toxicity, patients who experienced severe toxicity were still surprised and disappointed. These perspectives highlight patient and caregiver preferences for learning about ICIs and opportunities to support patients in coping with advanced cancer.

e14629 Background: Immune checkpoint inhibitors (ICIs) have significantly improved the survival of patients with advanced esophageal squamous cell cancer (ESCC), however, the benefit of ICIs was limited to a few patients. It is vital to comprehend the factors influencing the response in order to identify patients who might benefit from ICIs. Cachexia, an intricate multifaceted syndrome characterized by the loss of skeletal muscle and substantial weight reduction, might impact on the immune response and efficacy of ICIs in cancer patients. The purpose of this study is to explore the impact of longitudinal dynamics of cachexia on the efficacy and adverse effect of ICIs for advanced ESCC patients. Methods: Advanced ESCC patients received at least two cycles of ICIs were enrolled from 2017 to 2021. The baseline and longitudinal changes of cachexia during ICI treatment were collected. Based on the longitudinal weight changes during ICI treatment, patients exhibiting cachexia at baseline were categorized into "reversible cachexia" and "irreversible cachexia" group, and patients without cachexia at baseline were also divided into "latent cachexia" and "cachexia-free" group. Kaplan-Meier curves and Cox regression analysis were performed to explore the impact of cachexia on the efficacy ICIs for ESCC patients. And chi-square test was used to evaluate the correlation between cachexia and immune-related adverse effects (irAEs). Results: A total of 278 individuals who had either received or were presently undergoing ICI treatment were enrolled, with the median progression free survival (PFS) of 5.8 months and overall survival (OS) of 8.3 months. Patients with cachexia before treatment had notably poorer outcomes, with median PFS of 7.9 vs 5.3 months (P=0.001), median time to progression (TTP) of 10.9 vs 6.1 months (P<0.001), and median OS of 14.3 vs 9.2 months (P=0.001). In terms of the longitudinal dynamics of cachexia, significantly inferior outcomes were observed for patients in irreversible cachexia compared to reversible cachexia, with the PFS of 4.4 months and 9 months (P<0.001), the TTP of 4.9 months and 9 months (P=0.006), and the OS of 7.8 months and 15 months, respectively (P=0.003). Although patients in latent cachexia group had inferior survival compared to cachexia-free group, no statistical difference was observed, with the PFS of 10.0 and 7.9 months and OS of 13.9 and 16.2 months. Besides, neither baseline nor longitudinal changes of cachexia was associated with irAEs for ESCC patients. Conclusions: This study indicated the impact of baseline and longitudinal cachexia on the efficacy of ICIs for advanced ESCC patients with ICIs. Dynamic monitoring and management of cachexia was recommended during the ICI treatment of ESCC patients.

Background The use of antibiotics may influence the efficacy and toxicity of immune checkpoint inhibitors (ICIs) by altering the gut microbiota. However, current evidence on the link between antibiotic use and immune-related adverse events (irAEs) is limited. This study aims to evaluate whether antibiotics increase the risk of irAEs in ICI-treated patients and to examine their relationship to the timing of irAEs onset. Methods We analyzed data from the FAERS database from 2014 to the fourth quarter of 2024. Using multivariable logistic regression and descriptive statistical analyses, we evaluated the association between antibiotic co-reporting and irAE reporting frequency and the timing across different antibiotic categories and ICIs regimens. Results Our study included 155,157 patients treated with ICIs, of whom 9,518 (6.1%) received antibiotic therapy. Patients who used antibiotics had a significantly higher reported frequency risk of irAEs (OR = 1.17; 95%CI: 1.12–1.23; FDR<0.001) compared to those who did not. The strongest associations were observed in patients receiving fluoroquinolones, sulfonamides, penicillin, macrolides, cephalosporins, and monobactams. Co-reporting was associated with a higher reported frequency of irAEs in patients receiving PD-L1 inhibitors (OR = 1.51; 95% CI: 1.39–1.65; FDR<0.001). In exploratory descriptive analysis restricted to patients who reported irAEs, the median time to first reported irAE was shorter in the antibiotic co-reporting group than in the non-co-reporting group (31 days (IQR: 9–105) vs. 42 days (IQR: 14–122), Wilcoxon rank-sum test P < 0.001). Stratified analysis by ICI type showed that this pattern was most evident in patients receiving PD-1 inhibitors. Conclusions Analysis of the FAERS database suggests that antibiotic co-reporting during ICIs therapy is associated with a higher reported frequency of irAEs and a shorter median time to first reported irAE among patients who experienced irAEs. These findings are subject to the inherent limitations of the FAERS database, including the inability to determine the temporal sequence of antibiotic and ICI exposure, unmeasured confounding, reporting artifacts, and the unsuitability of spontaneous reporting data for formal time-to-event analysis. Prospective cohort studies with detailed medication timing, clinical phenotyping, and microbiome profiling are needed to validate these signals.

326 Background: Overall survival from metastatic renal cell carcinoma (RCC) has risen in recent years due in part due to therapies such as immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitors (TKI). TKI and ICI have unique and high-impact side effect profiles, and deficits persist in clinicians’ understanding of patient tolerance of and response to treatment, particularly in rural and community practices. We developed a tele-mentoring series to improve knowledge and clinical care gaps in ICI and TKI toxicity assessment and management for persons treated for RCC. Methods: Rural and community cancer care teams were invited by the Masonic Cancer Alliance, the outreach network of The University of Kansas Cancer Center, to participate in a five session Project ECHO (Extension for Community Health Outcomes) didactic and case-based educational series. Topics included distress screening, shared decision-making for RCC treatment, ICI and TKI toxicity assessment and management, at-home ICI administration, and implementing toxicity monitoring protocols. A mixed-methods approach collected data from participants pre- and post-TOQQ-RCC series. Clinician interviews assessed current practice protocols and were transcribed and analyzed thematically. Organizational Readiness for Implementing Change (ORIC) was administered pre- and post-TOQQ-RCC intervention; mean scores were calculated to determine readiness for change in toxicity monitoring and management protocols. Participant engagement and satisfaction were assessed; satisfaction measure included a Likert-like scale of poor, fair, average, good, and outstanding. Results: Fifty-two attendees from 11 cancer care institutions across Kansas and Missouri registered for the TOQQ-RCC sessions. An average of 15 participants attended each session including physicians, advanced practice providers, nurses, and other disciplines. Session evaluations rated content/delivery as good or outstanding. Themes from qualitative analysis revealed patient education as a primary barrier to effective toxicity identification and management. One-third of participants completed ORIC post-assessment; mean ORIC scores dropped by a mean 0.4 (10%) post-TOQQ-RCC series, indicating decreased readiness to implement changes to toxicity monitoring and management protocols. Conclusions: Rural and community oncology clinicians are willing to engage in tele-mentoring to improve knowledge and clinical care gaps regarding ICI and TKI toxicity assessment and management. Decrease in ORIC scores post-TOQQ-RCC series may indicate increased understanding of the complex processes and resources required to institute meaningful improvement to toxicity monitoring and management protocols for patients treated in rural and community settings. Future directions will include formal organizational needs assessments.

Immune-related hematologic adverse events in the context of immune checkpoint inhibitor therapy.

Despite the expansion of immune checkpoint inhibitor (ICI) indications, the relationship between ICI dose and toxicity or response is not well established. To understand this correlation, we performed a meta-analysis of ICI trials that used dose escalation. We searched PubMed and abstracts presented at (inter)national meetings for trials using FDA-approved ICIs. The reported rates of grade 3-5 adverse events (G3-5 AE), immune-related adverse events (irAE), and response were correlated with doses within each ICI using marginal exact generalized linear models. A total of 74 trials (7,469 patients) published between January 2010 and January 2017 were included. For ipilimumab, the incidence of G3-5 AEs was 34% with a significant 27% reduced risk in lower doses (P = 0.002). However, no relationship was observed between dose and irAEs or response. For nivolumab, the incidence of G3-5 AEs was 20.1% which was lower in non-small cell lung cancer (NSCLC) compared with renal cell carcinoma (RCC) or melanoma (P ≤ 0.05) with no dose-toxicity relationship. In melanoma and NSCLC, a dose-response association was observed, which was not observed in RCC. For pembrolizumab, the incidence of G3-5 AEs was 13.3%, which was lower in melanoma compared with NSCLC (P = 0.03) with no dose-toxicity relationship. In melanoma, lower dose levels correlated with decreased odds of response (P = 0.01), a relationship that was not observed in NSCLC. Our analysis shows a lack of consistent dose-toxicity or dose-response correlation with ICIs. Therefore, dose escalation is not an appropriate design to conduct ICI studies. Here we present an innovative trial design for immune-modulating agents.

<div>AbstractPurpose:<p>Despite the expansion of immune checkpoint inhibitor (ICI) indications, the relationship between ICI dose and toxicity or response is not well established. To understand this correlation, we performed a meta-analysis of ICI trials that used dose escalation.</p>Experimental Design:<p>We searched PubMed and abstracts presented at (inter)national meetings for trials using FDA-approved ICIs. The reported rates of grade 3–5 adverse events (G3–5 AE), immune-related adverse events (irAE), and response were correlated with doses within each ICI using marginal exact generalized linear models.</p>Results:<p>A total of 74 trials (7,469 patients) published between January 2010 and January 2017 were included. For ipilimumab, the incidence of G3–5 AEs was 34% with a significant 27% reduced risk in lower doses (<i>P</i> = 0.002). However, no relationship was observed between dose and irAEs or response. For nivolumab, the incidence of G3–5 AEs was 20.1% which was lower in non–small cell lung cancer (NSCLC) compared with renal cell carcinoma (RCC) or melanoma (<i>P</i> ≤ 0.05) with no dose-toxicity relationship. In melanoma and NSCLC, a dose–response association was observed, which was not observed in RCC. For pembrolizumab, the incidence of G3–5 AEs was 13.3%, which was lower in melanoma compared with NSCLC (<i>P</i> = 0.03) with no dose-toxicity relationship. In melanoma, lower dose levels correlated with decreased odds of response (<i>P</i> = 0.01), a relationship that was not observed in NSCLC.</p>Conclusions:<p>Our analysis shows a lack of consistent dose-toxicity or dose–response correlation with ICIs. Therefore, dose escalation is not an appropriate design to conduct ICI studies. Here we present an innovative trial design for immune-modulating agents.</p></div>

<div>AbstractPurpose:<p>Despite the expansion of immune checkpoint inhibitor (ICI) indications, the relationship between ICI dose and toxicity or response is not well established. To understand this correlation, we performed a meta-analysis of ICI trials that used dose escalation.</p>Experimental Design:<p>We searched PubMed and abstracts presented at (inter)national meetings for trials using FDA-approved ICIs. The reported rates of grade 3–5 adverse events (G3–5 AE), immune-related adverse events (irAE), and response were correlated with doses within each ICI using marginal exact generalized linear models.</p>Results:<p>A total of 74 trials (7,469 patients) published between January 2010 and January 2017 were included. For ipilimumab, the incidence of G3–5 AEs was 34% with a significant 27% reduced risk in lower doses (<i>P</i> = 0.002). However, no relationship was observed between dose and irAEs or response. For nivolumab, the incidence of G3–5 AEs was 20.1% which was lower in non–small cell lung cancer (NSCLC) compared with renal cell carcinoma (RCC) or melanoma (<i>P</i> ≤ 0.05) with no dose-toxicity relationship. In melanoma and NSCLC, a dose–response association was observed, which was not observed in RCC. For pembrolizumab, the incidence of G3–5 AEs was 13.3%, which was lower in melanoma compared with NSCLC (<i>P</i> = 0.03) with no dose-toxicity relationship. In melanoma, lower dose levels correlated with decreased odds of response (<i>P</i> = 0.01), a relationship that was not observed in NSCLC.</p>Conclusions:<p>Our analysis shows a lack of consistent dose-toxicity or dose–response correlation with ICIs. Therefore, dose escalation is not an appropriate design to conduct ICI studies. Here we present an innovative trial design for immune-modulating agents.</p></div>

Drug-induced hypersensitivity syndrome like reaction with angioedema and hypotension associated with BRAF inhibitor use and antecedent immune checkpoint therapy

3090 Background: Immune-related adverse events (IrAEs) arising from immune checkpoint inhibitors (ICIs) can be unpredictable. As genomic variation underlies both disease susceptibility and drug responses, genomic markers may predict for the development of IrAEs. We perform a pioneering pharmacogenomic study across a multi-ethnic Asian patient population to uncover genomic biomarkers associated with IrAEs from ICIs. Methods: From March 2018 – July 2023, cancer patients treated with ICIs from the National University Cancer Institute Singapore and Tan Tock Seng Hospital were recruited. IrAEs were characterized and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5. DNA was extracted and genotyped by Infinium Global Screening Array (700K markers). Statistical analyses were performed by SVS/HelixTree, PLINK and R. Genetic association was performed by logistic regression (additive model), accounting for all possible confounding factors. Bonferroni corrected P < 1.28E-07 (0.05/390,925 SNPs passed QC) was considered statistically significant. Results: Genome-wide association study (GWAS) was conducted amongst 507 patients of Asian Ancestry (Chinese, Malay, Indian and Others). Median age was 63. Majority were male (66.5%), Chinese (76.7%), ECOG PS 0-1 (40.1%) and had stage IV cancer at diagnosis (67.2%). Non-small cell lung cancer (37.1%), renal cell carcinoma (12.2%) and hepatocellular carcinoma (7.7%) were the three most common cancers. Top four ICIs used were pembrolizumab, nivolumab, durvalumab and atezolizumab, respectively (47.1%, 23.9%, 12.5%, 11.3%). 0.8% of patients received dual ICIs concurrently. Median duration of treatment was 142 days and median follow-up was 147 days. IrAEs were seen in 43.7% of patients. Skin (24.1%), endocrine (8.1%) and hepatotoxicity (6.1%) were the most common IrAEs. 4.9% of patients had grade ≥3 toxicity, of which skin (3.6%), hepatotoxicity (3.0%) and pulmonary toxicity (1.8%) were the most common. Multi-ethnic GWAS analysis identified one potential novel genetic locus associated with CTCAE grade ≥3 IrAEs. chr3:163402331 rs146525069; P = 7.29E-08, OR (95%CI) = 17.08 (5.40- 54.04); minor allele = A, 10.91% in Cases vs 0.71% in Controls. Conclusions: This pharmacogenomics GWAS uncovered a novel locus for susceptibility to serious immune-related adverse events from immune checkpoint inhibitors. Further pharmacogenomic discovery/replication and functional validation studies are currently on-ongoing. Our study provides a potential biological mechanism for IrAEs and a step towards more effective clinical translation of pharmacogenetic testing to personalize ICI use.

Immune-Related Adverse Events and Outcomes in Patients with Advanced Non–Small Cell Lung Cancer: A Predictive Marker of Efficacy?