Efficacy and safety of two-year fixed versus continuous immune checkpoint inhibitor therapy in advanced or metastatic non-small cell lung cancer: a systematic review.

8584 Background: The optimal duration of immune checkpoint inhibitor (ICI) therapy in advanced or metastatic non-small cell lung cancer (NSCLC) is unknown. While multiple randomized clinical trials (RCTs) have shown the benefit of ICI-based regimens over chemotherapy, they were not designed to test optimal duration of ICI. Most trials opted to continue ICI indefinitely or stopping at two years if no progressive disease or treatment limiting immune-related adverse events (irAEs) emerged. There is concern for increased cumulative risk of irAEs with indefinite treatment. Methods: A systematic review of randomized controlled trials (RCTs) and real-world evidence (RWE) studies was performed for adult patients with advanced/metastatic NSCLC treated with ICI therapy (alone or in combination) up to August 24, 2024. Studies were included if they specifically reported on patients who completed a minimum of 2 years of therapy. Databases, conference abstracts and clinical trials were queried. Patients were divided into two cohorts: a two year-fixed cohort where ICI therapy was discontinued after 2 years, and a continuous cohort where ICI therapy was continued beyond 2 years. Results: The database search identified 8741 records of which 174 articles were screened. The final qualitative analysis included 20 studies (11 RCTs and 9 RWE studies) and 5027 patients. There were 23 cohorts that belonged to the 2 year-fixed group (N=2051) and 7 that belonged to the continuous group (N=2976). Outcomes of patients in the 2 year-fixed arms from RCTs were excellent with 5-year overall survival (OS) rates in the range of 69-83%. This was supported by RWEs which showed similar OS rates. Continuous treatment with ICIs had similar OS rates in both RCTs and RWE and was comparable to the 2 year-fixed arms. Four RWE studies compared hazard ratios (HR) for survival outcomes among 2 year-fixed vs continuous arms and did not find any statistically significant difference. Patients that completed 2 years of therapy in RCTs tended to have greater rates of irAEs compared to the baseline population but lower rates of grade 3 or 4 events. Three out of four RWEs reported higher rates of irAEs in the continuous vs 2 year-fixed arms. These findings were likely associated with longer exposure to immunotherapy. A large proportion of patients that developed progressive disease after the 2 year-mark in both 2 year-fixed and continuous arms was alive at data cut-off. Many of these were re-challenged with ICI therapy. Data from RWEs showed that larger/academic centers tended to favor 2 year-fixed therapy whereas the reverse was true for community centers. Conclusions: Survival outcomes after ICI discontinuation at 2 years are comparable to continuous therapy in advanced/metastatic NSCLC. Immune-related adverse events tend to accumulate over time. Progressive disease is often localized and amenable to ICI re-challenge.

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

P09.20 Impact of Antibiotics During Immune Checkpoint Inhibitor (ICI) Therapy for Non-Small Cell Lung Cancer: A Real-World Analysis

Cutaneous adverse events to immune checkpoint inhibitors in pediatric populations: A retrospective cohort study

Over the last decade, the treatment of advanced non-small cell lung cancer (NSCLC) has undergone rapid changes with innovations in oncogene-directed therapy and immune checkpoint inhibitors. In patients with epidermal growth factor receptor (EGFR) gene mutant (EGFRm) NSCLC, newer-generation tyrosine kinase inhibitors (TKIs) are providing unparalleled survival benefit and tolerability. Unfortunately, most patients will experience disease progression and thus an urgent need exists for improved subsequent lines of therapies. The concurrent revolution in immune checkpoint inhibitor (ICI) therapy is providing novel treatment options with improved clinical outcomes in wild-type EGFR (EGFRwt) NSCLC; however, the application of ICI therapy to advanced EGFRm NSCLC patients is controversial. Early studies demonstrated the inferiority of ICI monotherapy to EGFR TKI therapy in the first line setting and inferiority to chemotherapy in the second line setting. Additionally, combination ICI and EGFR TKI therapies have demonstrated increased toxicities, and EGFR TKI therapy given after first-line ICI therapy has been correlated with severe adverse events. Nonetheless, combination therapies including dual-ICI blockade and ICI, chemotherapy, and angiogenesis inhibitor combinations are areas of active study with some intriguing signals in preliminary studies. Here, we review previous and ongoing clinical studies of ICI therapy in advanced EGFRm NSCLC. We discuss advances in understanding the differences in the tumor biology and tumor microenvironment (TME) of EGFRm NSCLC tumors that may lead to novel approaches to enhance ICI efficacy. It is our goal to equip the reader with a knowledge of current therapies, past and current clinical trials, and active avenues of research that provide the promise of novel approaches and improved outcomes for patients with advanced EGFRm NSCLC.

Atypical Antiglomerular Basement Membrane Nephritis Following Immune Checkpoint Inhibitor

BackgroundProtein glycosylation is the most abundant and complex form of post-translational protein modification. Glycosylation profoundly affects protein structure, conformation, and function. The elucidation of the potential role of differential protein...

Background: Protein glycosylation is the most common and complex form of post-translational protein modification. Glycosylation profoundly affects protein structure, conformation, and function. The elucidation of the potential role of differential protein glycosylation as biomarkers has been limited by the technical complexity of generating and interpreting this information. We have recently established a novel, powerful platform that combines liquid chromatography-mass spectrometry with a proprietary artificial-intelligence-based data processing engine that allows, for the first time, highly scalable interrogation of the glycoproteome. Here we report the performance of this platform to predict likely benefit from immune-checkpoint inhibitor (ICI) therapy in advanced non-small cell lung cancer (NSCLC). Methods: Our platform was utilized to assess 532 glycopeptide (GP) and peptide signatures representing 75 serum proteins in pretreatment blood samples from a cohort of 123 individuals (54 females, 69 males, age range 30 to 88 years). Inclusion criteria were a diagnosis of unresectable stage 3 or 4 NSCLC, treatment with pembrolizumab monotherapy (26 patients), or treatment with combination pembrolizumab-chemotherapy (97 patients). Overall survival (OS) data were available for all patients. Results: An ensemble multivariable-model-based glycoproteomic classifier consisting of 7 GP and non-glycosylated peptide biomarker features selected from a generalized additive model for OS was developed using ≈2/3rds of the full cohort (n=88) and validated in the remainder of patients (n=35). The classifier yielded similar statistical significance in Cox regression analysis for separating patients who are likely to benefit from ICI therapy from those who are not, to accurately predict likely ICI benefit with a sensitivity of >95% while performing at a specificity of 33% to predict those who are unlikely to benefit. Results were further analyzed in patients with either non-squamous or squamous NSCLC with first-line therapy (n=98). The classifier yielded a hazard ratio (HR) for prediction of likely ICI benefit of 3.6 with median OS of 13.9 vs. 4.2 months, and of 3.5 with median OS of 13.5 vs. 4.5 months in the entire cohort and the first-line treated patients, respectively. Conclusions: The glycoproteomic classifier described here predicts with high sensitivity which patients are likely to benefit from ICI therapy. In addition to potentially reducing the use of ICIs in a safe manner in patients who would be unnecessarily subjected to possible adverse drug reactions, our classifier simultaneously has the potential of reducing the burden of health care expenditures. Our results indicate that glycoproteomics holds a strong promise as a predictor for ICI treatment benefit which appears to significantly outperform other currently pursued biomarker approaches. Citation Format: Klaus Lindpaintner, Chad Pickering, Alan Mitchell, Gege Xu, Xin Cong, Daniel Serie. A peripheral blood-based glycoproteomic predictor of checkpoint inhibitor treatment benefit in advanced non-small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5314.

BackgroundPatients (pts) receiving immune checkpoint inhibitor (ICI) therapy can experience periods of prolonged disease control after treatment discontinuation. Previous studies have used treatment-free survival (TFS) to characterize this interval in...

Non-small-cell lung cancer (NSCLC) accounts for most new diagnoses of lung cancer, with high morbidity and mortality worldwide. Immune checkpoint inhibitor (ICI) therapy has transformed the treatment of metastatic and advanced NSCLC. For resectable NSCLC, while surgery is the cornerstone of standard treatment, a number of clinical trials of neoadjuvant immunotherapy have been conducted. To perform a systematic review on the safety and efficacy of neoadjuvant ICI therapy in patients with resectable NSCLC. This systematic review was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We undertook a comprehensive literature search of PubMed, Embase, Cochrane Library, and abstracts and posters from annual meetings of the major oncology societies, American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), American Association for Cancer Research (AACR) up until 29 April 2021. A total of 399 patients were identified from six articles and four meeting abstracts. 229, 140, and 30 patients received anti-programmed cell death ligand 1 therapy (anti-PD-L1, atezolizumab and durvalumab), anti-programmed cell death 1 therapy (anti-PD-1, nivolumab, pembrolizumab, sintilimab), and anti-PD-1/anti-CTLA-4 combination therapy (nivolumab and ipilimumab), respectively. 255 patients received only ICI therapy before surgery, and 144 patients received ICI and chemotherapy. While ICI therapy was generally well tolerated, grade 3 or higher immune-related adverse events were observed in 13 of 144 patients (9.0%) in the five studies that reported such adverse events data. Patients displayed an overall mean surgical resection rate of 87.5% (349/399, range, 66.7-100%), a surgical delay rate of 1.4%, and an incidence of surgical complications of 21%. On average, 45.6% (159/349), (range 17-83%) of patients exhibited major pathological response (MPR), while 76/349 (21.8%) patients achieved pathological complete response (pCR). In the studies with patients undergoing ICI and chemotherapy, the MPR rate was 66.7% and pCR rate was 35.4%. ICI neoadjuvant therapy may be a safe and efficacious treatment option in patients with resectable NSCLC. Combined with chemotherapy, ICI appears to be more efficacious, but displays more adverse events. More ongoing clinical trials will shed further light on the safety and efficacy of ICI neoadjuvant therapy in patients with resectable NSCLC.

e20630 Background: Immune checkpoint inhibitor (ICI) therapy is a cornerstone in the treatment of metastatic non-small cell lung cancer (NSCLC). However, many patients develop resistance or fail to respond to ICI. There has been a lot of interest in studying the host factors that might influence the response to immunotherapy. In recent years, the Obesity paradox phenomenon has been studied in multiple cancers. However, there is scarce information on the impact of obesity on the various ICI therapies on NSCLC patients in the US. In this study, we are presenting the first real-world analysis of the effect of obesity on survival in US based patients diagnosed with metastatic NSCLC and receiving ICIs. We also tried to unveil any possible underlying mechanisms that might explain this phenomenon like complications and immune‐related adverse events (irAEs). Methods: Data was retrospectively collected from the independent US population-based TriNetX network, a national electronic health record database with 120 million US patients from over 70 healthcare organizations. We identified patients ≥ 18 years old with non-small cell lung cancer diagnosis who received ICI therapy between 2012 and 2024. ICI therapies included pembrolizumab, nivolumab, atezolizumab, durvalumab, ipilimumab and cemiplimab. Patients were then split into two cohorts: those with normal BMI (18.5-24.9) and obese BMI (≥30). Patients were then 1:1 propensity score matched based on age, sex, race, ethnicity, type of ICI therapy used, comorbidities and staging. Overall survival (OS), NSCLC related complications and irAEs were measured at 6 months, 1 year and 3 years after initiation of ICI treatment. Results: We identified 10,056 patients over the age of 18 who received ICI therapy for NSCLC. After 1:1 matching, each cohort in our analysis included 2762 patients. In the normal and obese groups mean age in both groups was 66.2 ± 10.8 and 66.3 ± 9.69 years respectively. Patients were also more likely to be white (73%) and male (49%) in both groups. Obesity BMI was associated with significantly improved OS at 6 months (hazard ratio [HR], 0.78 [95% CI, 0.66-0.83]), 1 year (HR, 0.81 [95% CI, 0.74-0.89]), and 3 years (HR, 0.88 [95% CI, 0.81-0.95]) after ICI treatment, compared with patients with normal BMI. There was no difference in rates of NSCLC specific complications or irAEs at any of the time points from 6 months to 3 years. Conclusions: Analysis of one of the largest US based databases showed that obesity is associated with better overall survival without significant difference in complications or irAEs which suggest that the difference in the survival is likely due to the direct effect of the obesity on the cancers. Further clinical trials and transitional studies should be geared towards investigating the effects of obesity on tumor microenvironment.

Immune Checkpoint Inhibitor (ICI) therapy is the most exciting development in cancer treatments in recent years. As of the end of 2021, more than a hundred of clinical trials have been carried out by several major drug makers and research hospitals all over the world just to explore the use of ICI antibodies in almost every type of cancer and under various clinical settings. These clinical trials have resulted waves of good news in every year’s major academic conferences and FDA approvals, and now ICI therapy is in the move to take over traditional therapy to become the major player in clinical management of cancer. On the other hand, most of these clinical trials have failed to show clear benefits in most cancer patients, and only few have been reported in public. In real-world clinical setting, ICI antibodies are being massively and sometimes abusively prescribed for almost every desperate situation with clear clinical benefit in only a few (<10%). Yet, the enthusiasm behind ICI therapy is not dampened by the massive clinical failure but has been growing. The reason for the consistent enthusiasm among clinicians and patients is the miracle-like clinical responses seen in some of the responders that even including late-stage hopeless cases. Every clinician wants to repeat this miracle in the next seemingly identical patient, and every patient and their family members want to believe that they are in line for that miracle. But the reality is disheartening in that clinicians do not see the predictable repeat of miracle-like responses in seemingly identical patients and most patients selecting ICI therapy as the last straw in life did not benefit from it, if not hurt by it. What then are the reasons that ICI therapy is so impressive when working and so unpredictable in responses? This review attempts to draw some mechanistic aspects based on our own experiences in ICI therapy and to come up with a different explanation for the unexplained clinical observations. The goal of this review is to alert the clinical field about the danger and irreversible damages that wrongly used ICI antibodies may cause, and at the same time to introduce some preliminary criteria to select proper patient for the benefits and to avoid the harms of ICI therapy

Background The optimal duration of immune checkpoint inhibitor (ICI) therapy for maximum benefits remains unclear. Recently, the long-term follow-up data from clinical trials suggest the existence of a durable response (DR)that maintains the therapeutic effect even after ICI discontinuation. The study aimed to explore how the characteristics of ICI therapy influence the effectiveness of subsequent treatments in patients with advanced non-small-cell lung cancer (NSCLC). Methods The medical records of 134 patients with NSCLC who received ICIs before December 31, 2022, were retrospectively reviewed. We evaluated the impact of pretreatment ICIs on survival after completion of ICI administration. Results Among the 116 included patients, long ICI use (≥180 days) was the only independent prognostic factor for post-ICI overall survival (OS) in the multivariate analysis (HR: 0.382, 95% CI: 0.206-0.708, p=0.002). Patients who received ICIs for < 180 days showed significantly improved survival with subsequent chemotherapy (SC) compared to those who received only best supportive care (BSC) (p<0.001). However, among patients treated with ICIs for ≥ 180 days, no significant difference in OS or post-ICI OS was observed between the SC and BSC groups (p=0.188). In patients who discontinued ICIs due to PD, the impact of ICI treatment duration on survival outcomes differed. Among those with short ICI use, the SC group showed significantly better post-ICI OS compared to the BSC group (p=0.007). However, in patients with long ICI use, there was no significant difference in post-ICI OS between the SC and BSC groups (p=0.913). Regarding OS, no statistically significant differences were observed between the SC and BSC groups, regardless of ICI treatment duration. The 2-year OS was 47.6% in the SC group and 46.0% in the BSC group among patients with short ICI use (p=0.549), and 93.3% vs. 66.7% among those with long ICI use (p=0.136). Similarly, in patients who discontinued ICIs without PD, survival outcomes varied depending on ICI duration. Among those with short ICI use, the BSC group had a 2-year post-ICI OS of 21.1%, which was lower than that of the SC group (50.0%; p=0.08). The 2-year OS was also significantly higher in the SC group (64.3%) compared to the BSC group (31.6%; p=0.008). In contrast, no significant differences were observed in post-ICI OS (p=0.104) or OS (64.3% vs. 31.6%; p=0.104) between the SC and BSC groups among patients with long ICI use. Conclusion The achievement of a DR through prolonged ICI use may reduce the need for immediate subsequent chemotherapy in selected patients.

2584 Background: Cancer immune checkpoint inhibitor (ICI) therapy may be associated with kidney immune-related adverse events (IRAEs) and other causes of acute kidney injury (AKI). In clinical trials, the frequency of AKI events was uncommon, however, further real-world study is warranted. Methods: We evaluated the proportion of AKI events among patients with advanced cancer (bladder, head and neck, lung, kidney and malignant melanoma) treated with ICI therapy in Ontario, Canada from 2012 - 2018. AKI was defined by a rise in the concentration of serum creatinine as per Kidney Disease: Improving Global Outcomes (KDIGO) criteria. A multivariable regression model was used to identify predictors of AKI while accounting for the competing risk of death. Results: A total of 4,380 patients received ICI therapy. In follow-up, 1,283 (29%) had recorded AKI event (any stage AKI) and 289 (7%) had a severe AKI event (≥ stage 2). Median time to AKI was 6 months (Interquartile Range 2-16 months) and ≤ 1 % of patients received dialysis therapy. Within 30 days of any observed AKI event, 853 (58%) discontinued ICI therapy, 372 (29%) were hospitalized and 266 (21%) died. Mortality was significantly higher among patients who experiencing a severe AKI event (≥ stage 2) as compared to patients with a less severe AKI event (stage 1) or no observed AKI event. Among patients alive at 30 days following an AKI event, 14% received an outpatient corticosteroid or immunosuppressive therapy prescription, 7% had a visit with a nephrologist. Characteristics associated with a higher risk of AKI included female sex, bladder or kidney cancer (reference malignant melanoma), history of hypertension or diabetes, higher Charlson comorbidity score, a baseline estimated glomerular filtration rate less than 30 mL/min/1.73 m2, or outpatient prescription for either a proton pump inhibitor or non-steroidal anti-inflammatory drug. Among patients with an AKI event and treatment discontinuation, re-challenge of ICI therapy was infrequent (16%) with a significant risk of a recurrent AKI event (57%). Conclusions: In a population-based study among patients with cancer receiving ICI therapy, the rate of AKI was common (29%) but severe AKI was less frequent (7%). Rates of ICI discontinuation, hospitalization and death are substantial following an AKI event. Kidney function should be monitored carefully among patients undergoing ICI therapy who have common risk factors for developing renal disease. Nephrology consultation may be optimized among patients who develop a severe AKI event, especially among individuals who are considered for ICI therapy re-challenge.

Immune checkpoint inhibitor (ICI) therapy has led to significant improvement in outcomes for patients with nononcogene-driven advanced non-small cell lung cancer (NSCLC). The rate of crossover and receipt of postprotocol ICI in frontline trials for advanced NSCLC has not been systematically evaluated. ClinicalTrials.gov was used to identify phase 3 studies evaluating the use of immunotherapy or combination chemoimmunotherapy against chemotherapy alone in the frontline management of advanced NSCLC. Data on outcomes, rate of crossover and/or subsequent post-protocol receipt of immunotherapy, and the start dates of these clinical trials were then extracted. Twenty-three frontline trials in nononcogene-driven advanced NSCLC were identified. Six trials with ICI monotherapy/dual ICI therapy and 17 trials evaluating chemotherapy/ICI in first-line advanced NSCLC were included in the analysis. The crossover rate ranged 0% to 54% in ICI monotherapy/dual ICI trials and 0% to 52% in chemotherapy/ICI trials. Nineteen of 23 trials provided information on subsequent postprotocol therapies. Among the trials not allowing crossover, postprotocol ICI was administered to 17% to 45.8% of patients. Information regarding the eventual receipt of ICI therapy was available for 22 of 23 trials. Of 6631 patients, 2507 (37.8%) randomized to the control arm eventually received ICI therapy. The rate of crossover and postprotocol ICI use was low in frontline trials for first-line NSCLC incorporating ICI. Given the proven improved overall survival of ICI in a broad population, there is a need to ensure availability of this life-prolonging therapy in future trials, either by crossover treatment or postprotocol administration.