Outcomes Of Immune Checkpoint Inhibitors Research Articles

Detrimental effect of an early exposure to antibiotics on the outcomes of immunotherapy in a multi-tumor cohort of patients.

Immune checkpoint inhibitors (ICI) have changed the therapeutic landscape of many solid tumors. Modulation of the intestinal microbiota by antibiotics (Abx) has been suggested to impact on ICI outcomes. Retrospective analysis of 475 patients with advanced solid tumors treated with ICI from 2015 to 2022. For each patient, the use of Abx was recorded from 1 month before ICI initiation until disease progression or death. The impact of Abx on objective response rates (ORR), disease control rates (DCR), progression-free survival (PFS), and overall survival (OS) was analyzed. Kaplan-Meier and log-rank tests were used to compare survival outcomes. In total 475 patients with advanced solid tumors were evaluated. Median age was 67.5 years and performance status (PS) was 0-1 in 84.6%. 66.5% of patients received Abx during treatment with ICI, mainly beta-lactams (53.8%) and quinolones (35.9%). The early exposure to Abx (from 60 days before to 42 days after the first cycle of ICI) was associated with a lower ORR (27.4% vs 39.4%; P < .01), a lower DCR (37.3% vs 57.4%; P < .001), lower PFS (16.8 m vs 27.8 m; HR 0.66; P < .001]) and lower OS (2.5 m vs 6.6 m; HR 0.68; P = .001]). The negative impact of Abx on OS and PFS was confirmed by a multivariable analysis. This effect was not observed among patients receiving Abx after 6 weeks from ICI initiation. Our results validate the hypothesis of a detrimental effect of an early exposure to Abxon the efficacy of ICI in a multi-tumor cohort of patients.

Efficacy of immune checkpoint inhibitors according to programmed cell death-ligand 1 expression in patients with non-small cell lung cancer and brain metastasis: A real-world prospective observational study.

Studies have shown the antitumor efficacy of immune checkpoint inhibitors (ICI) in patients with non-small cell lung cancer (NSCLC) and brain metastases (BM). However, it is unclear whether the efficacy of ICI is similar between patients with and without BM. It is yet unclear whether the efficacy of ICI in patients with BM increases with higher levels of programmed cell death-ligand 1 (PD-L1) expression, as observed in patients without BM. We compared the outcomes of ICI treatment between patients with and without BM using a cohort containing 1741 prospectively enrolled patients with lung cancer. We investigated whether there were differences in the outcomes of ICI based on PD-L1 expression levels between these patients. We enrolled 240 patients with NSCLC with or without BM who were treated with ICI or both chemotherapy and ICI. There were no significant differences in overall survival (OS) between all patients with or without BM (p = 0.489). However, OS was significantly shorter in patients with BM than in those without in the PD-L1 ≥ 50% group (16.5 M vs. 30.6 M, p = 0.003) but not in the PD-L1 ≥ 1% or negative group. BM was an independent poor prognostic factor for OS (hazard ratio: [95% confidence interval], 2.045; [1.058-3.953], p = 0.033) in the PD-L1 ≥ 50% group. Our study indicated that the outcomes of patients with or without BM treated with ICI were not significantly different. The efficacy of ICI in patients with PD-L1 expression ≥50% would be lower in patients with BM than in those without.

Clinicogenomic predictors of outcomes in patients with hepatocellular carcinoma treated with immunotherapy.

Immune checkpoint inhibitor (ICI) combinations extend overall survival (OS) while anti-PD-1/L1 monotherapy is non-inferior to sorafenib in treatment-naïve, patients with advanced hepatocellular carcinoma (HCC). Clinicogenomic features are posited to influence patient outcomes. The primary objective of this retrospective study was to define the clinical, pathologic, and genomic factors associated with outcomes to ICI therapy in patients with HCC. Patients with histologically confirmed advanced HCC treated with ICI at Memorial Sloan Kettering Cancer Center from 2012 to 2022 were included. Association between clinical, pathological, and genomic characteristics were assessed with univariable and multivariable Cox regression model for progression-free survival (PFS) and OS. Two-hundred and forty-two patients were treated with ICI-based therapy. Patients were predominantly male (82%) with virally mediated HCC (53%) and Child Pugh A score (70%). Median follow-up was 28 months (0.5-78.4). Median PFS for those treated in 1st line, 2nd line and ≥ 3rd line was 4.9 (range: 2.9-6.2), 3.1 (2.3-4.0), and 2.5 (2.1-4.0) months, respectively. Median OS for those treated in 1st line, 2nd line, and ≥ 3rd line was 16 (11-22), 7.5 (6.4-11), and 6.4 (4.6-26) months, respectively. Poor liver function and performance status associated with worse PFS and OS, while viral hepatitis C was associated with favorable outcome. Genetic alterations were not associated with outcomes. Clinicopathologic factors were the major determinates of outcomes for patients with advanced HCC treated with ICI. Molecular profiling did not aid in stratification of ICI outcomes. Future studies should explore alternative biomarkers such as the level of immune activation or the pretreatment composition of the immune tumor microenvironment.

Baseline eosinophil proportion is a useful predictor of immune-related adverse events following immune checkpoint inhibitor treatment for recurrent metastatic head and neck cancer

Background Immune checkpoint inhibitors (ICIs) occasionally cause immune-related adverse events (irAEs) in various organs. However, predictors of irAEs remain unidentified. Objectives We evaluated the predictors of irAEs and compared the outcomes of ICIs with and without irAEs in patients with recurrent/metastatic head and neck cancers (R/M HNCs). Materials and methods We retrospectively analyzed 157 patients with R/M HNCs who were administered an anti-PD-1 antibody between September 2014 and December 2022. We examined whether various pretreatment factors were associated with irAEs. The overall survival (OS) and progression-free survival (PFS) in patients with and without irAEs were analyzed. Results Overall, 44 patients (28.0%) developed irAEs. The survival curve estimated for patients with and without irAEs showed a significant difference in PFS (p = 0.018), but not in OS (p = 0.208). Multivariate analysis revealed significant differences in relative eosinophil counts (p < 0.001), TP (p = 0.014), and NLR (p = 0.002), which may be independent predictors of irAEs. Conclusion IrAEs may be associated with higher efficacy of ICIs and longer PFS. The relative eosinophil count may be predictors of irAEs and useful in routine medical practice. Using these biomarkers to predict irAEs will help predict ICI effects and manage irAEs.

Unveiling the role of KRAS in Chinese colorectal cancer patients: a positive influence on tumor mutational burden.

One of the main challenges associated with the development of therapeutic and diagnostic strategies for patients with colorectal cancer (CRC) is the establishment of minimally invasive and efficient biomarkers. Pertinent genes in CRC have been identified through their functions in systematic mutagenesis screens. KRAS is considered a dominant mutated oncogene that contributes to pathogenesis of CRC. This study aimed to explore the genomic alternations of KRAS in a CRC population. Sequencing data of 94 Chinese patients with CRC were prospectively collected and analyzed using next-generation sequencing (NGS). The influence of KRAS and its associated subtype co-mutations on the expression level of the tumor mutational burden (TMB) was investigated. The objective of our study was to assess the potential prognostic significance of KRAS and other driving oncogenes in determining the clinical efficacy of immunotherapy. The gene mutation rates of TP53, APC, and KRAS were 81.91%, 71.28%, and 43.62%, respectively. Additionally, KRAS G12D displayed a relatively higher mutation rate than other KRAS-mutant subtypes. Increased TMB was observed in cases of KRAS and BRAF mutation combined with APC single mutation; furthermore, the expression of TMB in G12V was the highest, and G12D presented the lowest TMB in single KRAS-mutant subtypes or the combination with APC mutations. The TMB driven by KRAS co-mutations may have the potential to be used as a key biomarker for prediction of treatment outcomes of immune checkpoint inhibitors (ICIs) in patients with CRC, especially with APC co-mutation.

Lymphocyte T Subsets and Outcome of Immune Checkpoint Inhibitors in Melanoma Patients: An Oncologist's Perspective on Current Knowledge.

Melanoma is the most aggressive and deadly form of skin cancer, and its incidence has been steadily increasing over the past few decades, particularly in the Caucasian population. Immune checkpoint inhibitors (ICI), anti-PD-1 monotherapy or in combination with anti-CTLA-4, and more recently, anti-PD-1 plus anti-LAG-3 have changed the clinical evolution of this disease. However, a significant percentage of patients do not benefit from these therapies. Therefore, to improve patient selection, it is imperative to look for novel biomarkers. Immune subsets, particularly the quantification of lymphocyte T populations, could contribute to the identification of ICI responders. The main purpose of this review is to thoroughly examine significant published data on the potential role of lymphocyte T subset distribution in peripheral blood (PB) or intratumorally as prognostic and predictive of response biomarkers in advanced melanoma patients treated with ICI regardless of BRAFV600 mutational status.

Potential of Nutritional Markers as Predictors After Immunotherapy in Advanced Head and Neck Squamous Cell Carcinoma.

Immune checkpoint inhibitors (ICIs) are the standard treatment for advanced head and neck squamous cell carcinoma (HNSCC). Programmed death-ligand 1 (PD-L1) is clinically assessed before initiating ICIs; however, there are no established biomarkers for predicting the response to immunotherapy. In this study, inflammatory and nutritional parameters were examined to determine the therapeutic outcomes of ICIs for HNSCC. Sixty-five patients with metastatic or recurrent HNSCC who received programmed death-1 (PD-1) blockade were enrolled. Inflammatory and nutritional indices were correlated with patient outcomes, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and prognostic nutritional index (PNI). Patients aged <70 years were significantly associated with a high NLR, whereas those with a performance status of 2 or 3 were closely related to a high NLR, high SII, and low PNI. Although all patients achieved an objective response rate of 24.6% and a disease control rate of 36.9%, the NLR, PLR, SII, and PNI values were not significantly different between responders and non-responders. Univariate analysis showed that the NLR, PLR, SII, and PNI were significant predictors of progression-free survival (PFS) and overall survival (OS). Multivariate analysis identified PNI as an independent predictor of PFS and OS. PNI, as a nutritional marker, was identified as a significant predictor of outcomes following PD-1 blockade administration in patients with advanced HNSCC, compared to inflammatory markers, such as NLR, PLR, and SII.

Clinical outcomes for immune checkpoint inhibitors plus chemotherapy in non-small-cell lung cancer patients with uncommon driver gene alterations

BackgroundLimited data exists on the efficacy of immune checkpoint inhibitor (ICI) combinations in non-small-cell lung cancer (NSCLC) with uncommon driver alterations in genes such as ERBB2, BRAF, RET, and MET. This study retrospectively assessed ICI-combination therapy outcomes in this molecular subset of NSCLC.MethodsWe retrospectively analyzed patients with advanced NSCLC confirmed with driver alterations in genes including ERBB2, BRAF, RET or MET, and received ICI combined with chemotherapy (ICI + chemo) and/or targeted therapy (ICI + chemo/TT) as first-line (1L) or second- or third-line (≥ 2L) treatment at Hunan Cancer Hospital between January 2018 and May 2024.ResultsOf the 181 patients included in the study, 131 patients received 1L-ICI + chemo (ERBB2, n = 64; BRAF, n = 34; RET, n = 23; and MET, n = 10), and 50 patients received ≥ 2L-ICI + chemo/TT (ERBB2, n = 16; BRAF, n = 7; RET, n = 14; MET, n = 13). The full cohort had an overall response rate (ORR) of 45.9% and disease control rate of 84.0%. Among patients who received 1L-ICI + chemo, ORR ranged between 51.6% and 60.0%, with the median progression-free survival (mPFS) and overall survival (mOS) of 8.2 and 21.0 months for those with ERBB2-altered tumors, 10.0 and 15.0 months for BRAF-altered tumors, 12.1 months and OS not reached for RET-altered tumors, and 6.2 and 28.0 months for MET-altered tumors, respectively. Additionally, ORR ranged between 14.3% and 30.8% for ≥ 2L-ICI + chemo/TT; mPFS and mOS were 5.4 and 16.2 months for patients with ERBB2-altered tumors, 2.7 and 5.0 months for BRAF-altered tumors, 6.2 and 14.3 months for RET-altered tumors, and 5.7 and 11.5 months for MET-altered tumors, respectively.ConclusionICI-based combination therapies, regardless of treatment line, were effective in treating patients with advanced NSCLC harboring driver alterations in ERBB2, BRAF, RET, or MET. This suggests their potential as alternative treatment options in this patient population.

Adjuvant Therapy with Immune Checkpoint Inhibitors after Carbon Ion Radiotherapy for Mucosal Melanoma of the Head and Neck: A Case-Control Study.

The development of new treatment strategies to improve the prognosis of mucosal malignant melanoma of the head and neck (MMHN) after carbon ion radiotherapy (CIRT) is essential because of the risk of distant metastases. Therefore, our objective was to evaluate the outcomes of immune checkpoint inhibitor (ICI) treatment to justify its inclusion in the regimen after CIRT. Thirty-four patients who received CIRT as an initial treatment were included in the analysis and stratified into three groups: those who did not receive ICIs (Group A), those who received ICIs after recurrence or metastasis (Group B), and those who received ICIs as adjuvant therapy after CIRT (Group C). In total, 62% of the patients (n = 21) received ICIs. The 2-year local control and overall survival (OS) rates for all patients were 90.0% and 66.8%, respectively. The 2-year OS rates for patients in Groups A, B, and C were 50.8%, 66.7%, and 100%, respectively. No significant differences were observed between Groups A and B (p = 0.192) and Groups B and C (p = 0.112). However, a significant difference was confirmed between Groups A and C (p = 0.017). Adjuvant therapy following CIRT for MMHN may be a promising treatment modality that can extend patient survival.

Effects of KRAS, STK11, KEAP1, and TP53 mutations on the clinical outcomes of immune checkpoint inhibitors among patients with lung adenocarcinoma.

This study aimed to identify the associations between individual KRAS, STK11, KEAP1, or TP53 mutations, as well as the comutation status of these genes, and the tumor mutation burden (TMB) with clinical outcomes of lung adenocarcinoma patients treated with immune checkpoint inhibitors (ICIs). We collected data from patients with lung adenocarcinoma treated with ICIs from the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database between June 2019 and August 2023. The main endpoints were the treatment response and overall survival (OS). Among 343 patients with lung adenocarcinoma, 61 (18%), 69 (20%), 41 (12%), and 222 (65%) patients had KRAS, STK11, KEAP1, and TP53 mutations, respectively. An overall objective response was observed in 94 of 338 patients (28%), including 2 (1%) who achieved a complete response and 92 (27%) who achieved a partial response. Patients with STK11, KEAP1, or TP53 mutations had a significantly greater TMB (P<0.001). According to the univariate analysis, the treatment response was significantly correlated with TP53 mutation in both the general (P = 0.041) and KRAS wild-type (P = 0.009) populations. KEAP1 and TP53 mutations were associated with worse OS among assessable patients (hazard ratio (HR) = 2.027, P = 0.002; HR = 1.673, P = 0.007, respectively) and among patients without KRAS mutations (HR = 1.897, P = 0.012; HR = 1.908, P = 0.004, respectively). According to the multivariate analysis, KEAP1 (HR = 1.890, P = 0.008) and TP53 (HR = 1.735, P = 0.011) mutations were found to be independent factors for OS. STK11, KEAP1, and TP53 mutations are significantly associated with a high TMB. TP53 mutation could affect the treatment response to some degree, and both KEAP1 and TP53 mutations resulted in inferior OS in the general patient population and in those with KRAS-wild-type lung adenocarcinoma, indicating that KEAP1 and TP53 mutations might act as prognostic factors for ICI treatment in lung adenocarcinoma patients.

Preclinical study and phase II trial of adapting low-dose radiotherapy to immunotherapy in small cell lung cancer

Immune checkpoint inhibitors (ICIs) provide modest but unsatisfactory benefits for extensive-stage small cell lung cancer (ES-SCLC). Developing strategies for treating ES-SCLC is critical. We preliminarily explored the outcomes of salvage low-dose radiotherapy (LDRT) plus ICI on refractory SCLC patients. Next, we evaluated the combinational efficacy in murine SCLC. The tumor immune microenvironment (TIME) was analyzed for mechanistic study. Subsequently, we conducted a multicenter, prospective phase II trial that administered concurrent thoracic LDRT plus chemoimmunotherapy to treatment-naive ES-SCLC patients (MATCH trial, NCT04622228). The primary endpoint was confirmed objective response rate (ORR), and the key secondary endpoints included progression-free survival (PFS) and safety. Fifteen refractory SCLC patients treated with LDRT plus ICI were retrospectively reviewed. The ORR was 73.3% (95% confidence interval [CI], 44.9-92.2). We identified a specific dose of LDRT (15 Gy/5 fractions) that exhibited growth retardation and improved survival in murine SCLC when combined with ICIs. This combination recruited a special Tcell population, TCF1+ PD-1+ CD8+ stem-like Tcells, from tumor-draining lymph nodes into the TIME. The MATCH trial showed a confirmed ORR of 87.5% (95% CI, 75.9-94.8). The median PFS was 6.9months (95% CI, 5.4-9.3). These findings verified that LDRT plus chemoimmunotherapy was safe, feasible, and effective for ES-SCLC, warranting further investigation. This research was funded by West China Hospital (no. ZYJC21003), the National Natural Science Foundation of China (no. 82073336), and the MATCH trial was fully funded by Roche (China) Holding Ltd. (RCHL) and Shanghai Roche Pharmaceuticals Ltd. (SRPL).

PP01.40 Treatment Patterns and Survival Outcomes of Immune Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer Survival at a Safety-Net Hospital

PP01.40 Treatment Patterns and Survival Outcomes of Immune Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer Survival at a Safety-Net Hospital

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.

Clinical Outcomes of Immune Checkpoint Inhibitors in Unique Cohorts Underrepresented in Clinical Trials.

Regulatory approval of immune checkpoint inhibitors (ICIs) was based on results of large, randomized clinical trials, resulting in limited outcomes data in patient cohorts typically underrepresented in such trials. The objective of this study was to evaluate the efficacy and safety of ICIs in these unique patient cohorts. This is a multicenter, retrospective analysis of real-world data at six academic and community clinics in the United States from 1 January 2011 to 1 April 2018. Patients were included if they had received at least one cycle of ICI treatment. Unique patient cohorts included age > 75 years, non-White race, positive smoking history, ECOG performance status (PS) ≥ 2, BMI ≥ 30 kg/m2, autoimmune diseases (AIDs), chronic viral infections (CVI), extensive prior lines of therapy (LOTs), or >three metastatic sites. Immune-related adverse events (irAEs), overall survival (OS), and time to treatment failure were evaluated in the entire cohort and in NSCLC patients treated with PD-(L)1 monotherapy. Outcomes and their association with unique patient cohorts were compared on univariate analysis and multivariate analysis to those without a particular characteristic in the entire NSCLC PD-(L)1 monotherapy cohorts. In total, 1453 patients were included: 56.5%-smokers, 30.4%-non-White, 22.8%-elderly, 20.8%-ECOG PS ≥ 2, 15.7%-history of AIDs, and 4.7%-history of CVI. The common ICIs were nivolumab (37.1%) and pembrolizumab (22.2%). Black patients, compared to White patients, experienced fewer irAEs (OR 0.54, p < 0.001). An ECOG PS of ≥2 (HR = 2.01, p < 0.001) and an increased number of previous LOTs were associated with poor OS (the median OS of 26.2 vs. 16.2 vs. 9.6 months for one vs. two vs. three prior LOTs, p < 0.001). The above results were confirmed in anti-PD-(L)1 monotherapy non-small cell lung cancer patients (n = 384). Overall, ICIs were safe and efficacious in these typically underrepresented patient cohorts. We noted ECOG PS ≥ 2 and an increased prior LOTs were associated with poor ICI efficacy, and Black patients, compared to White patients, experienced fewer irAEs.

Spatially Informed Gene Signatures for Response to Immunotherapy in Melanoma.

We aim to improve the prediction of response or resistance to immunotherapies in patients with melanoma. This goal is based on the hypothesis that current gene signatures predicting immunotherapy outcomes show only modest accuracy due to the lack of spatial information about cellular functions and molecular processes within tumors and their microenvironment. We collected gene expression data spatially from three cellular compartments defined by CD68+ macrophages, CD45+ leukocytes, and S100B+ tumor cells in 55 immunotherapy-treated melanoma specimens using Digital Spatial Profiling-Whole Transcriptome Atlas. We developed a computational pipeline to discover compartment-specific gene signatures and determine if adding spatial information can improve patient stratification. We achieved robust performance of compartment-specific signatures in predicting the outcome of immune checkpoint inhibitors in the discovery cohort. Of the three signatures, the S100B signature showed the best performance in the validation cohort (N = 45). We also compared our compartment-specific signatures with published bulk signatures and found the S100B tumor spatial signature outperformed previous signatures. Within the eight-gene S100B signature, five genes (PSMB8, TAX1BP3, NOTCH3, LCP2, and NQO1) with positive coefficients predict the response, and three genes (KMT2C, OVCA2, and MGRN1) with negative coefficients predict the resistance to treatment. We conclude that the spatially defined compartment signatures utilize tumor and tumor microenvironment-specific information, leading to more accurate prediction of treatment outcome, and thus merit prospective clinical assessment.

Integrated analysis of single-cell data on role of NKG7high CD8+ Teff cells in driving immune-related adverse events.

e24114 Background: Immune-related adverse events (irAEs) frequently occur during immunotherapy and can impact various organ systems, which dampen the clinical outcomes of immune checkpoint inhibitors (ICIs). However, the precise immune hallmarks associated with irAEs remain further explored. Methods: We collected public (Bukhari et al., Zhu et al., Su et al., and Ma et al.) and our own scRNA-seq data across patients with different irAE types or without irAEs. By comparing T cell compositions between irAE and no-irAE patients, the subcluster correlated with the occurrence of irAE was identified. Subsequently, the integrated analyses were performed to explore its mechanisms in driving irAEs in both peripheral blood and local tissues. Results: Compared to no-irAE patients, a subcluster of effector T (Teff) cells was observed to increase notably in the peripheral blood of irAE patients during immunotherapy. This specific subcluster, named "NKG7high CD8+ Teff cells," was characterized by the significant expression of effector genes such as GZMH, CCL5, and especially NKG7. In contrast to other CD8+ T cells, the NKG7high CD8+ Teff cells exhibited stronger cytotoxicity functions, increased exosome secretion, and enhanced MIF-CD74 interaction with monocytes, which suggests the mechanistic link between its increased infiltration and the development of irAEs. Further investigation showed these characteristics were more remarkable in NKG7high CD8+ Teff from irAE patients than no-irAE patients. Subsequently, the increase of NKG7high CD8+ Teff during immunotherapy was validated in our own scRNA from immune thyroiditis patients, which was not observed in no-irAE patients. Across various irAE types, NKG7high CD8+ Teff subsets, along with their NKG7 expression, demonstrated heightened infiltration and expression in immune-related arthritis and myocarditis samples. After investigating the role of NKG7high CD8+ Teff in peripheral blood, we focused on its distribution and roles in local irAE tissue. NKG7high CD8+ Teff cells accumulated in immune-related thyroiditis tissues, and recruited macrophages through the IFNG and CSF1 signaling pathways, thereby inducing an immune overreaction. Meanwhile, in immune-related myocarditis mice heart tissues, NKG7high CD8+ Teff cells could interact with macrophages via the SPP1 signaling pathway and cause endothelial cell damage through the FASL-FAS pathway. Conclusions: This comprehensive study revealed the intricate mechanisms of NKG7high CD8+ Teff in inducing irAEs, providing valuable insights into their roles and potential implications in irAE treatment.

Social determinants of health and treatment outcomes among a retrospective cohort of patients receiving immunotherapy for cancer.

e13744 Background: Disparities due to socioeconomic status persist in the treatment of cancer. Newer therapies, such as immune checkpoint inhibitors (ICIs), offer easier administration, lower risk of toxicity, and may improve accessibility compared to cytotoxic chemotherapy. Prior studies on ICI outcomes have shown mixed results at the county level, and there is a need to investigate social determinants of health at a more granular level. Our study aims to compare long-term ICI outcomes between socioeconomic groups at the census tract level among patients with cancer. Methods: The investigators compiled data from 2/1/2011 to 4/7/2022 on patients who received at least one dose of an ICI at a comprehensive cancer center and its outreach clinics to create a retrospective patient registry. Investigators used a secure, cloud-based REDCap registry, validated it with data quality rules, and resolved discrepancies. Clinical research specialists at Vasta Global captured most of the data. Investigators correlated patients’ ZIP codes with 2010 US Department of Agriculture Rural-Urban Commuting Area (RUCA) classifications and census tracts with 2020 Center for Disease Control Social Vulnerability Index (SVI) data. The univariate analyses used the ANOVA or Kruskal-Wallis tests, chi-square tests, and Kaplan-Meier methods. The multivariate analyses used Cox and logistic regressions, adjusting for age, race, ethnicity, type of cancer, smoking status, age-adjusted Charlson Comorbidity Index, and other comorbidities. Results: Our cohort consisted of 1,807 patients who were an average of 66 years old, predominantly male (60.8%), white (84%), non-Hispanic (98%), and had lung cancer (45.1%) as the most common tumor type. Univariate analyses found no associations between either RUCA or SVI and overall survival (OS), progression-free survival (PFS), immune-related adverse events (irAE), or time to irAE. For RUCA, multivariate analysis found that rural location of residence was associated with shorter PFS (all covariates, p 0.0386). For SVI, multivariate analysis showed no significant association with OS, PFS, number of irAEs, or time until irAE (including high-grade irAEs). Conclusions: Rural residence by ZIP code was associated with shorter PFS, indicating that there may be decreased access to ICI for these patients. However, the overall findings suggest similar ICI treatment outcomes across patients with widely variable social determinants of health by census tract. Further research is needed to understand how newer therapies can be best positioned to overcome disparities in cancer care.

Multimodal fully automated predictive model for therapeutic efficacy of first-line cancer immunotherapy based on clinical information and imaging modalities including brain MRI and chest CT images in advanced non-small cell lung cancer.

1555 Background: The integration of imaging and clinical data through artificial intelligence (AI) holds promise for more accurately predicting the therapeutic efficacy of immune checkpoint inhibitors (ICI) ± platinum-based chemotherapy in individual patients with advanced non-small cell lung cancer (NSCLC). However, tumor segmentation still relies entirely on radiologist evaluation and has not yet achieved fully automated tumor evaluation for image analysis. Furthermore, while central nervous system (CNS) metastasis is a critical prognostic factor in patients with advanced NSCLC, radiomics has primarily focused on chest imaging, with few studies incorporating brain MRI analysis. Methods: This study included patients with advanced NSCLC treated with ICI ± platinum-based chemotherapy as first-line therapy from March 2017 to August 2023. We developed an ensemble model combining a logistic regression model that analyzes clinical information with a deep learning model that extracts image features. Each sub-model was independent, allowing for individual adjustments and the ability to be attached or detached. Both models were trained to predict response, 12-month progression-free survival (PFS), and 12-month overall survival (OS) using cross-entropy loss. The dataset was randomly divided into training, validation, and test sets in a 5:3:2 ratio. This random assignment was repeated four times, and the average area under the curve (AUC) was calculated. The test sets were further classified into high- and low-risk groups based on the predicted results, and log-rank tests were performed on their survival curves. Results: The study included 232 patients, with 89 (38%) receiving ICI alone and 143 (62%) receiving ICI + platinum-based chemotherapy. In the entire population, the overall response rate (ORR) for ICI ± platinum-based chemotherapy was 49.5%, with a median PFS of 7.1 months (95% confidence interval [CI]: 5.8-9.1) and a median OS of 24.5 months (95% CI: 21.2-30.3). The model achieved an AUC of 0.70 (95% CI: 0.65- 0.76) for predicting response, 0.65 (95% CI: 0.59-0.71) for 12-month PFS, and 0.69 (95% CI: 0.48-0.90) for 12-month OS. Test sets were classified into high-risk (N = 55) and low-risk (N = 60) groups. The median PFS was 6.8 months in the high-risk group and 14.7 months in the low-risk group (p &lt; 0.05). The median OS was 21.5 months in the high-risk group and 34.3 months in the low-risk group (p &lt; 0.05). Conclusions: We have demonstrated that a multimodal, fully automated ensemble model has significant predictive accuracy for the efficacy and survival outcomes of ICI ± platinum-based chemotherapy in patients with advanced NSCLC.

Intrapatient variation in PD-L1 expression and tumor mutational burden and the impact on outcomes to immune checkpoint inhibitor therapy in patients with non-small-cell lung cancer

Programmed death receptor ligand 1 (PD-L1) tumor proportion score (TPS) and tumor mutational burden (TMB) are key predictive biomarkers for immune checkpoint inhibitor (ICI) efficacy in non-small-cell lung cancer (NSCLC). Data on their variation across multiple samples are limited. Patients with NSCLC and multiple PD-L1 TPS and/or TMB assessments were included. Clinicopathologic and genomic data were analyzed according to PD-L1 and TMB variation. In total, 402 PD-L1 sample pairs and 413 TMB sample pairs were included. Concordance between pairs was moderate for PD-L1 (ρ= 0.53, P < 0.0001) and high for TMB (ρ= 0.80, P < 0.0001). Shorter time between biopsies correlated with higher concordance in PD-L1, but not in TMB. Major increases (ΔTPS ≥+50%) and decreases (ΔTPS ≤-50%) in PD-L1 were observed in 9.7% and 8.0% of cases, respectively. PD-L1, but not TMB, decreased with intervening ICI (P= 0.02). Acquired copy number loss of CD274, PDCD1LG2, and JAK2 were associated with major decrease in PD-L1 (q < 0.05). Among patients with multiple PD-L1 assessments before ICI, cases where all samples had a PD-L1 ≥1%, compared to cases with at least one sample with PD-L1 <1% and another with PD-L1 ≥1%, achieved improved objective response rate and progression-free survival (PFS). Among patients with at least one PD-L1 <1% and one ≥1% before ICI, cases where the most proximal sample was PD-L1 ≥1% had longer median PFS compared to cases where the most proximal PD-L1 was <1%. Among patients with multiple TMB assessments before ICI, patients with a TMB ≥10 mut/Mb based on the most recent assessment, as compared to those with a TMB <10 mut/Mb, achieved improved PFS and overall survival to ICI; instead, no differences were observed when patients were categorized using the oldest TMB assessment. Despite intrapatient concordance in PD-L1 and TMB, variation in these biomarkers can influence ICI outcomes, warranting consideration for reassessment before ICI initiation when feasible.

Impact of steroids indication on the efficacy of immunotherapy in a multi-tumor cohort of patients: Time and dose-dependent evaluation.

12083 Background: The detrimental impact of steroids (ST) on patients receiving immune checkpoint inhibitors (ICI) has been described in several studies. However, the influence of indication, time of administration, and dosage is more controversial. Methods: This is a retrospective analysis of 475 patients with advanced solid tumors treated with ICI at a tertiary university hospital, between 2015 and 2022. Data related to baseline characteristics and clinical outcomes were collected. For each patient, the daily ST dose (equivalent in mg/kg of prednisone) and indication were registered until progression or death. We evaluated the impact of ST indication on the objective response rate (ORR) and progression-free survival (PFS). In addition, we analyzed the potential influence of cumulative dose (CD) (patients were divided into quartiles (Q) based on the total dose of steroids received throughout ICI treatment) and time of administration (30 days from C1 (D1-30), 3 months from C1 (D1-D90) and after 6 months (m) from C1 (&gt;6m)). Results: We analyzed 475 pts with advanced solid tumors (NSCLC: 33.9%; urothelial: 17.3%; renal: 13.7%; melanoma: 11.2%; head and neck: 11.0%; others: 12.9%) treated with ICI (anti-PD1 [64.4%], anti-PDL1 [20.4%], anti-PD1 plus anti-CTLA4 [13.3%] or anti-CTLA4 [1.9%]). 49.5% of pts received ST during ICI treatment (20.6% due to an immune-related adverse event [irAE] and 33.9% with other indications). 24.2% of patients received ST in D1-30 (5.7% irAE vs 20.6% other indications), 32.6% in D1-D90 (10.7% vs 25.1%) and 17.1% in &gt;6m (12% vs 8%). The ORR was significantly higher in pts who received ST for irAES than in those treated with ST for other reasons both in D1-30 (40% vs 15.3%; p = 0.028) and in D1-90 (42.6% vs 17%; p = 0.001). Furthermore, the ORR was very similar to that of patients who did not receive any ST treatment (40% vs 37.8% in D1-30, and 42.6% vs 37.7% in D1-90). There was an inverse correlation between the CD of ST in D1-30 and the ORR (37.78% [no steroids], 29.63% [Q1], 21.42% [Q2], 11.11% [Q3] and 22.22% [Q4]). However, this association was not observed among patients receiving ST for irAEs during D1-30 (37.8% [no steroids], 100% [Q1], 0% [Q2], 33.3% [Q3] and 42.9% [Q4]; p = 0.21) and in D1-90 (37.7% [no steroids], 0% [Q1], 41.7% [Q2], 42.9% [Q3] and 52.9% [Q4]; p = 0.29). Finally, among patients without progression after 6 months from C1, PFS tended to be longer in those exposed to ST. However, PFS was similar regardless of the reason for ST use. Conclusions: Exposure to ST is associated with poorer ICI outcomes. Our study showed that the impact of ST is time- and dose-dependent. Interestingly, these results were not observed among patients exposed to ST due to irAEs, suggesting that immune toxicity may attenuate ST detrimental effects.