First-line Immune Checkpoint Inhibitors Research Articles

Abstract 4969: Investigating digital pathology tumor microenvironment features for immunotherapy outcome in patients with advanced non-small cell lung cancer

Abstract Introduction The composition of the tumor microenvironment (TME) has been shown to influence response to immunotherapy (IO). In this study, we investigated digital pathology TME features of IO outcomes among patients with non-squamous, non-small cell lung cancer (NSCLC) within a real-world dataset. Methods From the nationwide de-identified Flatiron Health-Foundation Medicine NSCLC clinico-genomic database, a cohort of 50 EGFR/ALK-negative, non-squamous NSCLC patients treated with first-line pembrolizumab monotherapy (mono-IO) or pembrolizumab in combination with carboplatin/cisplatin and pemetrexed (chemo-IO) that had available whole slide images of H&E-stained tissue resection specimens were included. The de-identified data originated from approximately 280 US cancer clinics (~800 sites of care). AI-powered TME characterization models developed by PathAI (Boston, MA; commercially available as PathExplore™) were deployed on scanned H&E slides to extract a panel of cell- and tissue-level human interpretable features (HIFs). Cox proportional hazards regression was used to identify digital pathology features or HIFs associated with overall survival. Results 17 HIFs were associated with better survival and 19 HIFs were associated with worse survival among patients treated with mono-IO (p < 0.05). Lymphocyte features were among the HIFs associated with favorable survival, including density of lymphocyte cells in cancer epithelium (hazard ratio (HR) per unit standard deviation (SD) = 0.46 [0.24, 0.88], p-value = 0.02) and proportion of lymphocyte cells relative to total immune cells in cancer epithelium (HR per unit SD = 0.61 [0.39, 0.95], p-value = 0.03). Cell-level features associated with worse survival included density of fibroblast cells in stroma (HR per unit SD = 1.51 [1.01, 2.25], p-value = 0.05). These associations remained after adjusting for tumor mutational burden (TMB) (N = 29 low, 21 high) and PD-L1 status (N = 0 negative, 1 low-positive, 17 high-positive, 32 unknown). Additionally, similar associations were not observed among patients treated with chemo-IO. High lymphocyte density was associated with better survival compared to low lymphocyte density in mono-IO treated patients (adjusted HR per unit SD = 0.36 [0.18, 0.74], p-value = 0.01) but not in chemo-IO treated patients (adjusted HR per unit SD = 1.10 [0.76, 1.60], p-value = 0.6). Conclusion These results indicate that the composition of TME assessed via digital pathology may have utility in identifying NSCLC patients that will respond to first-line immune checkpoint inhibitors beyond the established IO biomarkers. Citation Format: Ericka M. Ebot, Kuei-Ting Chen, Mikayla Biggs, Douglas I. Lin, Julia A. Elvin, Garrett M. Frampton, James J. Pao. Investigating digital pathology tumor microenvironment features for immunotherapy outcome in patients with advanced non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4969.

Abstract 5132: Multi-omics analysis uncovers predictive biomarkers for the efficacy and outcomes of immune checkpoint inhibitor in combination with chemotherapy in advanced unresectable biliary tract cancers

Abstract Background: Biliary tract cancer, typically diagnosed at advanced stages with a poor prognosis, has witnessed a glimmer of hope in the progress of immune checkpoint inhibitors (ICIs). Yet, their limited response rates necessitate the search for effective biomarkers to refine patient selection. Methods: A total of 125 patients with a confirmed histological diagnosis of unresectable advanced or metastatic biliary tract cancers (BTC) who received first-line ICIs in combination with chemotherapy (chemoimmunotherapy) were prospectively enrolled. All baseline samples from 125 patients underwent targeted DNA sequencing, with an additional 62 patients undergoing RNA sequencing, and 85 patients had accessible mIHC data. The associations between molecular characteristics and the response to chemoimmunotherapy, progression-free survival (PFS) and overall survival (OS) were evaluated. Results: The cohort had a median age of 63 years (range from 34 to 82) and 52.8% (66/125) were male, including 54 with gallbladder cancer, 57 with intrahepatic cholangiocarcinoma, and 14 with extrahepatic cholangiocarcinoma. The median duration of follow-up was 14.8 months for the entire cohort, with the median PFS and OS of 6.9 months (95%CI: 6.2-7.9) and 11.8 months (95%CI: 10.3-14.8), respectively. The most mutated genes were TP53 (64/125, 51.2%), KRAS (34/125, 27.2%), ERBB2 (18/125, 14.4%), and ARID1A (17/125, 13.6%). Mutations of TP53 (51.2%, p = 0.042), BRCA2 (4.8%, p = 0.002), cytokine genes (6.4%, p = 0.004), and high tumor mutation burden (p = 0.072) demonstrated significant correlation with chemoimmunotherapy response. KRAS G12D mutations (PFS: P < 0.001; OS: P = 0.034) and ARID1A loss-of-function mutations (PFS: P = 0.009; OS: P = 0.012) were adverse survival factors, while high CXCL9 or CTLA4 expression was associated with response (CXCL9, P = 0.014; CTLA4, P = 0.067), improved PFS (CXCL9, P = 0.018; CTLA4, P = 0.008), and longer OS (CXCL9, P = 0.010; CTLA4, P = 0.008) under chemoimmunotherapy. Patients were classified into three subtypes using the identified survival biomarkers. Among them, Type I patients, characterized by the absence of KRAS G12D or ARID1A mutations but expressing high levels of CTLA4 or CXCL9, demonstrated the best outcomes under chemoimmunotherapy. Interestingly, further RNA analysis suggested that elevated CXCL9 expression correlated with heightened immune checkpoint expressions, including CTLA4, PD-L1, and PD-1 (all P < 0.001), as well as increased tumor microenvironment immune activity, findings validated in two additional independent patient cohorts both internal and external. Conclusions: Our study revealed predictive biomarkers relevant to the response and efficacy of immune checkpoint inhibitors in combination with chemotherapy in advanced biliary tract cancer. Citation Format: Jieer Ying, Qi Xu, Jiaojiao Ni, Hanlin Chen, Chaoqun Li, Yanru Xie, Qinhong Zheng, Jianying Jin, Junrong Yan, Xiaoying Wu, Qiuxiang Ou, Li Yuan, Wei Zhuo, Haimeng Tang. Multi-omics analysis uncovers predictive biomarkers for the efficacy and outcomes of immune checkpoint inhibitor in combination with chemotherapy in advanced unresectable biliary tract cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5132.

Abstract 6118: Sex-related disparity in immune checkpoint inhibitor benefit for patients with esophageal squamous cell carcinoma: A systematic review and meta-analysis

Abstract Sex-related dimorphism in cancer incidence and immune response is widely recognized, yet the impact of an individual's sex on the effectiveness of Immune Checkpoint Inhibitors (ICIs) for patients with advanced esophageal squamous cell carcinoma (ESCC) remains poorly understood. In this study, we conducted a comprehensive meta-analysis to evaluate the heterogeneity of ICIs in patients with advanced ESCC. We collected studies from PubMed, MEDLINE, Embase, and Scopus, spanning from the inception of the databases to September 30, 2023. These studies focused on phase III randomized trials comparing first-line ICIs (PD-1/PD-L1) plus chemotherapy with chemotherapy alone for advanced or metastatic ESCC. Additionally, we reviewed abstracts and presentations from AACR, ASCO, ESMO, and WCLC. Inclusion criteria mandated the reporting of overall survival (OS) data stratified by sex and nonselective baseline PD-L1 expression. The study adhered to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The analysis included 6 randomized clinical trials comprising 3603 ESCC patients, of whom 3090 (85.8%) were male and 513 (14.2%) were female. A significant OS benefit was observed for ICIs plus chemotherapy in all patients (HR, 0.68; 95% CI, 0.62-0.74; P < 0.001). Similarly, ICIs plus chemotherapy correlated with a significantly prolonged OS in males (HR, 0.67; 95% CI, 0.61-0.74, P < 0.001). However, there was no significant OS benefit observed in females with ICIs plus chemotherapy (HR, 0.79; 95% CI, 0.58-1.09; P = 0.148). Females had a tendency toward less benefit than males (pooled HR, 1.18; 95% CI, 0.89-1.57; P = 0.245). Our findings suggest that there is no statistically significant association between patient sex and the efficacy of ICIs for ESCC patients. Importantly, we report, for the first time, a lack of survival benefit with the ICI plus chemotherapy regimen in the first-line setting compared to chemotherapy alone in female ESCC patients. Citation Format: Chaoqi Zhang, Peng Wu, Jingjing Liu, Dongyu Li, Nan Sun, Jie He. Sex-related disparity in immune checkpoint inhibitor benefit for patients with esophageal squamous cell carcinoma: A systematic review and meta-analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6118.

Memory/Active T-Cell Activation Is Associated with Immunotherapeutic Response in Fumarate Hydratase-Deficient Renal Cell Carcinoma.

Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare and lethal subtype of kidney cancer. However, the optimal treatments and molecular correlates of benefits for FH-deficient RCC are currently lacking. A total of 91 patients with FH-deficient RCC from 15 medical centers between 2009 and 2022 were enrolled in this study. Genomic and bulk RNA-sequencing (RNA-seq) were performed on 88 and 45 untreated FH-deficient RCCs, respectively. Single-cell RNA-seq was performed to identify biomarkers for treatment response. Main outcomes included disease-free survival (DFS) for localized patients, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) for patients with metastasis. In the localized setting, we found that a cell-cycle progression signature enabled to predict disease progression. In the metastatic setting, first-line immune checkpoint inhibitor plus tyrosine kinase inhibitor (ICI+TKI) combination therapy showed satisfactory safety and was associated with a higher ORR (43.2% vs. 5.6%), apparently superior PFS (median PFS, 17.3 vs. 9.6 months, P = 0.016) and OS (median OS, not reached vs. 25.7 months, P = 0.005) over TKI monotherapy. Bulk and single-cell RNA-seq data revealed an enrichment of memory and effect T cells in responders to ICI plus TKI combination therapy. Furthermore, we identified a signature of memory and effect T cells that was associated with the effectiveness of ICI plus TKI combination therapy. ICI plus TKI combination therapy may represent a promising treatment option for metastatic FH-deficient RCC. A memory/active T-cell-derived signature is associated with the efficacy of ICI+TKI but necessitates further validation.

Efficacy and safety of first-line PD-L1/PD-1 inhibitors in limited-stage small cell lung cancer: a multicenter propensity score matched retrospective study.

The prognosis of small cell lung cancer (SCLC) patients is poor, and the standard first-line treatment for limited-stage small cell lung cancer (LS-SCLC) is still chemotherapy and thoracic radiotherapy. The primary objectives of our study were to confirm the superior efficacy of first-line immune checkpoint inhibitors (ICIs) plus etoposide and platinum (EP) for LS-SCLC and find crucial biomarkers. We analyzed LS-SCLC patients from three medical centers, employing propensity score matching for group comparability. Survival outcomes were estimated by Kaplan-Meier and Cox regression analyses. Additionally, we conducted univariate and multivariate analyses to investigate potential predictive factors. Among 150 patients in our study, we successfully matched 41 pairs. The median overall survival (OS) was 29.5 months in the EP + ICIs group and 20.0 months in the EP group {hazard ratio (HR) =0.64 [95% confidence interval (CI): 0.41-1.02], P=0.059}. The median progression-free survival (PFS) was significantly extended in the EP + ICIs group (14.6 months), compared to the EP group (8.6 months) [HR =0.42 (95% CI: 0.28-0.63), P<0.001]. After matching, patients receiving chemo-immunotherapy had a median OS of 36.1 months, significantly surpassing those receiving chemotherapy alone (19.0 months) [HR =0.51 (95% CI: 0.28-0.93), P=0.02]. And the patients in the EP + ICIs group also had longer PFS after matching [HR =0.42 (95% CI: 0.25-0.71), P=0.001]. No significant difference in the objective response rate (ORR) and treatment-related adverse events (trAEs) between the two groups was found (ORR: EP: 81.0%, EP + ICIs: 90.0%, P=0.14; trAEs: EP: grade 1-2, 49.3%; grade 3-4, 42.5%; EP + ICIs: grade 1-2, 40.0%; grade 3-4, 49.1%, P=0.62). The multivariate analysis presented that the history of immunotherapy [EP + PD-1 inhibitors: HR =0.33 (95% CI: 0.17-0.62), P=0.001; EP + PD-L1 inhibitors: HR =0.18 (95% CI: 0.06-0.60), P=0.005] and baseline lung immune prognostic index (LIPI) [intermediate: HR =2.22 (95% CI: 1.20-4.13), P=0.01; poor: HR =2.03 (95% CI: 0.71-5.77), P=0.18] were independent prognostic factors for PFS among all LS-SCLC cases. However, no independent prognostic factor was identified for OS. Our real-world data showed promising clinical efficacy and tolerable safety of first-line programmed cell death protein 1 (PD-1) inhibitors or programmed cell death ligand 1 (PD-L1) inhibitors in cases with LS-SCLC. Additionally, LIPI may serve as a valuable prognostic factor.

Efficacy and safety of thoracic radiotherapy in extensive-stage small-cell lung cancer patients receiving first-line immunotherapy plus chemotherapy: a propensity score matched multicentre retrospective analysis

BackgroundPlatinum-etoposide chemotherapy combined with immune checkpoint inhibitors (ICIs) has been recommended as the first-line standard treatment for extensive-stage small-cell lung cancer (ES-SCLC). However, the effect of thoracic radiotherapy (TRT) on these patients is still unknown. This study aimed to evaluate the efficacy and safety of TRT for ES-SCLC patients who responded to first-line ICIs and chemotherapy (CHT).MethodsPatients who received 4 to 6 cycles of ICIs and CHT as first-line therapy at three hospitals between 2018 and 2022 were included in the analysis. All patients were divided into two groups based on whether they received TRT as first-line treatment, and propensity score matching (PSM) was performed to ensure that the characteristics of two groups were well-balanced. The primary endpoints were overall survival (OS) and progression-free survival (PFS), and the secondary endpoint was toxic effects.ResultsA total of 276 patients were included, and the median follow-up time was 22.3 (range, 4.0-53.73) months. After PSM, 197 patients were further analysed, and 99 of whom received TRT. The baseline characteristics were well-balanced between patients in the TRT and non-TRT groups. There were significant differences in PFS between the TRT and non-TRT groups, with the median PFS of 10.76 and 7.63 months, respectively (P = 0.014). Significantly improved OS was observed in the TRT group (21.67 vs. 16.6 months, P = 0.009). In addition, the use of TRT was an independent prognostic factor for PFS and OS of ES-SCLC patients receiving ICIs plus CHT. In terms of safety, no significant increase of any grades adverse event (AE) (P = 0.874) and G3-4 AE (P = 0.909) was observed for patients receiving TRT. Radiation esophagitis, gastrointestinal and hematologic toxicities were the most common AEs in TRT group, which were tolerable. And high-dose radiotherapy was associated with higher incidence of pneumonitis.ConclusionAddition of TRT showed significant survival benefits and well tolerability in ES-SCLC patients receiving platinum-etoposide CHT and ICIs, which could be a feasible first-line treatment strategy for ES-SCLC patients.

DNA Methylation Signatures Correlate with Response to Immune Checkpoint Inhibitors in Metastatic Melanoma.

DNA methylation profiles have emerged as potential predictors of therapeutic response in various solid tumors. This study aimed to analyze the DNA methylation profiles of patients with stage IV metastatic melanoma undergoing first-line immune checkpoint inhibitor treatment and evaluate their correlation with a radiological response according to immune-related Response Evaluation Criteria in Solid Tumors (iRECIST). A total of 81 tissue samples from 71 patients with metastatic melanoma (27 female, 44 male) were included in this study. We utilized Illumina Methylation EPIC Beadchips to retrieve their genome-wide methylation profile by interrogating >850,000 CpG sites. Clustering based on the 500 most differentially methylated genes was conducted to identify distinct methylation patterns associated with immune checkpoint inhibitor response. Results were further aligned with an independent, previously published data set. The median progression-free survival was 8.5 months (range: 0-104.1 months), and the median overall survival was 30.6 months (range: 0-104.1 months). Objective responses were observed in 29 patients (40.8%). DNA methylation profiling revealed specific signatures that correlated with radiological response to immune checkpoint inhibitors. Three distinct clusters were identified based on the methylation patterns of the 500 most differentially methylated genes. Cluster 1 (12/12) and cluster 2 (12/24) exhibited a higher proportion of responders, while cluster 3 (39/45) predominantly consisted of non-responders. In the validation data set, responders also showed more frequent hypomethylation although differences in the data sets limit the interpretation. These findings suggest that DNA methylation profiling of tumor tissues might serve as a predictive biomarker for immune checkpoint inhibitor response in patients with metastatic melanoma. Further validation studies are warranted to confirm the efficiency of DNA methylation profiling as a predictive tool in the context of immunotherapy for metastatic melanoma.

Real-world data on the first-line immune checkpoint inhibitors or in combination with chemotherapy in older patients (aged ≥ 75 years) with advanced non-small cell lung cancer

PurposeThe purpose of this study is to investigate the efficacy and safety of immune checkpoint inhibitors (ICIs) or plus with chemotherapy in older patients. MethodsWe enrolled 110 older patients with non-small cell lung cancer (NSCLC ≥75 years) who received either chemotherapy alone (chemo), ICI plus chemotherapy (ICI + chemo), or ICI alone and ICI plus other therapies, which included anti-angiogenesis drugs or other novel ICI (ICIs). Patient characteristics, treatment response, survival, and toxicity were evaluated. ResultsIn total population, the ICIs group has the highest disease control rate (DCR 75%). There were no significant differences in progression-free survival (PFS) and overall survival (OS) among older patients between ICI + chemo and ICIs groups (PFS: 5.3 months vs. 5.5 months, p = 0.70, OS: 10.7 months vs. 20.3 months, p = 0.995). Meanwhile, we observed ICIs had a longer PFS and OS than chemo group (PFS: 3.9 months vs. 5.5 months, p = 0.01, OS: 10.9 months vs. 20.3 months, p = 0.05). Subgroup analysis showed that patients with programmed death ligand-1 (PD-L1) ≥ 1% had a distinct longer trend toward OS in ICIs group compared to ICI + chemo group (22.4 months vs. 10.7 months, p = 0.605), even though there was no significant difference. In terms of safety, ICIs was more tolerable and had a lower discontinuation rate than ICI + chemo group. ConclusionIn the real world, ICI + chemo is more likely to be discontinued due to adverse effects and does not significantly improve patient survival compared with ICIs treatment in total population and subgroup. Therefore, ICI alone or ICIs plus other therapies, such as anti-angiogenesis drugs or other novel ICI (ICIs) could be recommended for older cases with PD-L1 positive NSCLC.

Strategic treatment pause of first-line immune checkpoint inhibitor + VEGFR-tyrosine kinase inhibitor in patients with good or intermediate risk metastatic renal cell carcinoma (mRCC) in response at 1 year of treatment (SPICI-GETUG R05): A non-inferiority randomized clinical trial.

Strategic treatment pause of first-line immune checkpoint inhibitor + VEGFR-tyrosine kinase inhibitor in patients with good or intermediate risk metastatic renal cell carcinoma (mRCC) in response at 1 year of treatment (SPICI-GETUG R05): A non-inferiority randomized clinical trial.

East Asian patients who received immunotherapy-based therapy associated with improved survival benefit in advanced non-small cell lung cancer: An updated meta-analysis.

Immune checkpoint inhibitors (ICIs) combined with chemotherapy have been recommended as the standard treatment for advanced NSCLC patients without driver-gene mutations. However, there are different genetic characteristics and biological traits of tumors between non-East Asian (nEA) and East Asian (EA) patients with NSCLC, which may contribute to differences in the efficacy of ICIs in different ethnic populations. Previous findings regarding differences in the efficacy of ICIs among ethnic groups have been inconsistent. Therefore, we performed a meta-analysis by collecting published data to investigate the clinical outcomes of ICIs for EA NSCLC patients compared to nEA patients. Overall survival (OS) and progression-free survival (PFS) were used to access the difference in survival outcomes between the two populations. Subgroup analyses were performed based on the line of ICIs, the use of ICIs alone or in combination, and the type of ICIs. A total of 9826 NSCLC patients from 21 randomized controlled trials (RCTs) with 4064 EAs were included, which involved PD-1, PD-L1, and CTLA-4 inhibitors. EA NSCLC patients who received ICIs-based therapy were associated with significantly improved survival benefits in OS (p = 0.02) compared with nEA patients. Subgroup analysis indicated that EA patients receiving first-line ICIs showed significantly superior OS compared with nEA patients (p = 0.007). Chemo-ICIs treatment showed significant advantages in terms of OS (p = 0.002) and PFS (p = 0.02) among EA patients compared to nEA patients. In addition, PD-1 inhibitors were associated with improved OS among both EA patients and nEA patients compared with PD-L1 inhibitors. EA NSCLC patients who received ICIs-based therapy were associated with significantly improved survival benefits compared with nEA NSCLC patients. Earlier intervention with ICIs and combination treatment was more recommended for EA NSCLC patients. Moreover, PD-1 inhibitors are associated with prolonged survival among both EA and nEA patients.

The role of cytoreductive nephrectomy (CN) in the immune checkpoint inhibitor (ICI) era of metastatic renal cell carcinoma (mRCC): A systematic review and individual patient data (IPD) meta-analysis of 2319 patients.

425 Background: The combination of CN and systemic therapy has been established as one of the mainstay treatments for mRCC during the targeted therapy era. However, the role of CN in the ICI era remains unclear. Methods: We performed a systematic search of the MEDLINE, EMBASE, and Web of Science databases until August 26th, 2023, for studies comparing the combination of CN + ICI vs. ICI alone in mRCC. Using published Kaplan-Meier overall survival (OS) curves, we reconstructed IPD and then performed one-stage and two-stage meta-analyses with both parametric and non-parametric effect estimates. To account for immortal time bias, we performed 6-month and 12-month landmark analyses. We also performed a subgroup analysis according to ICI line of treatment. The risk of bias was assessed using the ROBINS-I tool. Results: We identified eight retrospective cohort studies fulfilling our inclusion criteria. Only two out of eight studies adjusted for immortal time bias and none of them adequately adjusted for all predetermined confounding factors. A total of 2319 (1264 CN + ICI and 1055 ICI only) patients were included in our analysis. Patients in CN + ICI group were younger (median age 58.2 vs. 62.8), had lower proportions of non-clear cell histology (8.8% vs. 15.2%), ≥2 metastatic sites (60.0% vs. 68.5%), liver metastases (9.0% vs. 21.9%), and poor IMDC risk score (21.7% vs. 43.9%), but had higher proportions of sarcomatoid histology (15.6% vs. 10.6%) and ≥2nd line treatment (38.1% vs. 17.1%). The combination of CN + ICI was associated with superior OS in the one stage (HR: 0.45, 95% CI 0.38–0.52), 6-month landmark (HR: 0.45, 95% CI 0.37–0.54), 12-month landmark (HR: 0.50, 95% CI 0.31–0.50) and two-stage (HR: 0.38, 95% CI 0.29–0.49) meta-analyses. Similarly, the combination of CN + ICI was associated with superior OS in the subgroup of patients receiving first-line ICI (HR 0.39, 95% CI: 0.30–0.48). Conclusions: The combination of CN + ICI for mRCC may be associated with superior OS compared to ICI alone, but currently available data are subject to selection bias. More studies, including well-designed randomized controlled trials, are needed to determine the role of CN in the ICI era. [Table: see text]

Updated pooled analyses of first-line anti-PD1/PD-L1 inhibitors plus chemotherapy in advanced esophageal squamous cell carcinoma.

366 Background: Advanced and metastatic esophageal squamous cell carcinoma (ESCC) patients have limited treatment options and poor prognosis. Recently, several studies demonstrated the clinical benefit of combining immune checkpoint inhibitors (ICI) and chemotherapy (CT), leading to its approval in the first-line setting. Since then, efforts have been made to identify the patients who may benefit the most or not from the combination of ICI plus CT. Methods: We searched PubMed, Scopus, and the Cochrane Library for randomized clinical trials investigating first-line ICI plus chemotherapy (CT) for advanced or metastatic ESCC patients. Outcomes of interest included: overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and OS according to gender, PD-L1 expression (&lt;1% / ≥1%), and PD-L1 CPS (&lt;10 / ≥10). We used I2 statistics to assess heterogeneity, and the fixed-effect model was used to pool studies. Results: Eight studies were included with 4,702 patients. Of them, most had an ECOG 0 or 1, and were younger than 65 years (62%), male (77%), and Asian (78%). Metastatic disease was diagnosed in 75% of patients. ICI plus CT was administered to 58%, and 43% received CT +/- placebo. Median follow-up ranged from 7.1 to 22.6 months. ICI plus CT significantly improved all efficacy outcomes compared to CT alone: decreasing the risk of death by 32% (HR for OS: 0.68; 95%CI 0.63-0.74; p&lt;0.00001); reducing the risk of progression or death by 38% (HR for PFS: 0.62; 95%CI 0.58-0.67; p&lt;0.00001); and increasing the objective response rate (risk difference: 0.17; 95%CI 0.14-0.20; p&lt;0.00001). A survival benefit was seen across all subgroup analyses, but it was significantly higher in patients with PD-L1 ≥1% compared to those with PD-L1 &lt;1% (reduction in the risk of death of 38% versus 23% respectively, p=0.03). OS was not significantly different between males versus females, or PD-L1 CPS≥10 versus CPS&lt;10. Conclusions: Our large systematic review and meta-analysis support the efficacy and survival benefit of ICI plus CT as first-line therapy for all ESCC patients, regardless of gender or PD-L1 expression.

Metastatic site and clinical outcome of patients with deficient mismatch repair metastatic colorectal cancer treated with an immune checkpoint inhibitor in the first-line setting.

55 Background: Nearly one-half of deficient mismatch repair (d-MMR) metastatic colorectal cancers (mCRC) demonstrate durable responses to immune checkpoint inhibitors (ICIs). Given preclinical data indicating that liver metastases sequester activated CD8+ T cells from systemic circulation, we examined clinical outcome by metastatic site. Methods: In a retrospective cohort of patients with d-MMR mCRCs treated at multiple centers in France (n=66), we sought to validate data from a U.S. cohort, and then performed pooled analysis (n=104). All patients received first-line ICI monotherapy. Metastatic site was analyzed in relationship to tumor response (RECIST version 1.1), and progression-free survival (PFS) by multivariable stratified Cox regression after adjustment for covariates. Results: Objective responses were achieved in 38/66 (58%) patients in the validation cohort. Best tumor response included 13 (20%) complete responses (CR), 25 (38%) partial responses (PR), 16 (25%) stable disease, and 11 (17%) progressive disease (PD). One-year and 5-year PFS rates were 73% and 67%, respectively; 18 (27%) patients progressed during immunotherapy. Best tumor response was attenuated in patients with liver metastasis ( P=0.03). Presence of liver metastasis, but not other sites, was associated with significantly poorer PFS after adjustment for covariates (HRadj 2.82; 95%CI, 1.08-7.39; Padj=0.03). In a pooled analysis, liver metastasis remained significantly and independently associated with poorer PFS (HRadj 3.18; 95%CI, 1.52-6.67; Padj=0.002) and with attenuated tumor best response (P=0.01). Conclusions: Metastasis to the liver, but not other sites, was validated as an independent factor associated with poorer response and survival after ICI treatment in d-MMR mCRCs. These data underscore the need for novel therapeutic strategies in these patients. [Table: see text]

Benchmarking mismatch repair testing for patients with cancer receiving immunotherapy.

179 Background: Mismatch repair deficiency (MMR-D) serves as a theranostic marker for directing immune checkpoint inhibitor (ICI) treatment across various cancer stages and tumor types. The College of American Pathologists endorses immunohistochemistry (IHC) as the primary approach for assessing mismatch repair (MMR) testing in colorectal (CRC) and endometrial cancer (EC) patients. An alternative method involves genetic evaluation of microsatellite instability (MSI). Previous studies have shown that resistance to immune checkpoint inhibitors (ICIs) may occur due to inaccurate MSI or MMR IHC status determination. Accurate assessment of MMR status is critical for treatment decision-making. Methods: We hypothesized that tumor-only next generation sequencing (NGS) for MMR mutation signature assessment for identification of MMR-D tumors is more sensitive than MMR IHC testing. Using a standardized, clinically validated, tumor-only NGS mutation signature pipeline in place in the Oncopanel assay at DFCI/BWH, we compared the concordance in MMR determination between NGS and IHC. We then evaluated a subset of ICI-treated patients to assess the clinical implications of these findings. Results: 1655 colorectal cancer (CRC) and endometrial carcinoma (EC) patients who had both NGS MSI (NGSd = deficient or NGSp = proficient) and MMR IHC (IHC- = absent or IHC+ = intact) assays performed were assessed. Discordant NGSd/IHC+ results were identified in 1% of CRC and 5% of EC cases that were IHC+. Importantly, patients with discordant NGSd/IHC+ (median OS: not reached [NR], 95% CI, 9.9 months-NR; median TTF: 44.4 months, 95% CI, 4.1-NR) and concordant NGSd/IHC- results, showed a similar overall survival and time to treatment failure with ICI treatment (p=non-significant) which contrasted with results for patients with concordant NGSp/IHC+ results (median OS: 14.9 months, 95% CI, 7.3-24.6, p-value 0.0025 and &lt; 0.0001; median TTF: 5.0 months, 95% CI, 3.2-7.3; p-value 0.0014 and &lt; 0.0001). Patients with EC or CRC and discordant NGSd/IHC+ results had better survival when treated with ICI-based regimens, compared to those who received non-ICI treatments (p= 0.054 and 0.017). Conclusions: In 2022, 151,030 new CRC and 65,950 new EC cases were diagnosed in the USA. Extrapolating our findings to this larger population, use of NGS mutational signature analysis instead of IHC would amount to about 1510 additional MMR-D CRC cases and 3297 additional MMR-D endometrial cases identified each year for whom first-line ICI therapy is preferred. Our findings support revisiting guideline recommendations for diagnostic testing of MMR to incorporate both IHC and targeted NGS tumor panel testing using sensitive and specific mutation signature calling algorithms. Larger prospective studies are warranted to confirm these findings in patients with mCRC and mEC treated with ICIs. Evaluation of this approach in other cancer types is also warranted.

Treatment patterns in metastatic bladder cancer in Japan: results of the CancerMPact® survey 2020.

Aim: To assess physician-reported treatment of metastatic bladder cancer in Japan. Methods: 76 physicians completed the CancerMPact® survey in July 2020, considering patients treated within 6months. Results: Physicians treated a mean of 38.1 patients per month. Of cisplatin-eligible and -ineligible patients, 97.6and 89.3%, respectively, received first-line platinum-based therapy, most commonly cisplatin plus gemcitabine (72.9%) and carboplatin plus gemcitabine (59.7%). 1.6and 5.6% received first-line immune checkpoint inhibitors, respectively. 48.4and 45.0%, respectively, progressed and received second-line therapy, most commonly with pembrolizumab (61.7%). Conclusion: In 2020, most patients with metastatic bladder cancer in Japan received first-line platinum-based chemotherapy; however, >50% received no subsequent treatment, highlighting the need for new treatment regimens to improve outcomes and maximize first-line treatment benefits.

Identification of non-actionable mutations with prognostic and predictive value in patients with advanced or metastatic non-small cell lung cancer.

Lung cancer is one of the most prevalent cancers and the leading cause of cancer death. Advanced non-small cell lung cancer (aNSCLC) patients frequently harbor mutations that impact their survival outcomes. There are limited data regarding the prognostic and predictive significance of these mutations on survival outcomes in the real-world setting. This observational retrospective study analyzed de-identified electronic medical records from the Flatiron Health Clinico-Genomic and FoundationCore® databases to identify patients with aNSCLC who initiated first-line immune checkpoint inhibitors (ICI; alone or in combination) or chemotherapy under routine care between 2016 and 2021. The primary objectives were to assess the prevalence of non-actionable mutations and to determine their association with overall survival (OS). Real-world progression-free survival (rwPFS) and real-world response (rwR) were investigated as secondary exploratory outcomes. Based on an assessment of 185 non-actionable mutations in 2999 patients, the most prevalent mutations were TP53 (70%), KRAS (42%), CDKN2A/B (31%), and STK11 (21%). STK11, KEAP1, and CDKN2A/B mutations were significantly associated with lower rwR, shorter rwPFS and OS. KRAS mutations were clinically associated with shorter rwPFS in CIT-treated patients. Subgroup analysis revealed that fast progressors were significantly more likely to harbor STK11, KEAP1, and CDKN2A/B mutations. Accordingly, long-term survivors (LTS) showed a significantly lower prevalence of these mutations. Our results provide evidence on the prognostic value of STK11, KEAP1, and CDKN2A/B mutations in patients with aNSCLC. Further research is required to better understand the implications of these findings on patient management and future trial design and treatment selection.

First-line immune checkpoint inhibitors in low programmed death-ligand 1-expressing population.

Introduction: Inhibitors of programmed cell death 1 (PD1) and its ligand (PDL1) have exhibited favorable long-term survival in many types of advanced-stage cancer and current approvals have to date been granted in certain tumour types irrespective of PD-L1 status. Methods: We extracted the following information: study sample size, trial period, cancer types, intervention of treatment, type of PD-L1 antibody, immunohistochemistry (IHC) scoring method, number and percentage of PD-L1 < 1% population, and median follow- up time. PD-L1 expression was defined as percentage of number of PD-L1-stained tumor cells (TPS), area of tumor infiltrated by PD-L1-stained immune cells (IPS), number of PD-L1-stained cells (tumor cells, lymphocytes and macrophages; CPS). Different trials used distinct method to define low PD-L1 expression. The risk of bias of the included trials was assessed by using the Cochrane risk of bias tool for RCTs. Results: Here, a total of 34 trials were included to extract individual patient data (IPD) to evaluate the survival benefit of first line PD1/PDL1 inhibitors vs. standard-of-care (SOC) in patients with PDL1 < 1%. In term of anti-PD-1/PD-L1 monotherapy, OS (HR = 0.90, 0.81-1.01) and PFS (HR = 1.11, 0.97-1.27) between PD-1/PD-L1 inhibitor group and SOC group were comparable. In term of anti-PD-1/PD-L1 combination therapy, PD-1/PD-L1 inhibitor group exhibited longer OS (median 19.5 months vs. 16.3 months; HR = 0.83, 0.79-0.88, p < 0.001) and PFS than those of SOC group (median 8.11 months vs. 6.96 months; HR = 0.82, 0.77-0.87, p < 0.001).Subgroup analysis showed that survival benefit was mainly observed in non-small cell lung cancer (NSCLC) (HROS = 0.74; HRPFS = 0.69; p < 0.001), small-cell lung cancer (SCLC) (HROS = 0.58, p < 0.001; HRPFS = 0.55, p = 0.030), esophageal squamous cell carcinoma (ESCC) (HROS = 0.62, p = 0.005; HRPFS = 0.79, p < 0.001), melanoma (HROS = 0.53, p < 0.001) and nasopharyngeal carcinoma (NPC) (HRPFS = 0.35, p = 0.013). Conclusion: Anti-PD-1/PD-L1 combinational therapy rather than monotherapy exhibit survival benefit in the low PD-L1 population in the first-line setting, and the survival benefit was mainly observed in specific tumor types.

Immunotherapy plus chemotherapy versus chemotherapy alone in the first-line treatment for advanced gastric cancer/gastroesophageal junction cancer: a real-world retrospective study.

Immunotherapy offers new hope for improved survival in patients with advanced gastric cancer. Although large randomized controlled trials (RCTs) have been conducted to explore the efficacy and safety of first-line immunotherapy plus chemotherapy versus chemotherapy alone for advanced gastric cancer, the results are not completely consistent. And the strict inclusion criteria of RCTs lead to limited extrapolation. Therefore, it is of great significance to continue to conduct real-world studies comparing the clinical efficacy and safety of immunotherapy combined withchemotherapy versus chemotherapy alone in advanced gastric cancer. This retrospective study included patients with HER-2 negative, unresectable advanced or recurrent gastric/gastroesophageal junction cancer (GC/GEJC) who received first-line immune checkpoint inhibitors (ICIs) in combination with chemotherapy or chemotherapy alone between January 1, 2018 to May 31, 2023. Progression-free survival (PFS), overall survival (OS), overall response rate (ORR), disease control rate (DCR) and adverse events (AEs) were compared between two groups. A total of 210 patients were enrolled in the combination treatment group (n=100) and chemotherapy alone group (n=110). After 12 months of follow-up, median PFS (mPFS) was 270 days (95%CI 177.510-362.490) in the chemotherapy alone group and 357 days (95%CI 250.103-463.897) in the combination treatment group (P<0.05). The median OS (mOS) was 14.9 months (95%CI 9.831-17.769) in the chemotherapy alone group and 15 months (95%CI 12.386-17.614) in the combination treatment group (P>0.05). There was no statistically significant difference in ORR between two groups (P=0.050). The DCR was 14.5% in the chemotherapy alone group and 38% in the combination treatment group (P<0.05). Subgroup analyses showed that primary tumor location of GEJC, ECOG PS of 1, without liver metastasis, and chemotherapy plus ICIs were associated with PFS benefit. Cox multivariate analysis showed that only surgery or not was correlated with patients' prognosis (P<0.05). Most of AEs were grade 1-2 and manageable. Compared with chemotherapy alone, first-line ICIs combined with chemotherapy in patients with advanced GC/GEJC could greatly prolong PFS, but OS was not significantly improved, and the AEs were manageable.

No detrimental association between antibiotic use and immune checkpoint inhibitor therapy: an observational cohort study comparing patients with ICI-treated and TKI-treated melanoma and NSCLC

BackgroundThe role of antibiotics in malignancies treated with immune checkpoint inhibitors (ICI) remains unclear. Several studies suggested a detrimental impact of antibiotic use on the response to ICI, but were...

Lipidomics reveals immune-related adverse events in NSCLC patients receiving immune checkpoint inhibitor

There is a lack of reliable biomarkers to predict and identify the risk of immune-related adverse events (irAEs) in non-small cell lung cancer (NSCLC) patients undergoing immune checkpoint inhibitor (ICI) treatment. This study aims to explore potential biomarkers using lipidomics to identify and predict the risk of irAEs in NSCLC patients receiving ICI treatment. This prospective study enrolled 94 NSCLC patients with IIIB/IV stage NSCLC who underwent first-line chemotherapy in combination with ICI treatment. The prediction cohort consisted of plasma samples collected from 60 patients before ICI treatment, and the occurrence of irAE was monitored within 6 months of initiating first-line ICI therapy. The validation cohort comprised 34 patients, with plasma samples obtained from 15 patients who did not develop irAE at 6 months of ICI treatment and plasma samples collected from 19 irAE patients at the onset of irAE. Through non-targeted lipidomics and semi-targeted lipid quantification analysis, we identify 11 differentially metabolized lipids and further screened these lipids with the area under the curve (AUC) > 0.7 to predict the occurrence of irAEs in NSCLC patients following ICI treatment. The results showed that the biomarker panel consisting of 9 lipids (LPC-18:2, PC-40:6, LPC-22:6, LPC-O-18:0, PS-38:0, PC-38:6, PC-37:6, PC-36:5,LPC-17:0) exhibited a good AUC of 0.859 in the prediction and 0.940 in the validation cohort phase of the receiver operating characteristic curve; The study utilizes plasma lipidomics to develop a rapid and effective prediction model for identifying irAEs in advanced NSCLC patients who treatment with first-line chemotherapy combined with immunotherapy.