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Immune checkpoint inhibitors (ICIs) have revolutionized the treatment paradigm of mismatch repair–deficient/microsatellite instability-high (MMMR-D/MSI-H) colorectal cancer (CRC). Unique molecular features of MMR-D/MSI-H CRC with frameshift alterations, which result in mutation-associated neoantigen (MANA) generation, create an ideal molecular framework for MANA-driven T-cell priming and antitumor immunity. These biologic characteristics of MMR-D/MSI-H CRC resulted in rapid drug development with ICIs for patients with MMR-D/MSI-H CRC. Observed deep and durable responses with the use of ICIs in advanced-stage disease have stimulated the development of clinical trials with ICIs for patients with early-stage MMR-D/MSI-H CRC. Most recently, neoadjuvant dostarlimab monotherapy for nonoperative management of MMR-D/MSI-H rectal cancer and neoadjuvant NICHE trial with nivolumab and ipilimumab for MMR-D/MSI-H colon cancer resulted in groundbreaking results. Although nonoperative management of patients with MMR-D/MSI-H rectal cancer with ICIs will potentially define our current therapeutic approach, therapeutic goals of neoadjuvant ICI therapy for patients with MMR-D/MSI-H colon cancer may differ given that nonoperative management has not been well established for colon cancer. Herein, we overview recent advancements in ICI-based therapies for patients with early-stage MMR-D/MSI-H colon and rectal cancer and elaborate on the future treatment paradigm of this unique subgroup of CRC.

IMbrave150 has established the superiority of atezolizumab plus bevacizumab over sorafenib in patients with unresectable hepatocellular carcinoma (HCC).We generated a prospectively maintained database including patients treated with atezolizumab plus bevacizumab for unresectable HCC across Europe, Asia and USA. Clinico-pathologic characteristics were assessed for their prognostic influence on overall survival (OS) and progression-free survival (PFS) in univariable and multivariate analyses. Overall response rate by RECIST v1.1 and treatment-related adverse events (TRAEs) per CTCAE v.5.0 were reported.Out of 433 patients, 296 Child-Pugh A and ECOG performance status01 patients received atezolizumab plus bevacizumab in first line and were included. Patients were mostly male (82.7%), cirrhotic (75%) with history of viral hepatitis (65.9%). Overall, 68.9% had Barcelona Clinic Liver Cancer C-stage HCC with portal vein tumour thrombosis (PVTT, 35%) and extrahepatic spread (EHS, 51.7%). After a median follow-up of 10.0 months (95% confidence interval (CI): 9.4-10.4), median OS and PFS were 15.7 (95% CI: 14.5-NE) and 6.9 months (95% CI: 6.1-8.3), respectively. In the response-evaluable patients (n = 273), overall response rate was 30.8%. Overall, 221 patients (74.6%) developed TRAEs, with 70 (23.6%) reporting grade 3 or higher TRAEs; 25 (8.4%) patients had bleeding events. OS was independently associated with baseline Albumin-bilirubin (ALBI) grade and PVTT. Shorter PFS was associated with AFP≥ 400 ng/ml, worse ALBI and presence of EHS.This global observational study confirms the reproducible safety and efficacy of atezolizumab plus bevacizumab in routine clinical practice. Within Child-Pugh-A criteria, the presence of PVTT and higher ALBI grade identify patients with poorer survival.

PURPOSE Subset analyses from phase III evaluation of epidermal growth factor receptor inhibition (EGFRi) suggest improved outcomes in patients with EGFR-amplified gastroesophageal adenocarcinoma (GEA), but large-scale analyses are lacking. This multi-institutional analysis sought to determine the role of EGFRi in the largest cohort of patients with EGFR-amplified GEA to date. PATIENTS AND METHODS A total of 60 patients from 15 tertiary cancer centers in six countries met the inclusion criteria. These criteria required histologically confirmed GEA in the metastatic or unresectable setting with EGFR amplification identified by using a Clinical Laboratory Improvement Amendments–approved assay, and who received on- or off-protocol EGFRi. Testing could be by tissue next-generation sequencing, plasma circulating tumor DNA next-generation sequencing, and/or fluorescence in situ hybridization performed by a Clinical Laboratory Improvement Amendments approved laboratory. Treatment patterns and outcomes analysis was also performed using a deidentified clinicogenomic database (CGDB). RESULTS Sixty patients with EGFR-amplified GEA received EGFRi, including 31 of 60 patients (52%) with concurrent chemotherapy. Across treatment lines, patients achieved a 43% objective response rate with a median progression-free survival of 4.6 months (95% CI, 3.5 to 6.4). Patients receiving EGFRi in first-, second-, and third-line therapy achieved a median overall survival of 20.6 months (95% CI, 13.5 to not reached [NR]), 9 months (95% CI, 7.9 to NR), and 8.4 months (7.6 to NR), respectively. This survival far exceeded the 11.2-month (95% CI, 8.7 to 14.2) median overall survival from first-line initiation of non-EGFRi therapy in patients with EGFR-amplified GEA in the CGDB. Despite this benefit, analysis of the CGDB (January 2011-December 2020) suggests that only 5% of patients with EGFR-amplified GEA received EGFRi. CONCLUSION Patients with EGFR-amplified GEA derive significant benefit from EGFRi. Further prospective investigation of EGFRi in a well-selected patient population is ongoing in an upcoming trial of amivantamab in EGFR and/or MET amplified GEA.

PURPOSE Compared with people living without HIV (PWOH), people living with HIV (PWH) and cancer have traditionally been excluded from immune checkpoint inhibitor (ICI) trials. Furthermore, there is a paucity of real-world data on the use of ICIs in PWH and cancer. METHODS This retrospective study included PWH treated with anti–PD-1- or anti–PD-L1-based therapies for advanced cancers. Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Objective response rates (ORRs) were measured per RECIST 1.1 or other tumor-specific criteria, whenever feasible. Restricted mean survival time (RMST) was used to compare OS and PFS between matched PWH and PWOH with metastatic NSCLC (mNSCLC). RESULTS Among 390 PWH, median age was 58 years, 85% (n = 331) were males, 36% (n = 138) were Black; 70% (n = 274) received anti–PD-1/anti–PD-L1 monotherapy. Most common cancers were NSCLC (28%, n = 111), hepatocellular carcinoma ([HCC]; 11%, n = 44), and head and neck squamous cell carcinoma (HNSCC; 10%, n = 39). Seventy percent (152/216) had CD4+ T cell counts ≥200 cells/µL, and 94% (179/190) had HIV viral load CONCLUSION Among PWH, ICIs demonstrated differential activity across cancer types with no excess toxicity. Safety and activity of ICIs were similar between matched cohorts of PWH and PWOH with mNSCLC.

Cancer is classically considered a disease of aging, with over half of all new cancer diagnoses occurring in patients over the age of 65 years. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, yet the participation of older adults with cancer in ICI trials has been suboptimal, particularly at the extremes of age. Despite significant improvement in treatment response and an improved toxicity profile when compared with conventional cytotoxic chemotherapies, many cancers develop resistance to ICIs, and these drugs are not free of toxicities. This becomes particularly important in the setting of older adults with cancer, who are generally frailer and harbor more comorbidities than do their younger counterparts. Immunosenescence, a concept involving age-related changes in immune function, may also play a role in differential responses to ICI treatment in older patients. Data on ICI treatment response in older adult with cancers remains inconclusive, with multiple studies revealing conflicting results. The molecular mechanisms underlying response to ICIs in older cancer patients are poorly understood, and predictors of response that can delineate responders from non-responders remain to be elucidated. In this review, we explore the unique geriatric oncology population by analyzing existing retrospective datasets, and we also sought to highlight potential cellular, inflammatory, and molecular changes associated with aging as potential biomarkers for response to ICIs.

BackgroundIn patients with cirrhosis, portal hypertension increases intestinal permeability, dysbiosis, and bacterial translocation, promoting an inflammatory state that can lead to the progression of liver disease and development of hepatocellular carcinoma (HCC). We aimed to investigate whether beta blockers (BBs), which can mediate portal hypertension, conferred survival benefits in patients treated with immune checkpoint inhibitors (ICIs).MethodsWe conducted a retrospective, observational study of 578 patients with unresectable HCC treated with ICI from 2017 to 2019 at 13 institutions across three continents. BB use was defined as exposure to BBs at any time during ICI therapy. The primary objective was to assess the association of BB exposure with overall survival (OS). Secondary objectives were to evaluate the association of BB use with progression-free survival (PFS) and objective response rate (ORR) according to RECIST 1.1 criteria.ResultsIn our study cohort, 203 (35%) patients used BBs at any point during ICI therapy. Of these, 51% were taking a nonselective BB. BB use was not significantly correlated with OS (hazard ratio [HR] 1.12, 95% CI 0.9-1.39, P = 0.298), PFS (HR 1.02, 95% CI 0.83-1.26, P = 0.844) or ORR (odds ratio [OR] 0.84, 95% CI 0.54-1.31, P = 0.451) in univariate or multivariate analyses. BB use was also not associated with incidence of adverse events (OR 1.38, 95% CI 0.96-1.97, P = 0.079). Specifically, nonselective BB use was not correlated with OS (HR 0.94, 95% CI 0.66-1.33, P = 0.721), PFS (HR 0.92, 0.66-1.29, P = 0.629), ORR (OR 1.20, 95% CI 0.58-2.49, P = 0.623), or rate of adverse events (OR 0.82, 95% CI 0.46-1.47, P = 0.510).ConclusionIn this real-world population of patients with unresectable HCC treated with immunotherapy, BB use was not associated with OS, PFS or ORR.

Aims: The authors present a systematic review/meta-analysis of the impact of BRAF mutations on prognosis and immune checkpoint inhibitor (ICI) response in deficient mismatch repair/microsatellite instability-high colorectal cancer. Methods: Hazard ratios for overall survival and odds ratios for objective response rate to ICIs were calculated in BRAF-mutated versus BRAF wild-type patients. Results: After screening, nine and three studies, respectively, were included for analysis of prognosis (analysis A) and ICI response (analysis B). Analysis A showed worse overall survival in BRAF-mutated compared with BRAF wild-type stage I–IV patients (hazard ratio: 1.57; 95% CI: 1.23–1.99), and analysis B showed no difference in objective response rate (odds ratio: 1.04; 95% CI: 0.48–2.25). Conclusion: BRAF mutations are associated with worse overall survival but not differential response to ICIs in deficient mismatch repair/microsatellite instability-high colorectal cancer.

PURPOSE To develop recommendations involving targeted therapies for patients with advanced gastroesophageal cancer. METHODS The American Society of Clinical Oncology convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice. RESULTS Eighteen randomized controlled trials met the inclusion criteria for the systematic review. RECOMMENDATIONS For human epidermal growth factor receptor 2 (HER2)–negative patients with gastric adenocarcinoma (AC) and programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥ 5, first-line therapy with nivolumab and chemotherapy (CT) is recommended. For HER2-negative patients with esophageal or gastroesophageal junction (GEJ) AC and PD-L1 CPS ≥ 5, first-line therapy with nivolumab and CT is recommended. First-line therapy with pembrolizumab and CT is recommended for HER2-negative patients with esophageal or GEJ AC and PD-L1 CPS ≥ 10. For patients with esophageal squamous cell carcinoma and PD-L1 tumor proportion score ≥ 1%, nivolumab plus CT, or nivolumab plus ipilimumab is recommended; for patients with esophageal squamous cell carcinoma and PD-L1 CPS ≥ 10, pembrolizumab plus CT is recommended. For patients with HER2-positive gastric or GEJ previously untreated, unresectable or metastatic AC, trastuzumab plus pembrolizumab is recommended, in combination with CT. For patients with advanced gastroesophageal or GEJ AC whose disease has progressed after first-line therapy, ramucirumab plus paclitaxel is recommended. For HER2-positive patients with gastric or GEJ AC who have progressed after first-line therapy, trastuzumab deruxtecan is recommended. In all cases, participation in a clinical trial is recommended as it is the panel's expectation that targeted treatment options for gastroesophageal cancer will continue to evolve. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .

Simple Summary The investigation of predictive and prognostic markers is pivotal in patients affected by hepatocellular carcinoma treated with immune-checkpoint-inhibitors. Inflammation has a central role in hepatocellular carcinoma development and progression; however, its role in influencing outcomes in the context of immunotherapy has not been fully elucidated yet. In the following study, we investigated the prognostic role of bloods derived inflammatory markers and we found that they predict survival and response of patients treated with immunotherapy for advanced hepatocellular carcinoma. Abstract Systemic inflammation is a hallmark of cancer, and it has a pivotal role in hepatocellular carcinoma (HCC) development and progression. We conducted a retrospective study including 362 patients receiving immune check-point inhibitors (ICIs) across three continents, evaluating the influence of neutrophiles to lymphocytes ratio (NLR), platelets to lymphocytes ratio (PLR), and prognostic nutritional index (PNI) on overall (OS), progression free survival (PFS), and radiologic responses. In our 362 patients treated with immunotherapy, median OS and PFS were 9 and 3.5 months, respectively. Amongst tested inflammatory biomarkers, patients with NLR ≥ 5 had shorter OS (7.7 vs. 17.6 months, p < 0.0001), PFS (2.1 vs. 3.8 months, p = 0.025), and lower objective response rate (ORR) (12% vs. 22%, p = 0.034); similarly, patients with PLR ≥ 300 reported shorter OS (6.4 vs. 16.5 months, p < 0.0001) and PFS (1.8 vs. 3.7 months, p = 0.0006). NLR emerged as independent prognostic factors for OS in univariate and multivariate analysis (HR 1.95, 95%CI 1.45–2.64, p < 0.001; HR 1.73, 95%CI 1.23–2.42, p = 0.002) and PLR remained an independent prognostic factor for both OS and PFS in multivariate analysis (HR 1.60, 95%CI 1.6–2.40, p = 0.020; HR 1.99, 95%CI 1.11–3.49, p = 0.021). Systemic inflammation measured by NLR and PLR is an independent negative prognostic factor in HCC patients undergoing ICI therapy. Further studies are required to understand the biological mechanisms underlying this association and to investigate the predictive significance of circulating inflammatory biomarkers in HCC patients treated with ICIs.

Background and Rationale: Immune checkpoint inhibitor (ICI) therapy is an expanding therapeutic option for hepatocellular carcinoma (HCC). Antibiotics (ATB) taken prior to or early during ICI therapy can impact immunotherapy efficacy across indications; however, the effect of ATB is undefined in HCC. Methods: In a large international cohort of 450 ICI recipients from Europe, North America, and Asia, we categorized patients according to timing of ATB focusing on exposure within −30 to +30 days from ICI (early immunotherapy period [EIOP]). EIOP was evaluated in association with overall survival (OS), progression-free survival (PFS), and best radiologic response using RECIST 1.1 criteria. Results: Our study comprised mostly cirrhotic (329, 73.3%) males (355, 79.1%) with a Child-Turcotte Pugh class of A (332, 73.9%), receiving ICI after 1 therapy line (251, 55.9%) for HCC of Barcelona clinic liver cancer stage C (325, 72.4%). EIOP (n = 170, 37.9%) was independent of baseline clinicopathologic features of HCC and correlated with longer PFS (6.1 vs. 3.7 months, log-rank p = 0.0135). EIOP+ patients had similar OS, overall response, and disease control rates (DCRs) compared to EIOP. The effect of EIOP persisted in landmark time analyses and in multivariable models, confirming the independent predictive role of EIOP in influencing PFS following adjustment for covariates reflective of tumor burden, liver function, and ICI regimen administered. In patients receiving programmed cell death-1 receptor/ligand inhibitors monotherapy, EIOP was also associated with higher DCRs (61.4% vs. 50.9%, p = 0.0494). Conclusions: Unlike other oncological indications, ATB in the 30 days before or after ICI initiation is associated with improved benefit from immunotherapy, independent of disease and treatment-related features. Evaluation of the immune microbiologic determinants of response to ICI in HCC warrants further investigation.

Immune checkpoint inhibitors (ICIs) became one of the most revolutionary cancer treatments, especially in melanoma. While they have been proven to prolong survival with lesser side effects compared to chemotherapy, the accurate prediction of response remains to be an unmet gap. Thus, we aim to identify accurate clinical and transcriptomic biomarkers for ICI response in melanoma. We also provide mechanistic insight into how high-performing markers impose their effect on the tumor microenvironment (TME). Clinical and transcriptomic data were retrieved from melanoma studies administering ICIs from cBioportal and GEO databases. Four machine learning models were developed using random-forest classification (RFC) entailing clinical and genomic features (RFC7), differentially expressed genes (DEGs, RFC-Seq), survival-related DEGs (RFC-Surv) and a combination model. The xCELL algorithm was used to investigate the TME. A total of 212 ICI-treated melanoma patients were identified. All models achieved a high area under the curve (AUC) and bootstrap estimate (RFC7: 0.71, 0.74; RFC-Seq: 0.87, 0.75; RFC-Surv: 0.76, 0.76, respectively). Tumor mutation burden, GSTA3, and VNN2 were the highest contributing features. Tumor infiltration analyses revealed a direct correlation between upregulated genes and CD8+, CD4+ T cells, and B cells and inversely correlated with myeloid-derived suppressor cells. Our findings confirmed the accuracy of several genomic, clinical, and transcriptomic-based RFC models, that could further support the use of TMB in predicting response to ICIs. Novel genes (GSTA3 and VNN2) were identified through RFC-seq and RFC-surv models that could serve as genomic biomarkers after robust validation.

The gut microbiome refers to microorganisms and their genetic material influencing local and systemic inflammation. Inflammation is known to contribute to cancer development, progression, and treatment. Evidence suggests that modulating the gut microbiome may affect responses to various cancer therapies. The gut microbiota has been suggested to have an impact on immunotherapy efficacy, especially the currently widely used immune checkpoint inhibitors in various malignancies. Microbial interventions like fecal microbiota transplantation, various probiotics, or even antibiotics can increase or decrease the tumor’s sensitivity to immunotherapy. However, not all tumors react in the same manner, highlighting the tumor microenvironment heterogeneity across tumor types and the influence this has on the crosstalk between the microbiome and therapy outcomes. In this study, we intend to review the association between the gut microbiota and immunotherapy response in cancer patients and the factors regulating this interaction.

Background Several systemic agents have been approved for use in advanced hepatocellular carcinoma (aHCC). However, it is unclear which treatment is superior in either the first- or second-line settings due to the paucity of head-to-head comparative trials. Therefore, we have conducted a systematic review and network meta-analysis for the indirect comparison of the systemic agents in the first line and second line settings. Methods Randomized clinical trials evaluating systemic agents in first and second line settings in aHCC from inception to April 2020 were identified by searching PubMed, EMBASE, and Cochrane Databases and the annual ASCO and ESMO conferences from 2017 to 2020. Studies in English reporting clinical outcomes including overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) were included. The primary outcomes of interest were pooled hazard ratios (HR) of OS and pooled odds ratios (OR) of ORR in first line studies and pooled HR of PFS and OR of ORR for second line studies. Additionally, OS for second line agents were reported in the qualitative analysis. Results Overall, first line studies comprised 8335 patients (13 studies) and second line studies comprised 4612 patients (11 studies). In the first line setting, atezolizumab plus bevacizumab was associated with the highest OS benefit over sorafenib (HR 0.58, 95% CI, 0.42-0.80; P-score 0.993). Additionally, lenvatinib was associated with the greatest ORR benefit (OR 3.34, 95% CI, 2.17-5.14; P-score 0.080) in the first line setting. In the second line setting, cabozantinib was associated with the highest PFS benefit over placebo (HR 0.44, 95% CI, 0.29-0.66; P-score 0.854) as well as the highest ORR benefit (OR 9.40, 95% CI, 1.25-70.83, P-score, 0.266). Conclusion Atezolizumab plus bevacizumab appears to have superior efficacy among first line agents whereas cabozantinib appears to be superior in the second line setting. Further studies are warranted to determine whether the type of prior therapy received affects the efficacy of subsequent second line therapy.

To provide an overview of the key findings from studies in upper gastrointestinal, hepatobiliary, pancreas, and colorectal malignancies presented at ASCO GI 2022.We reviewed the abstracts presented at ASCO GI 2022. The studies highlighted were selected by the authors based on their significant discoveries and potential impact on clinical practice.This year's hybrid ASCO-GI symposium (2022) introduced many promising new treatment strategies in GI oncology, with several changes in clinical practice for patients with advanced hepatocellular carcinoma (HCC), cholangiocarcinoma, and metastatic colorectal cancer (CRC).

BackgroundImmune checkpoint inhibitors (ICIs) have revolutionized treatment of advanced hepatocellular carcinoma. Integrated use of transarterial chemoembolization (TACE), a locoregional inducer of immunogenic cell death, with ICI has not been formally assessed for safety and efficacy outcomes.MethodsFrom a retrospective multicenter dataset of 323 patients treated with ICI, we identified 31 patients who underwent >1 TACE 60 days before or concurrently, with nivolumab at a single center. We derived a propensity score-matched cohort of 104 patients based on Child-Pugh Score, portal vein thrombosis, extrahepatic metastasis and alpha fetoprotein (AFP) who received nivolumab monotherapy. We described overall survival (OS), progression-free survival (PFS), objective responses according to modified RECIST criteria and safety in the multimodal arm in comparison to monotherapy.ResultsOver a median follow-up of 9.3 (IQR 4.0–16.4) months, patients undergoing multimodal immunotherapy with TACE achieved a significantly longer median (95% CI) PFS of 8.8 (6.2–23.2) vs 3.7 (2.7–5.4) months (log-rank 0.15, pConclusionsTACE can be safely integrated with programmed cell death 1 blockade and may lead to a significant delay in tumor progression and disease downstaging in selected patients.

Background: Given the inconclusive evidence behind the safety and efficacy of immune checkpoint inhibitors re-challenge, herein, we have conducted a systematic review and meta-analysis to synthesize available data. Results/methodology: PubMed, Embase, Cochrane Database, and ASCO and ESMO were searched for studies published from conception to March 2020. Pooled incidence of recurrent immune-related adverse events (irAEs), objective response rates, and odds ratios for irAEs at initial versus re-treatment were calculated. Overall, 437 patients (ten studies) were included. Incidence of any grade, grade 3/4, and steroid-requiring recurrent irAEs were 47%, 13.2%, and 26% respectively. Objective response rate in previous non-responders was 12.5% (5.8–24.8%). Odds ratio for severe irAEs was 0.28 (0.11–0.72) and steroid-requiring irAEs 0.19 (0.06–0.56). Discussion/conclusion: This analysis suggests that immune checkpoint inhibitors re-challenge is safe and potentially efficacious.

BackgroundPARP inhibitors (PARPi) have recently been approved for various malignancies based on the results of several clinical trials. However, these trials have mostly recruited patients with germline BRCA mutations, and it is unclear whether PARPi have similar efficacy in patients with somatic BRCA mutations. Our study aimed to determine the efficacy of PARPi in patients with somatic BRCA mutations.MethodsWe performed a meta-analysis comparing overall response rate to PARPi in patients harboring somatic versus germline BRCA mutations. We looked at studies including somatic and germline mutations in BRCA patients that received PARPi.ResultsAfter screening and removing duplicates, 18 studies met our criteria for including both somatic and germline BRCA mutations. Only 8 studies reported response rates for both somatic and germline BRCA mutations.In those studies, 24 out of 43 patients with somatic BRCA mutations (55.8%), and 69 out of 157 (43.9%) patients with germline BRCA patients had a response to therapy to PARPi. This difference was not statistically significant (p = 0.399).In all five studies that reported progression-free survival, there was no obvious difference in outcomes between somatic versus germline BRCA patients, however a precise statistical analysis could not be performed.ConclusionOur meta-analysis and systematic review of the literature indicates similar response rates of PARPi therapy in patients with somatic and germline BRCA mutations. Investigation of use of PARPi therapy in a broader patient population, and the inclusion of somatic BRCA mutations in further clinical trials is paramount in improving therapeutic options for our patients.

Background/aim Previous association studies have linked the functional miR-146a SNP rs2910164 with risk of digestive system cancer; however, the results of these studies are inconclusive and inconsistent. The objective of the following study is to provide an up-to-date and comprehensive meta-analysis of the association of miR-146a rs2910164 and digestive system cancer risk. Patients and methods We searched the PUBMED/MEDLINE and Cochrane/EBM databases. The following inclusion criteria were used for the study selection: i) Case-control studies; ii) studies with reported allelic frequency/genotype data; and iii) studies with reported association with risk of a digestive system cancer. The following exclusion criteria were used: Review article, meta-analysis, case report and case series; studies evaluating relationships of miR-146a rs2910164 with outcomes other than cancer incidence, such as cancer morbidity or mortality. Study quality was assessed using the Newcastle-Ottawa Scale and publication bias assessed graphically and numerically using Begg's funnel plot and Egger's regression test and rank test. Outcome measure was the pooled odds ratios under the allelic frequency, dominant, recessive, and over-dominant models. Subgroup analysis was conducted for country of study origin. Results No association of miR-146a rs2910164 with overall risk of digestive system cancer was identified. However, subgroup analysis showed an association with overall risk in the European population in the over-dominant model. Furthermore, miR-146a rs2910164 was associated with reduced risk of gastric cancer in the dominant model (pooled odds ratio=0.91, 95% confidence intervaI=0.83-0.99), increased risk of colorectal cancer under the recessive model and reduced risk of colorectal cancer under the over-dominant model in the European population. No significant within-study or publication biases were detected. Conclusion miR-146a rs2910164 was not associated with overall risk of digestive system neoplasms. However, the GG genotype and the CC genotype may be linked to higher risk of gastric cancer and colorectal cancer, respectively; and the CG genotype may be protective against digestive system neoplasms overall in the European population, especially for colorectal cancer.

9-ING-41 (elraglusib) is a potent and selective GSK-3 inhibitor that has shown anti-tumor activity in patient-derived xenograft models and phase1/2 clinical studies in patients (pts) with advanced solid tumors. Preclinical studies have demonstrated that elraglusib downregulates PD-1, TIGIT and LAG-3, upregulates expression of MHC class I proteins in tumor cells from “cold tumors”, and shows synergy when combined with PD-1 blockade in mouse xenografts. Clinical activity has been observed both as a single agent and in combination with standard of care chemotherapies in several advanced cancer histologies. Here we present initial ‘omics data from our phase 1/2 study (NCT03678883; ACT1801) spanning >100 pts with advanced cancer evaluating both single agent and chemotherapy combinations. The patients (pts) included in this study received elraglusib as a ≥3rd line therapy for advanced disease. Most pts with melanoma treated with elraglusib monotherapy (8/9; 89%) stayed on study for >2 cycles. One patient with melanoma refractory to checkpoint inhibitors achieved a confirmed and durable CR. Clinical benefit was also observed among pts with colorectal cancer with 4/12 (33.3%) pts treated with monotherapy and 12/15 (80%) that received elraglusib plus irinotecan rechallenge stayed on study >2 cycles reaching median overall survival of 106 and 211 days, respectively. Based on emerging in vivo and in vitro results demonstrating that elraglusib activates T and NK cells promoting anti-tumor immune responses, we hypothesize immunomodulation by elraglusib may be contributing to anti-tumor immune response in the 1801 trial. We have acquired TCRseq and RNAseq profiles of PBMC samples from seven patients in 1801 during the first two weeks of treatment with elraglusib monotherapy. In these pts, reduced TCR clonality was observed and specific TCR clonotypes expanded after treatment, indicating T cell activation and expansion. These pts also showed changes in PBMC populations during elraglusib therapy as measured by immune deconvolution of PBMC RNAseq. Taken together, these data support a novel, previously unrecognized immunomodulatory mechanism of action for elraglusib and could provide rationale for future clinical development of elraglusib in pts with advanced malignancies. Additional analysis from TCRseq, immune profiling and cytokine analysis from expanded cohort of pts is ongoing. Citation Format: Taylor Weiskittel, Joseph McDermott, Daniel Billadeau, Hu Li, Anwaar Saeed, Devalingam Mahalingam, Solmaz Sahebjam, Pamela Munster, Ludimila Cavalcante, Frank J. Giles, Andrew Mazar, Benedito Carneiro. Multimodal mechanism of action of the GSK-3 inhibitor 9-ING-41 (elraglusib) includes an immunomodulatory component: preliminary results from the 1801 phase 1/2 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT222.

Introduction Fluoropyrimidines (FP) are cornerstone drugs in the treatment of gastrointestinal (GI) malignancies. Cardiotoxicity secondary to an FP chemotherapy is a serious complication. There are no standardized guidelines on the treatment of FP induced cardiotoxicity which may result in interruption and even discontinuation of life saving treatment. We present our experience in FP rechallenge using a novel outpatient regimen based on our “up-front” triple agent antianginal protocol. Methods We report the retrospective study of the patients with suspected FP induced cardiotoxicity. Patients meeting the criteria were selected by C3OD (curated cancer clinical outcomes database) at Kansas University Medical Center (KUMC). We identified all patients with gastrointestinal malignancies who had suspected FP induced cardiotoxicity from January 2015 to March 2022. We then included the patients who were rechallenged with planned fluoropyrimidine regimen utilizing the three drug KU-protocol. We utilized a novel regimen by repurposing the already FDA-approved anti-anginal drugs in a manner that minimizes the risk of hypotension and bradycardia. Results In this retrospective study, 10 patients with suspected fluoropyrimidine induced cardiotoxicity were included from January-2015 to March-2022 at KUMC. Out of 10 patients who were rechallenged utilizing KU-protocol, eight patients (80%) were able to complete the previously planned fluoropyrimidine regimen. None of the patients required ER visits or hospital admission due to cardiac symptoms during the rechallenge utilizing the KU-protocol. Conclusions Utilizing our novel outpatient regimen, we have successfully and safely allowed re-challenge of FP chemotherapy with good tolerability and completion of the intended course of chemotherapy without recurrent morbidity.

249 Background: An estimated 85% of CRC are microsatellite stable (MSS) and this population has limited response to immune checkpoint inhibitors (ICIs). Biomarkers are needed to identify responders. Although pembrolizumab received FDA universal approval for chemorefractory cancers with tissue TMB-H > 10 mut/Mb, it is not effective across all TMB-H cancers. We aim to identify TMB-H/MSS CRC patients that derive benefit from ICIs through analysis of circulating tumor DNA (ctDNA). Methods: We retrospectively queried Guardant Health database (2020-2022) for patients with advanced CRC who had ctDNA NGS (Guardant360, Redwood City, CA) as part of routine clinical care. The assay covers a 1Mb panel for TMB that counts synonymous and non-synonymous somatic SNVs and indels to calculate a TMB score. Co-mutations were evaluated for MSS cancers with plasma TMB-H; ≥20mut/Mb vs those with low TMB (TMB-L; < 20mut/Mb). RAS- mutated signature was defined as those harboring an activating somatic alteration in KRAS, NRAS, or BRAF. Statistical significance was calculated using Fisher’s exact test. Results: We identified 6412 CRC patients: 11% (711) TMB-H/MSS (median age 64), 69% (4426) TMB-L/MSS (median age 62), 3% MSI-H, and 17% unevaluable. When compared to TMB-L/MSS, patients with TMB-H/MSS had a significantly higher frequency of select genetic mutations, including TP53, APC, KRAS, EGFR, and PIK3CA (p < 0.001). Treatment-naïve TMB-H/MSS cancers had a higher frequency of ARID1A (p = 0.05) and TERT (p = 0.02) alterations, while those post therapy progression had higher frequency of KRAS (p = 0.02), EGFR (p < 0.001), and MAP2K1 (p = 0.002) alterations. A total of 556 (78%) CRC patients in the TMB-H/MSS cohort harbored a RAS-mutated genetic signature. Of those, 432 (78%) belonged to the post therapy progression group, likely representing adaptive clones post anti-EGFR therapy. While RAS-mutated tumors had a higher prevalence of PIK3CA (p = 0.001) and SMAD4 (p = 0.007) co-alterations, RAS-wildtype ones carried a higher frequency of ERBB2 (p = 0.068) alterations. Conclusions: We describe the genomic landscape of patients with plasma TMB-H/MSS CRC. A clinical cohort of TMB-H/MSS CRC patients identified by ctDNA and treated with ICIs will be presented.

166 Background: Recently, there has been a breakthrough in the treatment and disease control of HER-2 positive mCRC using Trastuzumab (TRA) +Tyrosine Kinase inhibitor (TKI) regimens and regimens with trastuzumab based antibody drug conjugates (ADCs). Methods: A total of 14 randomized controlled trials and single arm clinical trials were collected from PubMed, Cochrane library, and Embase. 7 trials were excluded for being duplicate, irrelevant or because of lack of response from the trial researchers. Data from the remaining 7 articles was extracted either from the full publication or from researchers for undergoing studies. Trials using similar drug combinations were added up and results were reported cumulatively. Results: The data demonstrate an ORR of 30% or greater with the ADC, TRA deruxtecan or TRA+Tucatinib regimen with the Tucatinib combination being the most efficacious (38.10%), followed closely by the Deruxtecan ADC (36.99%). Promising disease control rate (DCR) was observed with all the combinations with TRA-Ematasin + Pertuzumab leading the charts (77.40%). TRA-Lapatinib provided the longest PFS (16.75 months) followed by TRA-Tucatinib (8.2 months) (Table). Most common treatment related adverse events (AEs) were fatigue, nausea, vomiting, diarrhea and dermatitis. More nausea/vomiting reported with TRA-deruxtecan (64.4%), while more diarrhea reported with TRA-lapatinib (81%) and TRA-tucatinib (52.3%). Dermatitis was reported mostly with TRA-lapatinib (44%) and TRA-tucatinib (17.4%). Conclusions: Our analysis shows that combination treatment with TRA-Deruxtecan and TRA-tucatinib are associated with the highest ORR and DCR in HER2+ mCRC. Long term data are needed to define clinical efficacious based on survival endpoints.[Table: see text]

592 Background: Tumor-agnostic approvals of immune checkpoint inhibitors (ICI) include deficient mismatch repair/microsatellite instability high (dMMR/MSI-H) and high tumor mutational burden (TMB) while in cancer like metastatic gastroesophageal cancers, ICI use has been predicated on PD-L1 expression. ICI are increasingly used for metastatic HCC, but without required markers. We aimed to examine the genomic landscape of HCC in context of PD-L1 expression, and to determine clinical responses to ICI in this setting. Methods: Next-generation sequencing of DNA (592 or WES) and RNA (WTS) was tested at Caris Life Sciences (Phoenix, AZ). PD-L1 expression was tested by IHC (SP142) and compared as high (2+,5%), low (1-2,1%) and negative (0). dMMR/MSI-H was tested by IHC/NGS and TMB-High was defined as ³10 mutations/MB. QuantiSEQ was used to estimate the tumor microenvironment. X2/Fisher-Exact were used and significance was determined as P-value adjusted for multiple comparison ( Q < 0.05). Real-world overall survival (rwOS) was obtained from insurance claims and calculated from tissue collection to last contact; time-on-treatment (TOT) was calculated from start to finish of ICI treatments. Results: Overall, 17.7% of HCC expressed PD-L1 by IHC; 79/1306 (6.1%) had high expression. The overall prevalence of dMMR/MSI-H was 0.2%; TMB was high in 5.1%. PD-L1 expression was not associated with MSI-H or high TMB. When comparing tumors that are PD-L1 high vs. negative vs. low, expression of several immuno-oncologic (IO) markers LAG3 (median TPM: 2.4, 0.8, 0.5), CTLA-4 (2.9, 1.2, 0.5), IDO1 (4.2, 1.3, 0.6) and others, as well as T-cell inflamed and IFNg scores all decreased significantly with PD-L1 (all q

TPS267 Background: The prognosis of patients with mCRC is poor, with a 5-year survival rate of 14% (American Cancer Society 2020). Patients who have progressed after front-line chemotherapy have limited treatment options. Regorafenib or trifluridine-tipiracil are approved for patients in the third- or later-line setting, but survival benefit is limited. While immune checkpoint inhibitor (ICI) therapy is approved (nivolumab ± ipilimumab, and pembrolizumab) in patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) mCRC, the MSI-H phenotype is limited to ~5% of mCRC patients. In phase 1/2 trials, ICIs in combination with VEGFR2 multi-kinase inhibitors (MKIs) have demonstrated encouraging clinical activity in mCRC, including atezolizumab and durvalumab (ICIs) in combination with the MKI cabozantinib, with data suggesting a greater benefit in RAS wild-type (wt) vs mutant (mut) disease (Abrams TA, et al. ASCO GI 2022:Abs 121; Saeed A, et al. ASCO GI 2022:Abs 135). XL092 is a novel MKI, targeting MET, VEGFR2, and the TAM kinases AXL and MER; the relatively short half-life (~21 hours) of XL092 is favorable for once-daily (QD) dosing and dose modification to manage tolerability. STELLAR-303 is a phase 3 study evaluating the efficacy and safety of XL092 + atezolizumab versus regorafenib in patients with previously treated RASwt or RASmut mCRC. Methods: STELLAR-303 (XL092-303; NCT05425940) is a global, open-label, randomized phase 3 study. Eligible patients are ≥18 years old and have mCRC that is measurable per RECIST v1.1, are documented not to have MSI-H or dMMR disease, and have an ECOG performance status of 0–1 and adequate organ function. RAS and MSI/dMMR status must be determined by a tissue-based analysis. Patients must have progressed during/after or be intolerant to standard-of-care treatments for mCRC; prior regorafenib, trifluridine/tipiracil, or PD-L1/PD-1 ICIs are not allowed. Patients are randomized 1:1 to XL092 100 mg PO QD + atezolizumab 1200 mg IV Q3W or to regorafenib 160 mg PO QD (21 days of 28-day cycle); randomization is stratified by geographic region (Asia vs other), RAS status (wt vs mut), and liver metastases (yes/no). The study plans to enroll 600 patients (400 RASwt and 200 RASmut). The primary endpoint is overall survival in the RASwt population, with additional efficacy endpoints of progression-free survival, objective response rate, and duration of response per RECIST v1.1 by investigator; efficacy endpoints will also be assessed in the overall study population and in patients with RASmut mCRC. Additional endpoints will assess safety, quality of life, changes in biomarkers, pharmacokinetics, immunogenicity of atezolizumab, and healthcare utilization. Enrollment is ongoing. Clinical trial information: NCT05425940 .

Hepatocellular carcinoma (HCC) is one of the deadliest and most common malignancies of the liver. Considering the rich immune background of carcinogenesis in HCC, efforts have been focused on further understanding the role of the immune system in tumor suppression and promotion. The utilization of immunotherapy in HCC has led to encouraging results that has translated to longer survival and better quality of life among patients. The development of novel HCC-tailored regimens such as vaccine therapy and adoptive cellular therapy coupled with a deeper understanding of biomarkers predictive of the response to immunotherapy will lead to better treatment outcomes.

BackgroundImmune checkpoint inhibitors (ICIs) are approved by the U.S. Food&Drug Administration in over 17 tumor types. Older adult patients make up about a quarter of all cancer patients but are historically understudied in cancer clinical trials. ICIs are associated with immune-related adverse events (irAEs), which may be particularly morbid for older adult patients with underlying comorbidities and impaired functional status. In this study, we provide insight into the real-world safety and efficacy of ICIs among older adult patients (≥80 years) with cancer.MethodsThis is a multicenter, international retrospective study of tumor-agnostic older adult patients with cancer treated with single-agent ICIs between 2010–2019 from 18 academic centers in the U.S. and Europe. A cohort of 928 patients aged ≥80 years during treatment with ICI was assembled and analyzed to evaluate clinical outcomes and irAE patterns in older adult patients treated with single-agent ICIs.ResultsMedian age at ICI initiation was 83.0 years (range 75.8–97.0). Most patients (86.9%) were treated with anti-PD-1 therapy. Among the full cohort, the three most common tumors were non-small cell lung cancer (NSCLC, 37.2%,n=345), melanoma (35.5%,n=329), and genitourinary (GU) tumors (16.5%,n=153). Objective response rates for patients with NSCLC, melanoma, and GU tumors were 32.2%, 39.3%, and 26.2%, respectively. Median progression-free survival (PFS) was 6.7 months (95%CI, 5.2–8.6) for patients with NSCLC, 11.1 months (95%CI, 8.9–16.0) for patients with melanoma, and 6.0 months (95% CI, 5.0–10.7) for patients with GU malignancy. Median overall survival (OS) was 10.9 months (95%CI, 8.6–13.1) for patients with NSCLC, 30.0 months (95%CI, 23.6–46.4) for patients with melanoma, and 15.0 months (95%CI 9.1–25.4) for GU patients (Figure 1A-C). Within histology-specific cohorts (NSCLC, melanoma and GU), clinical outcomes were similar across age subgroups (90). Among all patients (N=928), 41.3% experienced ≥1 irAE(s), including 12.2% reported to be grade (G)3–4. No irAE-related deaths occurred. The median time to irAE onset was 9.8 weeks; 57% occurred within the first 3 months after ICI initiation. ICI was discontinued due to irAEs in 16.1% patients. There was no significant difference in the rate of irAEs among patients age ConclusionsICIs are effective and generally well-tolerated among older patients with cancer. However, ICI discontinuation due to irAE is more frequent with increasing age.

Systemic inflammation is a key risk factor for hepatocellular carcinoma (HCC) progression and poor outcomes. Inflammatory markers such as the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) may have prognostic value in HCC treated with standard of care atezolizumab plus bevacizumab (Atezo-Bev). We conducted a multicenter, international retrospective cohort study of patients with unresectable HCC treated with Atezo-Bev to assess the association of NLR and PLR with overall survival (OS), progression-free survival (PFS), and objective response rates. Patients with NLR ≥ 5 had a significantly shorter OS (9.38 vs. 16.79 months, p < 0.001) and PFS (4.90 vs. 7.58 months, p = 0.03) compared to patients with NLR < 5. NLR ≥ 5 was an independent prognosticator of worse OS (HR 2.01, 95% CI 1.22–3.56, p = 0.007) but not PFS. PLR ≥ 300 was also significantly associated with decreased OS (9.38 vs. 15.72 months, p = 0.007) and PFS (3.45 vs. 7.11 months, p = 0.04) compared to PLR < 300, but it was not an independent prognosticator of OS or PFS. NLR and PLR were not associated with objective response or disease control rates. NLR ≥ 5 independently prognosticated worse survival outcomes and is worthy of further study and validation.

Microsatellite instability‑high/deficient mismatch repair colorectal cancer (MSI‑H/dMMR CRC) is a molecular subtype characterized by high‑frequency mutations within DNA mismatch repair genes. Defects in the DNA mismatch repair machinery lead to subsequent frame‑shift mutations, resulting in the generation of frame‑shift peptides that serve as neoantigens. This has translated into exquisite sensitivity to immune checkpoint inhibitors (ICIs) and a significant clinical benefit from immune therapies in this patient population. The present article provides a comprehensive review of the advances in the field of immune therapies for MSI‑H/dMMR metastatic CRC, with a focus on the major randomized clinical trials that led to Food and Drug Administration approval of specific ICIs for this population, a detailed review of the molecular background responsible for tumor response, as well as the mechanisms of resistance to ICI therapy. Finally, ongoing investigations of other immunotherapeutic strategies to address and overcome the challenges that currently limit response and long‑term response to ICIs were presented.

Gemcitabine plus cisplatin remains the standard first-line systemic therapy for advanced cholangiocarcinoma and offers a median survival of approximately 1 year. No standard regimens beyond the first line and no targeted or immunotherapy agents are approved yet in this disease. Development of molecular targeted therapy in this heterogenous and relatively rare malignancy continues to be a challenging area. The rapidly growing precision medicine efforts have uncovered the underlying mutational landscape of this lethal disease and paved the way for molecularly oriented clinical trials. The early results from such trials like those exploring IDH and FGFR2 derangements have highlighted its promising potential as alternative therapeutic options. Additionally, advances in cancer immunology have identified certain correlates as biomarkers of response to immune modulatory approaches. For instance, the presence of tumor DNA mismatch repair (MMR) deficiency and/or microsatellite instability (MSI), in 5% to 10% of cholangiocarcinoma, is associated with high rates and durability of responses to immune checkpoint blockade. Beside checkpoint inhibitors, other types of immune therapeutics like peptide and dendritic cell-based vaccines and adoptive cell therapies have been developed and are undergoing active evaluation in cholangiocarcinoma. With further research effort, the integration of tumor molecular profiling in trials exploring targeted immunotherapy will lead to better understanding of the predictive role of various molecular and immune biomarkers and ultimately shine the horizon for this patient population.

Purpose The development of treatment-related adverse events (trAE) correlates favorably with clinical outcomes in multiple studies of patients receiving immune checkpoint inhibitors (ICI); however, this relationship is undefined in patients with hepatocellular carcinoma (HCC). Patients and methods We derived a cohort of 406 patients with unresectable/advanced HCC receiving ICI therapy as part of international clinical trials submitted to the US Food and Drug Administration (FDA) in support of marketing applications. We tested whether the development of clinically significant trAE (i.e. graded ≥2, trAE2) predicted improved overall survival (OS), progression-free survival (PFS), and objective response rates (ORR) following ICI. We established an international consortium of 10 tertiary-care referral centres located in Europe (n = 67), United States (US, n = 248) and Asia (n = 42) to validate this association. Results In the FDA dataset of 406 patients, 325 (80%) with Barcelona Clinic Liver Cancer (BCLC) stage C HCC mostly treated with ICI monotherapy (n = 258, 64%), trAE2 were reported in 228 patients (56.1%). Development of trAE2 was associated with longer OS (16.7 versus 11.2 months) and PFS (5.5 versus 2.2 months) and persisted as an independent predictor of outcome after adjusting for viral aetiology, gender, Child-Pugh class, BCLC stage, AFP levels, ECOG-PS, ICI regimen (mono/combination therapy) and receipt of corticosteroid therapy. In a multi-institutional cohort of 357 patients with similar characteristics mostly treated with ICI monotherapy (n = 304, 85%), the development of trAE2 was associated with longer OS (23.3 versus 12.1 months) and PFS (9.6 versus 3.9 months). TrAE2 were confirmed predictors of improved OS (HR 0.43; 95% CI:0.25–0.75) and PFS (HR 0.48; 95% CI: 0.31–0.75), with multivariable analyses confirming their association with outcome independent of clinicopathologic features of interest. Additional time-varying multivariable analyses also indicated that trAEs were associated with a decreased risk of progression (HR 0.56, 95% CI: 0.46–0.67) in the FDA dataset and death (HR 0.55; 95% CI: 0.32–0.95) in the multi-institutional dataset. Conclusion Development of trAE2 correlates with improved outcomes in patients with HCC receiving ICI in clinical trials and in routine practice. Prospective studies aimed at understanding the underlying immunologic foundations of such relationships are warranted to identify predictive biomarkers of toxicity and response.

4010 Background: Bema is a first-in-class humanized IgG1 monoclonal antibody selective for fibroblast growth factor receptor 2b (FGFR2b). Results from the FIGHT study showed an improvement in progression-free survival (PFS), overall survival (OS), and overall response rate with the addition of bema to mFOLFOX6 in FGFR2b+, non HER2+ GC. This report provides updated analyses of patient (pt) subgroups, additional data on ocular adverse events (AEs), and the median OS result for the bema+mFOLFOX6 combination. Methods: Pts were treated with mFOLFOX6 and randomized 1:1 to bema (15 mg/kg) or placebo (pbo) every 2 weeks (wks) with an additional 7.5 mg/kg bema/pbo dose on cycle 1 day 8. Eligible pts had unresectable locally advanced or metastatic GC not known to be HER2+, and had FGFR2b overexpression (any 2+/3+ staining) by centrally performed immunohistochemistry (IHC+) or FGFR2 amplification by circulating tumor DNA (ctDNA+). Results: Of the 155 pts who were randomized, 149 (96%) were FGFR2b+ by IHC, 26 (17%) by ctDNA, and 20 (13%) by both. 96 pts (62%) had tumors with FGFR2b IHC 2+/3+ in ≥10% of tumor cells. The proportion of pts with ctDNA+ or with ≥5% or ≥10% tumor cells FGFR2b+ by IHC was similar across geographic regions. Bema showed a benefit vs pbo across pre-specified subgroups including age, gender, geographic region, and prior adjuvant therapy. Patients with FGFR2b overexpression irrespective of ctDNA gene amplification benefited from bema: IHC+/ctDNA- PFS hazard ratio (HR) 0.63 (95% CI 0.4, 0.99), OS HR 0.66 (95% CI 0.39, 1.12); IHC+/ctDNA+ PFS HR 0.15 (95% CI 0.02, 1.18), OS HR 0.10 (95% CI 0.01, 0.83). Frequency and severity of ocular AEs were similar for the overall enrolled population and for pts with ≥5% or ≥10% FGFR2b+ by IHC. Corneal AEs in the bema arm increased in frequency and severity over time; 10.5% (0% G3) wk 1-8 vs 44.1% (15.3% G3) wk ≥25. Following discontinuation of study treatment, subsequent anti-cancer therapy was balanced in the 2 arms (bema 53%; pbo 49%). With a median follow-up of 12.5 months (mo), the bema arm had a median OS of 19.2 mo (95%CI: 13.6, not reached) vs 13.5 mo (95%CI: 9.3, 15.9) for placebo (HR:0.60 95%CI: 0.38, 0.94) for the intent-to-treat population; for the subset of pts with ≥10% FGFR2b+ by IHC, the median OS for bema was 25.4 mo (95%CI: 13.8, not reached) vs 11.1 mo (95% CI: 8.4, 13.8) for placebo (HR: 0.41 95%CI: 0.23, 0.74). Conclusions: The addition of bema to mFOLFOX6 improved the OS of 1L FGFR2b+ GC pts vs mFOLFOX6 alone. Outcomes favored bema across pre-specified subgroups. Pts with overexpression of FGFR2b even without ctDNA amplification demonstrated a benefit from the addition of bema to mFOLFOX6, supporting further evaluation of bema in tumors with FGFR2b overexpression without the requirement for gene amplification. Clinical trial information: NCT03694522.

Simple Summary Biomarker research for immunotherapy in gastroesophageal cancer has been rapidly developing in parallel with the growing use of immune checkpoint inhibitors. Although several biomarkers have been approved for use in the clinical setting they are imperfect in predicting responses. Several novel biomarkers are currently being studied and demonstrate potential for application in the clinical setting. Future research should determine the ability of immunotherapy biomarkers to predict response and synergy in combination therapy. Abstract Advanced gastroesophageal cancer (GEC) has a poor prognosis and limited treatment options. Immunotherapy including the anti-programmed death-1 (PD-1) antibodies pembrolizumab and nivolumab have been approved for use in various treatment settings in GEC. Additionally, frontline chemoimmunotherapy regimens have recently demonstrated promising efficacy in large phase III trials and have the potential to be added to the therapeutic armamentarium in the near future. There are currently several immunotherapy biomarkers that are validated for use in the clinical setting for GEC including programmed death ligand-1 (PD-L1) expression as well as the tumor agnostic biomarkers such as mismatch repair or microsatellite instability (MMR/MSI) and tumor mutational burden (TMB). However, apart from MMR/MSI, these biomarkers are imperfect because none are highly sensitive nor specific. Therefore, there is an unmet need for immunotherapy biomarker development. To this end, several biomarkers are currently being evaluated in ongoing trials with some showing promising predictive potential. Here, we summarize the landscape of immunotherapy predictive biomarkers that are currently being evaluated in GEC.

TPS4195 Background: The efficacy of chemotherapy is often compromised due to poor penetration of drugs in solid tumors. The tumor microenvironment, which is characterized by dense extracellular matrix‐rich stroma that creates a physical barrier to penetration of anti‐cancer drugs, is especially pronounced in Pancreatic Ductal Adenocarcinoma (PDAC) and in peritoneal metastases from Colorectal/Appendiceal Adenocarcinoma. CEND‐1 is a tumor‐penetrating peptide (scientifically also known as iRGD) that has preclinically demonstrated to enhance the tumor penetration of chemotherapy agents through binding and activation of alphav-integrins and neuropilin‐1 (NRP-1). The 2-step mechanism leads to a higher delivery and concentration of chemotherapeutics selectively in the tumor, while sparing normal tissue. Hence CEND-1 therapy has the potential to improve the efficacy of anti‐cancer therapies and reduce side effects through increased tumor access, specificity, and sensitivity. We hypothesize that CEND‐1 may become a powerful adjuvant that safely enhances standard anti‐neoplastic therapy in the neoadjuvant setting for the above populations. Methods: A safety lead-in 6-9 patients (Phase Ib) will be followed by an open label, single arm, parallel (3 cohorts) Phase IIa study. A total of 50 patients (20 PDAC, 15 colorectal/appendiceal with peritoneal metastases, 15 oligometastatic colorectal) will be enrolled. A starting CEND-1 dose of 3.2 mg/kg in combination with the standard doses of FOLFIRINOX (+/- Panitumumab if RAS/RAF wild type) will be used for the safety lead-in. CEND-1 dose will be lowered for Phase IIa if > 1/6 patients experienced DLTs. Participants enrolled will receive standard doses of FOLFIRINOX q2w +/- Panitumumab q2w 6mg/kg IV q2w (14-day cycles) for Cycles 1-3. After a subsequent research biopsy, the CEND-1 + chemotherapy combo will be continued at RP2D q2w for cycles 4-6, followed by CEND-1 +/- Panitumumab ̃72h prior to resection. Assessment of tumor response using RECIST v1.1 will be done every 3 cycles. Up to 10 patients may receive Panitumumab. Eligible Pts are untreated, newly diagnosed, resectable/borderline resectable PDAC or colorectal/appendiceal adenocarcinoma with peritoneal metastases or oligometastases eligible for cytoreductive surgery, as determined by multidisciplinary evaluation. Inclusion criteria also include ECOG PS 0-1, adequate organ function, measurable or evaluable disease. Primary objectives are safety and biological activity of CEND‐1. Secondary objectives include ORR, R0 resection rate, DFS, OS. Exploratory objectives include pathologic response, tissue immune response, EGFR expression, tumor tissue-to-plasma concentration of Panitumumab pre and post CEND-1 treatment. Enrollment to the CENDIFOX trial is currently ongoing. Clinical trial information: NCT05121038.

2633 Background: Older patients (pts) with cancer are underrepresented in registrational clinical trials for immune checkpoint inhibitor (ICI) therapies. There may be relevant differences in the makeup of the tumor microenvironment (TME) and in genomic signatures of cancer in older pts. This analysis explores differences in the genomic makeup of common cancers and their TME in pts ≥ 80 years (yr) of age, compared to younger pts. Methods: Next-generation sequencing of DNA (592 gene panel, NextSeq or whole-exome sequencing, NovaSeq) and RNA (whole transcriptome sequencing, NovaSeq) was performed for non-small cell lung carcinoma (NSCLC; n = 19,891), melanoma (MEL n = 2,899), and renal cell carcinoma (RCC; n = 1,333) pt samples submitted to a CLIA-certified laboratory (Caris Life Sciences, Phoenix, AZ). PD-L1 expression was assessed by immunohistochemistry (IHC), and high tumor mutational burden (TMB-H) was defined as ≥10 mut/Mb. Pts were stratified into age subgroups of ≥80 and < 80 yr for comparison of DNA damage response (DDR) gene alterations, gene expression profiling, and TME analysis (MCP-counter; Becht, 2016). P-values were adjusted for multiple hypotheses testing (Benjamini-Hochberg) unless noted as exploratory. Results: Pts ≥80 yr accounted for 16.0%, 19.9% and 5.3% of NSCLC, MEL and RCC pts, respectively. Compared to pts < 80 yr, NSCLC and MEL pts ≥80 yr had similar DDR gene mutation rates, while BRCA1 mutations were more common in MEL pts ≥80 yr (2.1 vs 0.8%; exploratory- p < 0.05). NSCLC ≥80 yr TMEs had increased abundance of fibroblasts (1.09-fold, p < 0.01), dendritic cells (1.07-fold, p < 0.01) and macrophages (1.04-fold, p < 0.01), and MEL≥80 yr TMEs had fewer infiltrating T-lymphocytes (0.87-fold, p = 0.02). Increased expression of immune checkpoint (IC) genes PDCDL1G2 (PD-L2; 1.11-fold), HAVCR2 (TIM-3; 1.11-fold ), and CD80/86 (1.07/1.08-fold, p < 0.05) was seen in NSCLC pts ≥80 yr, while IL-6 expression was decreased (0.88-fold; p < 0.05). The largest change in IC gene expression was for IL-6 (1.24-fold, p = 0.78) in MEL, and GZMB (0.56-fold ; p = 0.17) in RCC ≥80 yr. TMB-H was less common in NSCLC (29.7 vs 36.5%, p < 0.001) and more common in MEL pts ≥80 yr (65.7 vs 49.0%, p < 0.01), and PD-L1 (IHC-SP142, ≥2+|5%) expression was less frequent in RCC pts ≥80 yr (9.1 vs 19.4%, exploratory p < 0.05). Profiling of glutamine and glucose metabolism-related genes revealed increased SLC38A5 (1.17-fold; p < 0.0001) and decreased G6PC (0.65-fold, p < 0.01) expression in NSCLC ≥80 yr. While not statistically significant, MEL and RCC pts ≥80 yr had opposite trends for SLC38A5 and G6PC expression. Conclusions: Our analysis provides new insights to immune landscape of NSCLC, MEL, and RCC pts ≥80 yr. Differential gene expression and TME composition changes in this population suggest unique, cancer-specific therapeutic opportunities, and a potential to explore biomarkers of response to ICIs.

4571 Background: p53 target and cell cycle inhibitor CDKN1A/p21(WAF1) was initially not found to be mutated in cancer. TCGA analysis identified CDKN1A mutations are present but rare with frequencies of < 1%, but enrich in bladder cancer (̃8%). Truncating WAF1 mutations are associated with sensitivity to cisplatin and are associated with truncating Rb mutations in bladder cancer (RW+). We hypothesized RW+ bladder cancers may represent a unique subgroup with sensitivity to therapeutics. Methods: A total of 1104 urothelial tumors underwent molecular profiling at Caris Life Sciences (Phoenix, AZ) utilizing NGS of DNA (592 Gene Panel, NextSeq, or WES, NovaSeq) and RNA (NovaSeq, WTS). Wilcoxon, Fisher’s exact were used for statistical significance (p value without and q value with multi comparison correction). Immune cell fraction (QuanTIseq) and pathway analysis (ssGSEA) were assessed by mRNA analysis. Immune epitope prediction was performed using the NetMHCpan v4.0 method in the Immune Epitope Database. Results: Concurrent truncating mutation (frameshift, nonsense) for RB1 and WAF1 were detected in 47 tumors (RW+, 4.25%) and tumors with wild-type status for both RB1 and WAF1 genes were classified as RW- group (54.08%). Tumors harboring only one RB1 or WAF1 mutation were excluded for further analysis. When compared to RW- group, RW+ tumors showed lower mutation rate of TP53 (54.5% vs 80.9%, q < 0.05), ARID1A (23.5% vs 38.3%, p < 0.05), and PIK3CA (18.4% vs 31.9%, p < 0.05). Interestingly, RW+ was mutually exclusive with FGFR3 mutation (18.0% vs 0%, p < 0.05). We further evaluated RNA expression of DNA repair and checkpoint arrest pathways. Notably, E2F pathway (Normalized Enrichment Scores, NES: 0.89 vs 0.86, q < 0.01) and DNA G2M checkpoint (NES: 0.89 vs 0.86, q < 0.01) were found to be the most enriched in RW+ with respect to RW- group. In addition, mRNA levels of FANCC/A, CHEK1, WEE1, CDC25A/C, PALB2 and BRCA1/2 were found to be overexpressed in RW+ group (q < 0.05). RW+ tumors also displayed a distinct immunological profile: They were associated with higher PD-L1 status (63.8% vs 37.3%, q < 0.01), higher median TMB (11 mut/Mb vs 8 mut/Mb, q < 0.01) and with less frequent loss of heterozygosity for HLA-DPA1 (51.1% vs 66.7%, p < 0.05), with more high-binding-affinity neoantigen load (4.78 vs 3.89, p < 0.05) to MHC proteins, consistent with the significantly more myeloid dendritic cells in in RW+ group (0.3 vs 0.04, q < 0.001). Conclusions: Concurrent truncating mutation in RB1 and WAF1 (RW+) bladder carcinomas have fewer p53, ARID1A, and PIK3CA mutations but are enriched for E2F targets, G2/M checkpoint genes, FANCC/A, CHEK1, WEE1, CDC25A/C, PALB2 and BRCA1/2 and have a distinct immunological profile. The findings suggest therapeutic strategies for RW+ bladder cancers including Chk1/Wee1, PARP inhibitors, -/+ immunotherapy that may impact on clinical outcomes.

2649 Background: PLWH and ca are inadequately represented in clinical trials evaluating ICI especially in the setting of low CD4 counts (ct) and elevated HIV viral loads (VL). We assembled an international cohort of PLWH and ca treated with ICI to evaluate toxicity profiles and clinical outcomes. Methods: We retrospectively collected data on 204 PLWH and ca receiving ≥ 1 cycle of ICI between 2015-2021 at 14 academic medical centers in the US and Europe. Immune-related adverse events (irAEs) were graded per the Common Terminology Criteria for Adverse Events (CTCAE) V5.0. Baseline CD4 ct, CD8 ct and HIV VL were collected within 3 months (mo) of ICI initiation when available. Fisher’s exact test was performed to compare categorical variables. Median (med) Overall Survival (OS) and Objective Response Rate (ORR) were calculated for 186 pts treated in the metastatic (met) setting. Results: Among 204 PLWH treated with ICI, 174 (85%) were cis-gender males. 61 (31%) were Black and 34 (18%) were Hispanic/Latinx. Pts were treated with pembrolizumab (n=93), nivolumab (n=71), atezolizumab (n= 20), nivolumab and ipilimumab (n=13), durvalumab (n=6), or avelumab (n=1). Med number of prior lines of systemic therapy was 1 (range: 0-5). Among pts with available baseline data, 36/133 (27%) had CD4 ct

e16254 Background: Neo-adjuvant therapy (NAT) and associated pathologic complete response (pCR) rates have correlated with improved survival in resected pancreatic ductal adenocarcinoma (PDAC). In this study, we explored the relationship between pathologic response, peri-operative therapy, and survival, especially the impact of change in adjuvant therapy in patients with no/poor path response to NAT. Methods: Retrospectively reviewed 66 PDAC patients who received NAT ± radiation and underwent resection at KU Cancer Center between 2011-2022. We compared DFS and OS between Path Responders vs Non-Responders based on standard Tumor Regression Scores from pathology reports. A subanalysis was performed in path non-responders based on switch in adjuvant therapy (AT) versus not. Results: Patient characteristics are summarized in the table. Among 66 PDAC patients, 50 (75.8%) achieved a path response (G0-G2), 16 (24.2%) experienced no/poor path response (G3). Of the 50 pts who achieved a path response, 4 (8.0%) had a complete path response (pCR; G0), 5 (10%) marked response (G1), 41 (82%) moderate response (G2). Median DFS (mDFS) was 17.3 months (95% CI: 12.7-22.4) in Path Responders vs 15.9m (95% CI: 9.6-35.8) in Non-Responders [p=0.59]. Median OS (mOS) was 32.9m (95% CI: 23.4-41.5) vs 27.7m (95% CI: 15.2-38.2), respectively [p=0.39). A sub-analysis in the Non-Responders (n=16) based on switch in AT (n=8) vs not (n=3), revealed mDFS 16.4m (95% CI: 9.6-41.8) when AT was switched vs mDFS 11.3m (95% CI: 5.9-16.6) when AT was not switched [p=0.24]; and mOS 30.6m (95% CI: 15.7-60.3) vs 17.2 months (95% CI: 6.7-27.7), respectively [p=0.18]. Conclusions: Our study found no statistical difference in DFS and OS between Pathologic Responders and Non-Responders to neo-adjuvant therapy. However, a sub-analysis within Pathologic Non-Responders revealed a longer DFS and OS after switching adjuvant therapy without reaching statistical significance, likely due to small sample size. Our findings warrant validation in a larger cohort as switch in adjuvant therapy could potentially change the treatment landscape for Pathologic Non-Responders.[Table: see text]

6542 Background: Access to health care including clinical trials (CT) leading to paradigm-changing cancer treatments are critical for high quality cancer care and equity in society. In this report, we highlight methods in accruing to ETCTN wherein underrepresented rural, low-income, and racial minorities comprise >50% of enrollment. Methods: University of Kansas Cancer Center (KUCC) is one of eight National Cancer Institute (NCI) designated cancer centers awarded CATCH-UP.2020 (CATCH-UP), a congressionally mandated P30 supplement to enhance access for minority/underserved populations to ETCTN precision medicine CT. KUCC catchment area is 23% rural by Rural Urban Continuum Codes (RUCC); almost 90 % of counties are designated primary care HPSA’s (Health Professional Shortage Areas). KUCC Early Phase and Masonic Cancer Alliance (rural outreach network) partnered to operationalize CATCH-UP. We engaged disease-focused champion investigators in disease working groups and MCA physicians who selected scientifically sound CT that fit catchment area needs. Patient and Investigator Voices Organizing Together, a patient research advocacy group provided practical feedback. MCA navigator coordinated recruitment. Telehealth was used for rural patients that would have a significant distance to travel just to be screened. Results: CATCH-UP was initiated in September 2020. Twenty-eight CT were activated, many in community sites. Average activation time was 81 days. Delays were mainly from CT amendments. KUCC enrolled the first patient in the CATCH-UP program. In 6 months, we met accrual requirements (24/year, 50% minorities). During first year, we enrolled 47 (>50% minorities), an increase of 680% from our average accrual of 6/year (>50% minorities) in ETCTN through Early Drug Development Opportunity Program (2016-2020). To date, we have enrolled 61, 54% from rural, HPSA, race and other minorities. Although the proportion of minorities did not change but remained high, this funding allowed us to substantially increase the number of patients from a catchment area with high proportion of geographically and socioeconomically underserved minorities given access to early phase CT through ETCTN. Conclusions: Amid COVID-19 pandemic, the NCI CATCH-UP program and methods we used allowed access to novel therapies for rural, medically underserved, and other minority groups. Funded by NIH: 3P30CA168524-09S2.

4142 Background: The composition of the tumor microenvironment (TME) in PDACs is more heavily driven by mutant (mt) KRAS than any other cancer. How genomic alterations of PDAC including KRAS status affect the immune cell (IC) landscape remains unclear. Thus, we characterized IC types and the prevalence of immuno-oncologic (IO) biomarkers in PDAC by genomic and transcriptomic analysis, and investigated associations of mt KRAS with IC estimates in the TME. Our findings were compared to our previous study in CRC. Methods: A total of 4,142 PDAC and 3,727 CRC with KRAS- mts were analyzed using next-generation DNA sequencing (NextSeq, 592 gene panel or NovaSeq, WES), IHC, and whole transcriptome RNA sequencing (NovaSeq) (Caris Life Sciences, Phoenix, AZ). MSI/MMR was tested by FA, IHC and NGS. TMB-H was classified based on a cut-off of >10 mutations per MB. ICs were estimated by QuantiSeq (Finotello 2019, Genome Medicine) or MCP counter (Betcht 2016, Genome Biology). Significance was determined by X2 and Fisher-Exact and p-adjusted for multiple comparisons (q+ & CD8+ T cells, T-reg, NK, myeloid dendritic and endothelial cells compared to KRAS wt. In CRC, a similar pattern was observed but more pronounced in PDAC. Immune-regulatory markers, were among multiple genes downregulated in KRAS-mt PDAC, including CTLA-4 and LAG3. Overall changes were most pronounced in cases harboring KRAS G12D, G12V, Q61, and rare KRAS variants. Conclusions: The TME of KRAS mt PDAC shows IC patterns similar to KRAS mt CRC. Actionable IO-targets, such as PDL1, are enriched in tumors harboring specific variants of KRAS mt PDAC including the targetable G12C variant. If G12D becomes druggable, it could be targetable in 35% patients with PDAC or 15% in CRC. These results demonstrate that the TME of PDAC and CRC shows immune-cold features. Tailored immunotherapeutic strategies would have to overcome these barriers in KRAS mt PDAC and CRC, possibly in combination with molecularly targeted treatment strategies.

2647 Background: DSP107 is a bi-functional, trimeric, fusion protein composed of sequences from the extracellular domain of SIRPα and 4-1BBL. The SIRPα arm targets CD47 overexpressed on tumor cells, blocking the “don’t eat me” checkpoint and triggering tumor cell phagocytosis. The trimeric 4-1BBL arm, once cross-presented and immobilized by SIRPα binding to CD47, interacts with 4-1BB expressed on activated immune cells, mainly T- and NK cells in the tumor microenvironment, and stimulates their proliferation and activation. Thereby, DSP107 triggers both an innate and an adaptive immune response. Here we describe data from the completed DSP107 monotherapy dose escalation portion of study NCT04440735. Methods: Adult patients with advanced solid tumors were treated with weekly intravenous DSP107 infusions (0.01 - 10 mg/kg) during 3-week treatment cycles. An accelerated dose escalation in single patient cohorts (dose levels 1-3) was followed by a standard 3 + 3 design. The primary objective was to determine safety, tolerability and pharmacokinetic (PK) parameters. Paired biopsies were obtained from 8 patients (screening, after cycle 2). Restaging imaging was performed every two months and evaluated by RECIST criteria. Results: In 23 patients, DSP107 demonstrated no treatment related hematologic or hepatic adverse events (AEs) and no dose limiting toxicities. Grade 1-2 treatment related AEs were observed in 70% of patients (16/23). The most frequent AEs included infusion related reaction (IRR; 26%), diarrhea (17%), fatigue (17%), nausea (13%) and constipation (9%). IRRs were managed during subsequent infusions by reducing the infusion rate and administering IV fluids. No significant systemic cytokine release was measured at any dose level using a 10-plex, pro-inflammatory panel. PK analysis revealed 100% CD47 receptor engagement on peripheral T and NK cells at doses of 3 mg/kg and above. DSP107 did not bind CD47 on red blood cells at any dose. Preliminary histologic assessment of paired biopsies by an independent, blinded pathologist demonstrated increased tumor necrosis compared to screening in 3 out of 4 patients associated with immune cell infiltration. Immuno-profiling of tumor by immunofluorescence is on-going. Stable disease as best response was observed in 11/22 patients with treatment duration up to 26 weeks. Conclusions: DSP107 is a novel, CD47 and 4-1BB targeting fusion protein with a differentiated safety, binding and pharmacodynamic profile compared to other CD47 and 4-1BB targeting agents. Clinical trial information: NCT04440735.

3546 Background: CXC-chemokine receptor 4 (CXCR4) is a ubiquitous chemokine receptor activated by the CXCL12 ligand and is implicated in tumor invasion, metastasis, and immune cell (IC) trafficking. High CXCR4 expression is associated with poor prognosis in colorectal cancer (CRC). < 10% of metastatic CRC cases harbor microsatellite instability (MSI-H) and demonstrate lower tumor mutation burden (TMB), decreased IC infiltration, and lack of response to current immunotherapy regimens. This study aims to interrogate the role of CXCR4 mRNA expression on the the tumor microenvironment (TME) and its prognostic and predictive value to tailor immunotherapeutic treatment strategies in CRC. Methods: A total of 15,026 CRC samples were analyzed using whole-exome sequencing, whole-transcriptome sequencing, and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). Study cohort was stratified by CXCR4 mRNA expression levels in quartiles (Q1 (low) vs Q4 (high)). IC fraction was calculated by QuantiSeq, and real-world overall survival information was obtained from insurance claims data and calculated from tissue collection time to last day of contact. Statistical significance was determined using chi-square/Fisher-Exact and adjusted for multiple comparisons (q < 0.05). Results: Samples obtained from metastatic sites showed higher CXCR4 mRNA expression than those from primary tumors (22.7 vs 18.6 median transcripts per million (TPM), p < 0.001). CXCR4 mRNA expression was significantly lower in liver metastases than in non-liver metastases (21.2 vs 24.8 TPM, p < 0.001). Median CXCR4 mRNA expression was highest in the consensus molecular subtypes 4 (33.3 TPM) and lowest in 3 (13.0 TPM, p < 0.05). CXCR4 mRNA expression was positively associated with TMB-H, MSI-H/dMMR, and positive PD-L1 IHC status. In the TME, high CXCR4 mRNA expression was observed in tumors with a higher IC infiltration including B cells, M1/M2 macrophages, NK cells, CD8+ T cells and T-regs, regardless of MSI status. High CXCR4 mRNA expression in the primary tumor was associated with poor prognosis (HR 0.77, 95% CI 0.70-0.85; p < 0.001), regardless of MSI-status. In metastatic tumors, low mRNA expression was correlated with improved survival (HR 0.89, 95% CI 0.80-0.99; p = 0.34); however, this did not reach statistical significance in the MSS cohort (HR 0.90, 95% CI 0.80-1.0; p = 0.06). Of note, high CXCR4 mRNA expression was associated with improved survival in all patients with CRC who received pembrolizumab (HR 2.12, 95% CI 1.16-3.91; p = 0.013). Conclusions: This is the largest clinical dataset to date demonstrating high CXCR4 expression as a predictor for poor survival in CRC. Furthermore, high CXCR4 expression was associated with improved outcome after checkpoint inhibition immunotherapy, indicating its strong potential as a predictive biomarker that could inform immunotherapeutic strategies in CRC.

e16139 Background: Despite the recent addition of atezolizumab to advanced HCC first-line treatment, response biomarkers are not well studied. The involvement of the NOTCH gene family in HCC tumorigenesis has been previously discussed, yet insights on its effect on the immune microenvironment are still lacking. Methods: We systematically analyzed differentially expressed genes (DEGs) in the KEGG NOTCH pathway across HCC transcriptomics datasets from the HCCDB platform. Immune and prognostic analyses were done using The Cancer Genomic Atlas (TCGA) HCC cohort (n = 372). The TIMER 2.0 tool was used to assess immune infiltration. cBioportal was used for tumor mutational burden (TMB) and microsatellite instability (MSI) correlations. The TIDE tool assessed T cell dysfunction and DEGs efficacy predictive value using the only trial administering atezolizumab (IMvigor210, n = 348). Results: Four DEGs were identified: NCSTN, APH1A, NOTCH3, HDAC2. All four genes were significantly directly associated (spearman’s ρ > 0.1, P < 0.05) with immunosuppressive cells: Tregs, macrophage M2 cells, cancer-associated fibroblasts (CAF), and myeloid-derived suppressor cells (MDSC). HDAC2 was associated with higher T cell dysfunction (z score = 2.07, P = 0.04). High NOTCH3 and low HDAC2 expression served as favorable overall survival (OS) prognostic markers (HR: 0.66, 95% CI: 0.48 - 0.90, P = 0.008 & HR: 1.52, 95% CI: 1.12–2.07, P = 0.006, respectively). Stratification based on the expression of these two genes and strongly associated immunosuppressive cells’ infiltration levels (ρ > 0.5), revealed two unique patients’ subsets with worse OS marked by “low NOTCH3 expression with high CAF levels” and “high HDAC2 expression with high MDSC levels”. Regarding immune checkpoint genes expression, NOTCH3 and HDAC2 expression levels were directly correlated with CTLA-4, PD-1, and TIM-3, whereas NCSTN and APH1A were inversely related with PD-L1, LAG-3, and TIM-3 after correction for multiple hypothesis testing (ρ > 0.2, Q value < 0.05). TMB count was inversely associated with NOTCH3 expression (ρ = - 0.2, P < 0.001), as for the MSI sensor score, NOTCH3 (ρ = -0.29) and APH1A (ρ = 0.29) expression had inverse and direct significant associations, respectively (P < 0.0001). Exploratory subgroup analysis from the IMvigor210 trial on metastatic urothelial carcinoma patients on atezolizumab showed a significant difference in OS favoring low NOTCH3 expression (P = 0.003) and high APH1A expression (P = 0.049). Conclusions: DEGs from the NOTCH family seem to impose an immunosuppressive effect on HCC’s microenvironment. High NOTCH3 and low HDAC2 expression were identified as potential favorable prognostic markers. Interestingly, high NOTCH3 expression translated into worse OS in patients on anti-PD-L1 which could be owed to the inverse relation with TMB and MSI described in our study, thus deserving further translational investigations.

4047 Background: Surgical rection is the only potentially curative intervention for locally advanced adenocarcinoma of esophagus, GEJ and stomach. Results from various studies have demonstrated the benefits of perioperative treatment including neoadjuvant and adjuvant chemotherapy or chemoradiation, however, there is lack of universally accepted standard. Recent data demonstrated the benefit of immune checkpoint inhibitor in adjuvant setting in patients who had pre-operative chemoradiation. This single arm phase 2 trial is aimed to evaluate efficacy and safety of pembrolizumab, an immune checkpoint inhibitor, in combination with mFOLFOX in patients with potentially resectable adenocarcinoma of distal esophagus, GEJ and stomach. The primary objective is pathological response rate (ypRR with tumor regression score, TRS ≤ 2). Methods: Newly diagnosed locally advanced (T1N1-3M0 or T2-3NanyM0), potentially resectable adenocarcinoma of distal esophagus, GEJ and stomach by PET, EUS, CT C/A/P and staging laparoscopy were treated with pre-operative mFOLFOX6 (oxaliplatin 85mg/m2, Leucovorin 400mg/m2, 5-FU bolus 400mg/m2, and 5-FU 2400mg/m2 infusion every 2 weeks) for 4 cycles and pembrolizumab (200 mg IV q3week) for 3 cycles. Patients with no evidence of metastatic disease by PET and CT C/A/P who are eligible for resection underwent surgery. Post-operative treatment consisted of 4 cycles of mFOLFOX and 13 cycles of pembrolizumab 4-8 weeks postoperatively. Results: Up to 2/10/2021, all 37 patients eligible for the study finished preoperative treatment. 27 had curative intended operations, and all had R0 resection. 5 of 27 (19%) achieved ypCR and 6/27 (22 %) with regression score of 0 in the primary cancer. All except 2 patients (25/27, 93%) had shown pathologic response to the treatment with TRS ≤ 2. 21 patients completed all planned treatment with an average follow-up of 27 months. 2 patients had recurrence/metastatic disease (at 9 and 10 months from the enrollment) with 1 died at 23 months, and the other is still alive at 20 month. The rest patients (19/21) are all free of disease. G3/4 toxicities were reported in 21 of all 37 treated patients. There were no unexpected toxicities. Conclusions: The combination of mFOLFOX and pembrolizumab as peri-operative (pre- and post-operative) therapy in patients with locally advanced adenocarcinoma of distal esophagus, GEJ and stomach is safe. The preliminary benefit data are very encouraging with ypRR of 93%, ypCR of 19 %, and the long-time survival. The data support the combination of chemotherapy and Immune checkpoint inhibitor at perioperative setting. In addition, the data supports the staging laparoscopy for peritoneal disease assessment as the standard in resctacbility evaluation. Clinical trial information: NCT03488667.

Several targeted therapies have shown efficacy in patients with advanced gastric cancer (GC) and gastroesophageal junction adenocarcinoma (GEJC), including anti-angiogenic agents and immune checkpoint inhibitors. Ramucirumab, an anti-VEGFR2 antibody, has shown efficacy in GC, but the benefits are limited, in part due to MET-mediated resistance. Other VEGF targeted agents like VEGF tyrosine kinase inhibitors (TKIs) with broad multi-kinase inhibitory spectrum like regorafenib and cabozantinib have also shown modest single agent activity in early phase trials. For immune checkpoint inhibitors, pembrolizumab (anti-PD-1) monotherapy confers survival advantage as 3rd line therapy for the PD-L1 expressing GC and GEJC population and has been approved for use in this setting. Extensive tumor microenvironment immune modulatory effects from antiangiogenic agents have been demonstrated from preclinical data which support the clinical study rationale of dual blockade of VEGF and immune checkpoint. In addition, FDA has approved combinations of anti-VEGF/VEGFR with anti-PD-1/PD-L1 agents in hepatocellular carcinoma and renal cell carcinoma. Promising clinical activity has been demonstrated in patients with refractory GC/GEJC when treated with dual blockade combination with antiangiogenic agents and immune checkpoint inhibitors like PD-1/PD-L1 inhibitors in several phase I/II trials. This review highlights the trials investigating these novel combinations as well as their preclinical rationale.

The impact of corticosteroid therapy (CT) on efficacy of immune checkpoint inhibitors (ICI) is undefined in hepatocellular carcinoma (HCC). We evaluated whether CT administered at baseline (bCT) or concurrently with ICI (cCT) influences overall (OS), progression-free survival (PFS) and overall response rates (ORR) in 341 patients collected across 3 continents. Of 304 eligible patients, 78 (26%) received >10 mg prednisone equivalent daily either as bCT (n=14, 5%) or cCT (n=64, 21%). Indications for CT included procedure/prophylaxis (n=37, 47%), management of immune-related adverse event (n=27, 35%), cancer-related symptoms (n=8, 10%) or comorbidities (n=6, 8%). Neither overall CT, bCT nor cCT predicted for worse OS, PFS nor ORR in univariable and multivariable analyses (p>0.05). CT for cancer-related indications predicted for shorter PFS (p

Several targeted agents including multi-tyrosine kinase inhibitors (mTKIs) and immunotherapy (IO) agents have been approved for use beyond the frontline setting in patients with advanced hepatocellular carcinoma (HCC). Due to lack of prospective head-to-head comparative trials, there is no standardized way for alternating those agents beyond frontline. Therefore, we performed a retrospective review of the Kansas University (KU) cancer registry to determine whether IO may be superior to non-IO therapy. Patients with advanced HCC were divided into two groups based on the second-line systemic regimen received (IO vs. non-IO). Progression-free survival (PFS) and overall survival (OS) were calculated under the Kaplan&ndash, Meier and Cox proportional hazards models. No statistically significant differences in PFS and OS were found, although a non-significant delayed separation in the survival curve favoring IO was identified (median PFS 3.9 months vs. 3 months, median OS 10 months vs. 10 months respectively for IO vs. non-IO). This retrospective analysis is one of the earliest and largest studies comparing second-line IO and non-IO therapies thus far reported. Future studies should aim to define specific biomarkers for response prediction and treatment optimization based on individual patient and tumor characteristics. Furthermore, combinatorial therapeutic strategies is an evolving approach showing early promising signal.

BackgroundNivolumab is Food and Drug Administration approved in sorafenib-experienced, advanced hepatocellular carcinoma (HCC). Post-registration data of treatment in a real-world setting is lacking.Patients and methodsWe performed an international, multicenter observational study to confirm safety and efficacy of nivolumab in 233 patients treated outside clinical trials from eight centers in North America, Europe and Asia.ResultsPatients received nivolumab for Barcelona Clinic Liver Cancer stage C (n=191, 92.0%) and Child-Pugh (CP) A (n=158, 67.8%) or B (n=75, 32.2%) HCC as first (n=85, 36.5%) or second to fourth systemic therapy line (n=148, 63.5%). Objective response rate (ORR) was 22.4% and disease control rate was 52.1%. Median overall survival (OS) was 12.2 months (95% CI 8.4 to 16.0) and median progression-free survival was 10.1 months (95% CI 6.1 to 14.2). Treatment-related adverse events of grade >2 occurred in 26 patients (11.2%). Efficacy and safety were similar across CP classes and therapy line. OS was shorter in CP-B than A (7.3 months vs 16.3 months, p=0.05). Achievement of an objective response predicted for improved OS (25.4 months vs 13.2 months, pConclusionsThis study confirms safety and efficacy of nivolumab in advanced HCC across various lines of therapy and degrees of liver dysfunction. Despite equal ORR and toxicity to nivolumab, patients with CP-B functional class have shorter survival than the patients with CP-A.

Immune checkpoint inhibitors (ICI) have shown positive results in patients with hepatocellular carcinoma (HCC). As liver function contributes to prognosis, its precise assessment is necessary for the safe prescribing and clinical development of ICI in HCC. We tested the accuracy of the albumin-bilirubin (ALBI) grade as an alternative prognostic biomarker to the Child-Turcotte-Pugh (CTP). In a prospectively maintained multi-centre dataset of HCC patients, we assessed safety and efficacy of ICI across varying levels of liver dysfunction described by CTP (A to C) and ALBI grade and evaluated uni- and multi-variable predictors of overall (OS) and post-immunotherapy survival (PIOS). We studied 341 patients treated with programmed-death pathway inhibitors (n = 290, 85%). Pre-treatment ALBI independently predicted for OS, with median OS of 22.5, 9.6, and 4.6 months across grades (p &lt, 0.001). ALBI was superior to CTP in predicting 90-days mortality with area under the curve values of 0.65 (95% CI 0.57&ndash, 0.74) versus 0.63 (95% CI 0.54&ndash, 0.72). ALBI grade at ICI cessation independently predicted for PIOS (p &lt, 0.001). Following adjustment for ICI regimen, neither ALBI nor CTP predicted for overall response rates or treatment-emerging adverse events (p &gt, 0.05). ALBI grade identifies a subset of patients with prolonged survival prior to and after ICI therapy, lending itself as an optimal stratifying biomarker to optimise sequencing of systemic therapies in advanced HCC.