Real world outcomes in patients with neuroendocrine tumor receiving peptide receptor radionucleotide therapy

Aim: 177Lu-Dotatate (Lu-177), a form of peptide receptor radionuclide therapy (PRRT), was approved by Food and Drug Administration (FDA) for the treatment of somatostatin-receptor-positive neuroendocrine tumors (NETs) in 2018. Clinical trials prior to the FDA approval of Lu-177 showed favorable outcomes but there is limited published real world outcomes data. This study aims to describe and analyze real world outcomes of patients with NET who received Lu-177. Methods: After obtaining institutional review board approval, retrospective evaluation was performed to analyze the efficacy of Lu-177 for somatostatin receptor-positive gastro-entero-pancreatic NETs (GEP-NETs) patients at the University of Kansas Cancer Center between June 2018 and September 2021. This study aims to determine the response rate to the treatment of the entire cohort and subgroups. Results: A total of 65 patients received Lu-177 of which 58 completed treatment. The 58 patients had a median age of 61.5 years, 24 females and 34 males, 86% Caucasian and 12% black. The origins of NETs were primarily small bowel (n = 24) and pancreatic (n = 14). Pathology showed grades 1 (n = 21), 2 (n = 25), and 3 (n = 4) and were primarily well-differentiated tumors (n = 4). Among the cohort, 52 patients had imaging to assess response with 14 (26.9%) patients with partial response (PR), 31 (59.6%) with stable disease (SD), and 7 (13.5%) with progressive disease (PD). In a subset analysis, patients with non-functional disease (n = 29) had higher rates of PR 42.3% (compared to 11.5%, P = 0.0147) and higher disease control rate of 96% (compared to 78%, P = 0.042) than patients with functional disease (n = 29). Patients with non-functional disease had a lower PD of 3.85% (compared to 23%, P = 0.0147) than those with functional disease. Conclusions: This real world outcomes analysis of NETs treated with Lu-177 shows improved PR when compared to the initial clinical trials and is promising for patients. In addition, patients with non-functional tumors were found to have a statistically significant improved response rate which has not been described in the literature before. If these study findings are validated in a larger cohort they may guide patient selection for Lu-177 therapy in the future

Tumor Molecular and Microenvironment Characteristics in EBV-Associated Malignancies as Potential Therapeutic Targets: Focus on Gastric Cancer

Although most people are infected with Epstein-Barr Virus (EBV) during their lifetime, only a minority of them develop an EBV-associated malignancy. EBV acts in both direct and indirect ways to transform infected cells into tumor cells. There are multiple ways in which the EBV, host, and tumor environment interact to promote malignant transformation. This paper focuses on some of the mechanisms that EBV uses to transform the tumor microenvironment (TME) of EBV-associated gastric cancer (EBVaGC) for its benefit, including overexpression of Indoleamine 2,3-Dioxygenase 1 (IDO1), synergism between H. pylori and EBV co-infection, and M1 to M2 switch. In this review, we expand on different modalities and combinatorial approaches to therapeutically target this mechanism

Characterization of Age-Associated, Neutrophil-to-Lymphocyte Ratio (NLR) and Systemic Immune-Inflammatory Index (SII) as Biomarkers of Inflammation in Geriatric Patients with Cancer Treated with Immune Checkpoint Inhibitors: Impact on Efficacy and Survival

Background: Geriatric patients (≥80 years) are underrepresented in immune checkpoint inhibitor (ICIs) clinical trials. However, their unique biology may affect their response to ICIs. There are currently no established biomarkers of the response to ICIs in adult patients with cancer that can help with patient selection. Methods: We built a multicenter, international retrospective study of 885 patients (<80 years: n = 417, 47.12%; ≥80 years: n = 468, 52.88%) with different tumor types treated with ICIs between 2011 and 2021 from 11 academic centers in the U.S. and Europe. The main outcome measures were objective response rates (ORR), progression-free survival (PFS) and overall survival (OS) stratified by age and circulating inflammatory levels (neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammatory index (SII)). Results: Patients ≥80 years with low NLR (NLR-L) and SII (SII-L) had significantly higher ORR (vs. high NLR [NLR-H], p < 0.01 and SII-H, p < 0.05, respectively). At median follow-ups (13.03 months), and compared to SII-H, patients with SII-L had significantly longer median PFS and OS in patients <80 (p < 0.001), and ≥80 years (p < 0.001). SII-L was independently associated with longer PFS and OS (HR: 0.61 and 0.62, respectively, p < 0.01). Conclusion: Lower inflammation pre-ICI initiation may predict an improved response and survival in geriatric patients with cancer

112 Circulating and molecular markers of inflammation: impact on treatment response and survival among older patients with cancer treated with immune checkpoint inhibitors

Background Age-associated pro-inflammatory states may result in decreased response to immune checkpoint inhibitors (ICI) in older patients (pts) with cancer. We explored the association of circulating inflammatory markers with response to ICIs, and investigate potential differences in transcriptional and TME signatures of pts ≥80-years (yr) of age and younger. Methods We built a multicenter, international database of pts with different tumors treated with ICIs monotherapy between 2011 and 2021 from 11 academic centers in the US and Europe. Retrospective analysis of 885 pts compared objective response rates (ORR; iRECIST), median progression-free survival (mPFS) and overall survival (mOS) between pts ≥80-yr and <80-yr, and stratified them across serum pre-treatment levels of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR) and systemic immune-inflammation index (SII=PxN/L). Optimal cut-off values for high (H) vs. low (L) levels were determined using receiver operating characteristic curves. DNA (592-gene panel/whole exome) and RNA (whole transcriptome) next-generation sequencing, immunohistochemistry (IHC) and TME analysis (MCP-counter) were performed on 24,123 independent samples of non-small cell lung cancer (NSCLC), melanoma (MEL) and renal cell carcinoma (RCC) submitted to a CLIA-certified laboratory (Caris Life Sciences, Phoenix, AZ). Results were compared between pts ≥80-yr and <80-yr. Results Table 1 summarizes pts baseline characteristics. Pts <80-yr had better ORR (P<0.01), but comparable mOS and mPFS to ≥80-yr (table 2). In pts ≥80-yr, NLR-L and SII-L were associated with higher ORR (P<0.01 and P<0.05; figure 1). All pts with NLR-L, MLR-L and SII-L, had longer mOS (P<0.01; figure 2). All PLR-L and SII-L pts had significantly longer mPFS (P<0.01; figure 3). Compared to pts <80-yr, NSCLC ≥80-yr had increased abundance of fibroblasts, dendritic cells and macrophages (P<0.01) in their TME and lower TMB-H (P<0.001). MEL ≥80-yr pts had fewer TME infiltrating T-lymphocytes (P=0.02), a1.24-fold increased expression of IL-6. RCC ≥80-yr pts had 0.56-fold decreased expression of GZMB, and lower PD-L1 (IHC-SP142, ≥2+|5%) expression (P<0.05; figure 4). Additional correlative biomarkers will be reported in the poster. Conclusions Lower levels of circulating inflammatory markers associated with significantly longer survival and better response rates to ICIs. SII-L and NLR-L specifically are potential biomarkers of response to ICI in pts ≥80-yr. This is the first study to evaluate the role of serum markers of inflammation as potential biomarkers of response to ICI in older pts with cancer, along with molecular correlate. Circulating inflammatory markers, and associated gene expression and TME composition suggest potential unique, cancer-specific biomarkers of response to ICIs in this population