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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.

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

Acquired resistance to BRAF/MEK-targeted therapy occurs in the majority of melanoma patients that harbor BRAF-mutated tumors, leading to relapse or progression and the underlying mechanism is unclear in many cases. The tumoral spatial heterogeneity is a potential key to the understanding of the therapy-response relationships, but they also bring challenges of proper parameterization and model validation. In this study, we developed a workflow to detect immune and tumor cells using multiplex immunohistochemistry and spatial imaging analysis from whole-tumor imaging data. Simultaneous characterization of CD11c+, CD8+, CD40+, CD80+ and SOX10+ cells using multispectral imaging was performed on paired tumor sections from eleven melanoma patients prior to BRAF/MEK-targeted therapy and when disease progressed on therapy. We observed a significant increase of tumor cellularity in the progressed tumors, and the close association of SOX10+ melanoma cells with CD8+ cytotoxic T cells (Tc) negatively correlated with patient’s progression-free survival, which may indicate a potential mechanism for acquired resistance to BRAF/MEK-targeted therapy. Using preclinical mouse model of YUMM3.3 BRAF-mutated tumors, we showed the detrimental role of PD-L1:PD-1 axis between melanoma-cell:Tc-cell in melanoma. In TCGA-melanoma dataset (n=445), SOX10hi is associated with a significant reduction of IFNG and GZMB, as well as poor overall survival (OS) in melanoma. Tumor cellularity (SOX10 and MLANA expression) exhibited additive prognostic value in the immune score signature to predict OS in patients with early-stage melanoma and prognoses OS independent of immune score in patients with late-stage melanoma. This work was supported by a VA Merit Award (I01BX002301) and SRCS award to AR and by R01-CA116021 (AR).

Although neoadjuvant chemotherapy (NAC) induces complete response in 30-40% of triple-negative breast cancers (TNBC), patients with residual disease at surgery have poor prognosis and limited treatment options until recurrence. Tumor-infiltrating lymphocytes (TILs) in the residual disease are a positive prognostic factor, but the composition of TILs has not been explored in granularity, and how specific immune composition of the tumor guides outcome is unclear, resulting in a lack of understanding of how to employ immunotherapies in the adjuvant setting. We assessed multiple immunologic biomarkers in a series of 100 residual TNBCs after NAC. Immune markers were assessed by multiple methods, including H&E TILs analysis, standard immunohistochemistry (IHC; HLA-A, CD4, CD8, LAG-3) and multiplexed immunofluorescence (mIF; HLA-DR, GZMB, CD4, CD8, PD-L1, pan-CK). TILs and IHC were scored by clinical research pathologists and IF was scored by AQUA® analysis. Where multiple markers were multiplexed together, subset analyses was performed. Association among parameters were assessed (n=83) including clinical outcome after surgery (n=79). As previously demonstrated, TILs in residual tumors after NAC predicted both RFS and OS. H&E-scored TILs were correlated to both CD4 and CD8 as scored by IHC or IF (Pearson’s r range 0.41-0.55; all p Citation Format: Caroline Nebhan, Paula I. Gonzalez-Ericsson, Roberto Salgado, Jennifer Bordeaux, Ju Young Kim, Christine Vaupel, Henry Gomez, Justin Micah Balko. Molecular characterization of residual triple-negative breast cancers after neoadjuvant chemotherapy identifies immune composition and features associated with clinical outcome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4050.

EGFR mutant lung cancers eventually become resistant to treatment with EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib. The combination of an irreversible EGFR TKI, afatinib, and the anti-EGFR monoclonal antibody, cetuximab, depletes both phosphorylated and total EGFR and can overcome resistance in mouse lung tumor models and human patients with acquired resistance. Since afatinib is also a potent HER2 inhibitor, here we investigated the role of HER2 in EGFR mutant tumor cells. We show in vitro and in vivo that afatinib plus cetuximab or the related antibody, panitumumab, significantly inhibits HER2 phosphorylation. HER2 overexpression or knockdown confers resistance or sensitivity, respectively, in all studied cell line models. Fluorescent in situ hybridization analysis revealed that HER2 was amplified in 3 of 26 (12%) tumors with acquired resistance versus only 1 of 99 (1%) untreated lung adenocarcinomas (p=0.03 Fisher's exact test). Notably, HER2 amplification and EGFR T790M were mutually exclusive (0 of 17 T790M-positive versus 3 of 9 T790M-negative cases (p=0.02 Fisher's exact test)). Collectively, these results reveal a previously unrecognized mechanism of resistance to EGFR TKIs and provide a rationale to assess the status and possibly target HER2 in EGFR mutant tumors with acquired resistance to EGFR TKIs.