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Introduction: Younger patients with non-small cell lung cancer (NSCLC) (<50 years) represent a significant patient population with distinct clinicopathological features and enriched targetable genomic alterations compared to older patients. However, previous studies of younger NSCLC suffer from inconsistent findings, few studies have incorporated sex into their analyses, and studies targeting age-related differences in the tumor immune microenvironment are lacking., Methods: We performed a retrospective analysis of 8,230 patients with NSCLC, comparing genomic alterations and immunogenic markers of younger and older patients while also considering differences between male and female patients. We defined older patients as those ≥65 years and used a 5-year sliding threshold from <45 to <65 years to define various groups of younger patients. Additionally, in an independent cohort of patients with NSCLC, we use our observations to inform testing of the combinatorial effect of age and sex on survival of patients given immunotherapy with or without chemotherapy., Results: We observed distinct genomic and immune microenvironment profiles for tumors of younger patients compared to tumors of older patients. Younger patient tumors were enriched in clinically relevant genomic alterations and had gene expression patterns indicative of reduced immune system activation, which was most evident when analyzing male patients. Further, we found younger male patients treated with immunotherapy alone had significantly worse survival compared to male patients ≥65 years, while the addition of chemotherapy reduced this disparity. Contrarily, we found younger female patients had significantly better survival compared to female patients ≥65 years when treated with immunotherapy plus chemotherapy, while treatment with immunotherapy alone resulted in similar outcomes., Discussion: These results show the value of comprehensive genomic and immune profiling (CGIP) for informing clinical treatment of younger patients with NSCLC and provides support for broader coverage of CGIP for younger patients with advanced NSCLC., Competing Interests: All authors except for KSS and PS are employed by Labcorp and have equity interest in Labcorp. KSS is an employee of Fortrea and reports consulting fees from the European Commission, and stock and/or other ownership interests in Labcorp Inc., Fortrea Inc., and Quantum Health Analytics UK Ltd. PS is employed by and has equity interest in Illumina. The reviewer LA declared a past co-authorship with the author SR to the handling editor., (Copyright © 2024 Wallen, Ko, Nesline, Hastings, Strickland, Previs, Zhang, Pabla, Conroy, Jackson, Saini, Jensen, Eisenberg, Caveney, Sathyan, Severson and Ramkissoon.)

Background: KEYNOTE-522 resulted in FDA approval of the immune checkpoint inhibitor pembrolizumab in combination with neoadjuvant chemotherapy for patients with early-stage, high-risk, triple-negative breast cancer (TNBC). Unfortunately, pembrolizumab is associated with several immune-related adverse events (irAEs). We aimed to identify potential tumor microenvironment (TME) biomarkers which could predict patients who may attain pathological complete response (pCR) with chemotherapy alone and be spared the use of anti-PD-1 immunotherapy. Methods: Comprehensive immune profiling, including RNA-seq gene expression assessment of 395 immune genes, was performed on matched FFPE tumor samples from 22 stage I-III TNBC patients (14 patients treated with neoadjuvant chemotherapy alone (NAC) and 8 treated with neoadjuvant chemotherapy combined with pembrolizumab (NAC+I)). Results: Differential gene expression analysis revealed that in the NAC group, IL12B and IL13 were both significantly associated with pCR. In the NAC+I group, LCK and TP63 were significantly associated with pCR. Patients in both treatment groups exhibiting pCR tended to have greater tumor inflammation than non-pCR patients. In the NAC+I group, patients with pCR tended to have greater cell proliferation and higher PD-L1 expression, while in the NAC group, patients with pCR tended to have lower cancer testis antigen expression. Additionally, the NAC+I group trended toward a lower relative dose intensity averaged across all chemotherapy drugs, suggesting that more dose reductions or treatment delays occurred in the NAC+I group than the NAC group. Conclusions: A comprehensive understanding of immunologic factors could potentially predict pCR to chemotherapy alone, enabling the avoidance of the unnecessary treatment of these patients with checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

Background: Although immunotherapy has revolutionized the treatment paradigm of many cancers including HNSCC, only a subset of patients derives meaningful clinical benefit from immune checkpoint inhibitors (ICIs). Currently, PD-L1 protein expression remains the only predictive biomarker for ICI response studied in prospective first line immunotherapy clinical trials in HNSCC. PD-L1 expression level, however, is an imperfect biomarker for ICI response due to several limitations such as the variability in expression level cut-offs defined as positive vs. negative between assays, subjective interobserver variability and clinical sampling bias in acquiring specimens. Research efforts are ongoing to develop other biomarkers that can precisely identify patients who will derive benefits from ICIs. Our objective was to assess the results of comprehensive genomic and immune profiling (CGIP) in patients with HNSCC and describe the immune microenvironment of tumors with different levels of PD-L1 expression. Methods: A retrospective analysis of 409 patients with HNSCC tested by CGIP during standard-of-care was performed to compare the immune microenvironment of tumors with high (N=168), moderate-low (N=183), or negative (N=58) PD-L1 expression. Patient tumors were categorized into PD-L1 expression groups using combined positive score (CPS) thresholds of ≥20 (high), 1 to 19 (moderate-low), and <1 (negative). These CPS scores were selected according to the cut-offs used in the Phase III Keynote-048 study that led to the approval of pembrolizumab in HNSCC. DNA-seq of 523 genes analyzed tumor mutational burden (TMB). RNA expression analysis was performed for 395 immune genes. Gene expression-based signatures for tumor immunogenicity score (TIGS), cellular proliferation (CP) and cancer testis antigen burden (CTAB) were calculated from percentile ranks of normalized gene expression values. Expressions of three emerging biomarkers linked to an immune checkpoint mechanism (LAG3, TIGIT and TIM3) were also determined by RNA-seq. PD-L1 expression was assessed using immunohistochemistry. Wilcoxon rank-sum tests were used to detect significant differences between PD-L1 groups in TMB, gene expression signatures, and gene expressions of TIM-3, TIGIT and LAG-3. Results: Tumors with high PD-L1 demonstrated increased expression of genes associated with tumor immunogenicity compared to moderate-low (median TIGS of 54 vs 41; p<1E-4) and negative (median TIGS of 54 vs 43; p<1E-4) tumors (Fig 1B). PD-L1 high tumors also showed increased expression of other emerging biomarkers involved in immune checkpoint pathways such as LAG-3, TIGIT and TIM-3, compared to moderate-low and negative tumors (Fig 1E-G). We found no significant differences between PD-L1 groups in TMB and the remaining composite gene expression signatures (p>0.05; Fig 1A,C,D). Conclusion: Our findings highlight the complex interplay of diverse immune cells and checkpoint markers in the tumor microenvironment (TME) beyond PD-L1 in HNSCC. Tumors with high PD-L1 expression harbored a greater degree of immune infiltration, demonstrating a higher TIGS score as well as other checkpoint markers of emerging clinical importance such as LAG-3, TIGIT and TIM-3. Interestingly, tumors with PD-L1 moderate-low expression did not exhibit significant differences in TIGS, TIGIT and TIM-3, compared to PD-L1 negative tumors. These results suggest that HNSCC tumors with PD-L1 CPS ≥ 20 have the most robust immunogenic profile. Understanding the different components of TME can aid in implementing innovative therapeutic strategies to enhance the immune responses and potentially overcome resistance to ICIs in HNSCC. [ABSTRACT FROM AUTHOR]