{
  "abstract": "Background Checkpoint inhibition clinical trials with PD-1 inhibitors yielded lack of efficacy as single agents in ALK+ lung cancer (LC) patients, leading many to conclude ALK+ LC patients are not candidates for checkpoint inhibition therapies. Because impacts of inhibiting one immune checkpoint are not likely generalizable to all immune regulators, we have analyzed transcriptional expression in ALK+, EGFR+, and KRAS+ LC tissues, identifying immune regulator functions expressed across these driver types. We present immunoregulatory genes that match with drugs in development, expressed in 100% of tumors. A list of genes expressed in >50% of tumors will be included in the presentation.Methods Bulk RNAseq data were obtained for 20 ALK+, 112 EGFR+ and 167 KRAS+ tumors, and 618 normal lung samples. To facilitate exploration of oncogene-addicted LC RNA expression, we developed an interactive R Shiny app that integrates 1,498 bulk RNA-seq samples (20 ALK+ cases), and over 1 million single-cell and single-nucleus profiles, including 12 ALK+ cases. Target-company affiliations were identified using oncologypipeline.com, and clinical trials were identified in clinicaltrials.gov and oncologypipeline.com.Results Nine immune regulator targets (excluding HLA genes) are expressed in 100% of 299 LC tumors with ALK+, EGFR+ or KRAS+ oncogenic variants ( table 1). All nine of these targets have been included in clinical development pipelines of one or more biotech and/or pharma companies, as of June 2025. Analysis of LC-directed trials for these nine targets reveals that none of these trials includes an arm focused solely on ALK+ LC patients. Given the greater success of developing therapies that inhibit pro-neoplastic cellular functions, we propose it may be most effective to evaluate therapies that focus on inhibition of immune regulator functions. These functions include CD47, SIRPA, LGALS9/GALECTIN9, VIR/VISTA, TNFRSF14/HVEM and CD276/B7-H3. Inhibition of CD47 enhances anti-tumor responses in preclinical studies with ALK+ tumors, validating this target for clinical studies.1 Conclusions Development of immune regulator inhibitor and agonist therapies that complement existing ALK-targeted kinase inhibition (TKI) therapies hold the potential to achieve durable disease control in ALK+ LC patients. We advocate for creation of clinical trials that include arms for ALK+ LC patients with enrollments sufficient to determine whether combination of immunoregulatory therapies with TKIs can achieve durable control, based on these RNA expression data. Early clinical failures in ALK+ LC patients with single agents such as PD-1 checkpoint inhibitors should not foreclose assessment of additional immune regulators as effective therapeutic options for ALK+ LC patients.Reference Vaccaro K, Allen J, Whitfield TW, et al. Targeted therapies prime oncogene-driven lung cancers for macrophage-mediated destruction. J Clin Invest. 2024;134:e16931.Abstract 898 Table 1Potential therapeutic immune regulator targets, expressed in 100% of ALK+, EGFR+ and KRAS+ oncogene-addicted lung cancers, for which drugs are in development",
  "authors": [
    {
      "affiliations": [
        "ALK Positive Inc., Atlanta, GA, USA"
      ],
      "name": "Ken Culver"
    },
    {
      "affiliations": [
        "ALK Positive Inc., Atlanta, GA, USA"
      ],
      "name": "Sadia Yaakov"
    },
    {
      "affiliations": [
        "ALK Positive Inc., Atlanta, GA, USA"
      ],
      "name": "Emily Venanzi"
    },
    {
      "affiliations": [
        "EirClin Co., Lexington, MA, USA"
      ],
      "name": "Zhengyu Ouyang"
    },
    {
      "affiliations": [
        "EirClin Co., Lexington, MA, USA"
      ],
      "name": "Kejie Li"
    },
    {
      "affiliations": [
        "ALK Positive Inc., Atlanta, GA, USA"
      ],
      "name": "Marc AT Muskavitch"
    }
  ],
  "title": "898 Transcriptional expression analysis in oncogene-addicted lung cancers identifies immune regulators under commercial development that could be therapeutic targets for ALK-positive lung cancer",
  "uid": "419c3404-2579-5556-88c6-837f2170f6f5"
}