Gene Signature Panel for Predicting Response to Immune Checkpoint Blockade in Solid Tumors

Background & Unmet Need

• While immune checkpoint blockade (ICB) therapies have transformed the management of solid tumors, only a small subset of patients achieve durable response (∼20%)
• PD-L1 expression is the most validated biomarker for predicting response to ICB, but shows inconsistency across treatment settings and may miss responders with low PD-L1 scores
• Moreover, issues with detection and heterogeneity within and between tumor types further confounds the predictive value of PD-L1
• Other known biomarkers, such as tumor mutational burden (TMB), encounter challenges with standardizing cut-off values and demonstrating predictive accuracy across different tumor types, especially in those without ICB approval
• Unmet Need: Molecular signatures to identify patients likely to respond to ICB therapies across a variety of solid tumors

Technology Overview

• The Technology: A 140-gene signature identifying a molecular subclass likely to respond to immune checkpoint blockade across various solid tumors
• The Discovery: RNA-seq data from a phase II trial of stereotactic body radiation therapy (SBRT) combined with anti-PD-L1 (durvalumab) in NSCLC revealed genes linked to highly proliferating cells
• This subclass is dominated by increased expression of cell cycle genes, as well as increased glycolysis, TMB, and immune suppression
• PoC Data: The 140-gene set was associated with reduced DFS and OS in lung adenocarcinoma with a hazard ratio of 1.6 (p = 3.04 × 10⁻⁶)
• 140-gene set was also tested against an additional five TCGA solid tumor types and demonstrated correlation with survival in breast, prostate, melanoma, and pancreatic cancer
• This molecular subclass is present in one-quarter to two-thirds of tumors, varying by disease

Technology Applications

• Identification of patients likely to respond to ICB or ICB in combination with SBRT in lung adenocarcinoma, melanoma, breast cancer, prostate cancer and pancreatic cancer
• ICB may include anti-PD/PD-L1 and anti-CTLA-4 therapies

Technology Advantages

• Broad applicability across multiple solid tumor types beyond lung cancer
• The 140-gene signature reflects biology independent of EGFR mutation status, TMB, and PD-L1/P1 expression

Figure 1: High proliferation index (PI) tumors (140-gene set) were associated with increased disease-free and overall survival in lung adenoma adenoma samples from The Cancer Genome Atlas (TCGA).