# Genomic biomarkers of immunotherapy plus chemotherapy in patients with advanced NSCLC: Insights from the phase 3 ORIENT-11 study

## TL;DR

A new 9-gene score helps identify which lung cancer patients benefit most from immunotherapy plus chemotherapy.

## Contribution

The ICPscore outperforms PD-L1 in predicting treatment response and reflects immune-active tumor environments.

## Key findings

- High ICPscore patients show better survival with immunotherapy plus chemotherapy.
- ICPscore was validated in multiple cancer cohorts and outperforms PD-L1 as a biomarker.
- High ICPscore correlates with immune-active tumor microenvironments involving myeloid cells.

## Abstract

To optimize patient selection for first-line immune-checkpoint inhibitor plus chemotherapy (ICI-Chemo) in advanced non-small cell lung cancer (NSCLC), we developed a 9-gene Immune-Chemotherapy Prediction Score (ICPscore) from the phase 3 ORIENT-11 trial. A high ICPscore identified patients with markedly superior progression-free and overall survival from ICI-Chemo versus chemotherapy alone, whereas low-scorers derived minimal benefit, outperforming existing biomarkers such as PD-L1. Its predictive value for immunotherapy efficacy was further validated in the OAK (NSCLC) and IMvigor210 (metastatic urothelial cancer) cohorts. Multi-cohort and single-cell analyses linked a high ICPscore to an immune-active tumor microenvironment characterized by myeloid cell activation, thus providing a biological rationale for its enhanced performance and positioning it as a robust tool for treatment personalization.

•9-gene ICPscore predicts survival benefit of ICI plus chemo in advanced NSCLC•High ICPscore patients benefit from ICI plus chemo; low scorers do not•ICPscore validated in independent cohorts and outperforms PD-L1 expression•ICPscore reflects an immune-active tumor microenvironment with myeloid activation

9-gene ICPscore predicts survival benefit of ICI plus chemo in advanced NSCLC

High ICPscore patients benefit from ICI plus chemo; low scorers do not

ICPscore validated in independent cohorts and outperforms PD-L1 expression

ICPscore reflects an immune-active tumor microenvironment with myeloid activation

Oncology; Therapeutics