Comutations in DDR Pathways Predict Atezolizumab Response in Non-Small Cell Lung Cancer Patients.

Anning Xiong,Hua Zhong,Shiqing Chen,Baohui Han,Kai Gu,Changhui Li,Ding Zhang,Xueyan Zhang,Fengcai Wen,Wei Nie,Yan Zhou

doi:10.3389/fimmu.2021.708558

Abstract

The presence of comutations (co-mut+) in DNA damage response and repair (DDR) pathways was associated with improved survival for immune checkpoint inhibitor (ICI) therapy in non-small cell lung cancer (NSCLC). However, it remains unknown whether co-mut+ status could be a predictive biomarker for immunotherapy. We aimed to explore the predictive role of co-mut+ status in the efficacy of ICIs. A total of 853 NSCLC patients from OAK and POPLAR trials were included in the analyses for the relationship between co-mut status and clinical outcomes with atezolizumab treatment. In co-mut+ NSCLC patients, significantly prolonged progression-free survival (PFS) (p = 0.004) and overall survival (OS) (p < 0.001) were observed in atezolizumab over docetaxel. The interaction between co-mut status and treatment was significant for PFS (p for interaction = 0.010) and OS (p for interaction = 0.017). In patients with negative or low programmed death receptor-ligand 1 expression, co-mut+ status still predicted improved clinical outcomes from atezolizumab therapy. These findings suggested that co-mut status may be a promising predictor of ICI therapy in NSCLC.

Highlights

Lung cancer is the leading cause of cancer-related mortality worldwide with non-small cell lung cancer (NSCLC) being the most common type [1, 2]
We found that co-mut+ status could predict improved clinical outcome with atezolizumab over docetaxel
The presence of comutations in damage response and repair (DDR) pathways may be a predictive biomarker for immune checkpoint inhibitor (ICI) therapy

Summary

Introduction

Lung cancer is the leading cause of cancer-related mortality worldwide with non-small cell lung cancer (NSCLC) being the most common type [1, 2]. Immune checkpoint inhibitors (ICIs) of programmed death receptor 1 (PD-1) and its ligand PD-L1 have improved outcomes in NSCLC patients [3, 4]. Due to the limited number of NSCLC patients benefiting from ICIs, there is an urgent need for robust predictor that can identify patients who are more likely to response to anti-PD-(L) immunotherapy. Tumor mutational burden (TMB) is defined as the total number of tumor somatic mutations [5]. Previous study reported that higher TMB was correlated with improved response to immunotherapy and prolonged progression-free survival, regardless of PD-L1 expression [6]. The result of KEYNOTE-158 involving patients with previously treated, advanced solid tumors demonstrated a similar relationship between higher TMB (≥10 mutations/Mb) and pembrolizumab monotherapy [7].

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