Data from HLA-I evolutionary divergence confers response to PD-1 blockade plus chemotherapy in untreated advanced non-small-cell lung cancer

• DOI: 10.1158/1078-0432.c.6762579.v3
• Publication Date: 2024-09-16T12:46:15Z
• Authors: Tao Jiang; Qiqi Jin; Jiahao Wang; Fengying Wu; Jian Chen; Gongyan Chen; Yunchao Huang; Jianhua Chen; Ying Cheng; QiMing Wang; Yueyin Pan; Jianying Zhou; Jianhua Shi; Xingxiang Xu; LiZhu Lin; Wei Zhang; Yiping Zhang; Yunpeng Liu; Yong Fang; Jifeng Feng; Zhehai Wang; Sheng Hu; Jian Fang; Yongqian Shu; Jiuwei Cui; Yi Hu; Wenxiu Yao; Xingya Li; Xiaoyan Lin; Rui Wang; Yongsheng Wang; Wei Shi; Gaohua Feng; Jun Ni; Beibei Mao; Dandan Ren; Huaibo Sun; Henghui Zhang; Luonan Chen; Caicun Zhou; Shengxiang Ren

<div>Abstract<p>Purpose: PD-1 blockade plus chemotherapy has become the new standard of care in patients with untreated advanced non-small-cell lung cancer (NSCLC), whereas predictive biomarkers remain undetermined. Patients and Methods: We integrated clinical, genomic and survival data of 427 NSCLC patients treated with first-line PD-1 blockade plus chemotherapy or chemotherapy from two phase 3 trials (CameL and CameL-sq) and investigated the predictive and prognostic value of HLA class I evolutionary divergence (HED). Results: High HED could predict significantly improved objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) in those received PD-1 blockade plus chemotherapy (In the CameL trial, ORR: 81.8% vs. 53.2%; <i>P</i> = 0.032; PFS: hazard ratio [HR], 0.47; <i>P</i> = 0.012; OS: HR, 0.40; <i>P</i> = 0.014; In the CameL-sq trial, ORR: 89.2% vs 62.3%; <i>P</i> = 0.007; PFS: HR, 0.49; <i>P</i> = 0.005; OS: HR, 0.38; <i>P</i> = 0.002), but not chemotherapy. In multivariate analysis adjusted for PD-L1 expression and tumor mutation burden, high HED was independently associated with markedly better ORR, PFS and OS in both two trials. Moreover, joint utility of HED and PD-L1 expression showed better performance than either alone in predicting treatment benefit from PD-1 blockade plus chemotherapy. Single-cell RNA sequencing of 58,977 cells collected from 11 patients revealed that tumors with high HED had improved antigen presentation and T cell mediated antitumor immunity, indicating an inflamed tumor microenvironment phenotype. Conclusion: These findings suggest that high HED could portend survival benefit in advanced NSCLC treated with first-line PD-1 blockade plus chemotherapy.</p></div>