Data from HLA-I Evolutionary Divergence Confers Response to PD-1 Blockade plus Chemotherapy in Untreated Advanced Non–Small Cell Lung Cancer

Abstract

<div>AbstractPurpose:<p>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.</p>Experimental Design:<p>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 III trials (CameL and CameL-sq) and investigated the predictive and prognostic value of HLA class I evolutionary divergence (HED).</p>Results:<p>High HED could predict significantly improved objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) in those who 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 trials. Moreover, the 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.</p>Conclusions:<p>These findings suggest that high HED could portend survival benefit in advanced NSCLC treated with first-line PD-1 blockade plus chemotherapy.</p><p><i><a href="https://aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-23-2152" target="_blank">See related commentary by Dimou, p. 4706</a></i></p></div>