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

Abstract 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%; P = 0.032; PFS: hazard ratio [HR], 0.47; P = 0.012; OS: HR, 0.40; P = 0.014; In the CameL-sq trial, ORR: 89.2% vs 62.3%; P = 0.007; PFS: HR, 0.49; P = 0.005; OS: HR, 0.38; P = 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.