The Superior Efficacy of Anti-PD-1/PD-L1 Immunotherapy in KRAS-Mutant Non-Small Cell Lung Cancer that Correlates with an Inflammatory Phenotype and Increased Immunogenicity

Abstract

Background: Mutations in KRAS are a common oncogene driver detected in approximately 30% of non-squamous non-small cell lung cancer (NSCLC) cases, conferring a poor prognosis without effective targeted therapy. Immune checkpoint inhibitors against PD-1/ PD-L1 yield improved survival rates of KRAS-mutant NSCLC patients while changing the paradigm of cancer therapy. Yet, the underlying association between KRAS mutations and immune responses remains unclear. Methods: We performed an integrated analysis of the data from publicly available repositories and from clinical center cohorts to explore the association between KRAS mutation status and tumor immunity-associated features, including PD-L1 expression, CD8+ tumor-infiltrating lymphocytes (TILs) and tumor mutational burden (TMB). Three-pool analysis was performed to assess the efficacies of different PD-1/PD-L1 inhibitors regarding objective response rates (ORR), durable clinical benefit, and overall survival (OS) in NSCLC patients with or without KRAS mutations. In addition, a KRAS-mutant lung adenocarcinoma mouse model was established to estimate the relative efficacy of anti-PD-L1 monoclonal antibody (mAb) monotherapy or combination treatment with docetaxel versus docetaxel alone. Findings: Pool analysis of 23 public studies suggested that patients with KRAS mutations had increased PD-L1 expression (OR=1.87; 95% CI: 1.34-2.61; P=0.0002). The combined analysis of PD-L1 and CD8+ TIL in the immunostained group showed increased dual-positive (PD-L1+/TIL+) cells in the KRAS-mutant group (P=0.008), suggesting KRAS mutations induce an inflammatory phenotype. Additional data verified a prominently increased KRAS mutant-associated TMB (TCGA: P=0.0155; Broad database: P=0.0001), indicating KRAS mutations promote tumor immunogenicity in NSCLC. Further molecular analyses revealed that KRAS mutations caused various defects in cell cycle checkpoints and DNA damage response pathways. Two-pool analysis confirmed that PD-1/PD-L1 inhibitors resulted in better ORR (OR=1.51; 95% CI: 1.17-1.96; P=0.002) and improved OS compared with docetaxel chemotherapy (HR=0.64; 95% CI: 0.43-0.95; P=0.03) KRAS-mutant NSCLC patients. Finally, anti-PD-L1 mAb significantly reduced tumor growth compared with docetaxel in KRASG12C lung adenocarcinoma mice (P<0.001), while PD-L1 mAb combined with docetaxel did not promote an anti-tumor response. Interpretation: KRAS-mutant NSCLC patients show remarkable clinical benefit from anti-PD-1/PD-L1 immunotherapy. We also uncovered a complex relationship among KRAS mutations, inflammatory phenotypes, and tumor immunogenicity. Importantly, our findings demonstrate that PD-1/PD-L1 inhibitor-based monotherapy may be more effective in KRAS-mutant NSCLC patients. Funding: This work was mainly supported by CIFMS. Declaration of Interest: The authors declare that they have no competing interests. Ethical Approval: This study was approved by the Ethics Committee of CICAMS, and all participants provided written informed consent.