Integration of comprehensive genomic profiling, tumor mutational burden, and PD‐L1 expression to identify novel biomarkers of immunotherapy in non‐small cell lung cancer

• Published in: Cancer medicine (Malden, MA) MA), 2021-04, Vol.10 (7), p.2216-2231
• Main Authors: Shi, Yunfei, Lei, Youming, Liu, Li, Zhang, Shiyue, Wang, Wenjing, Zhao, Juan, Zhao, Songhui, Dong, Xiaowei, Yao, Ming, Wang, Kai, Zhou, Qing
• Format: Article
• Language: English
• Subjects: Apoptosis; Biomarkers; Cancer immunotherapy; Cell death; Clinical Cancer Research; Copy number; DNA methylation; Epidermal growth factor receptors; Genomics; Genotypes; Histone methyltransferase; Immune checkpoint inhibitors; Immunotherapy; Kinases; Lung cancer; Lysine; lysine methyltransferase 2C; Methyltransferase; Mutation; Non-small cell lung carcinoma; non‐small cell lung cancer; Original Research; p53 Protein; Patients; PD-L1 protein; programmed cell death 1 ligand 1; Small cell lung carcinoma; Tumor cells; tumor mutation burden; tumor protein p53; Tumors
• ISSN: 2045-7634; 2045-7634
• DOI: 10.1002/cam4.3649

Objectives This study aimed to explore the novel biomarkers for immune checkpoint inhibitor (ICI) responses in non‐small cell lung cancer (NSCLC) by integrating genomic profiling, tumor mutational burden (TMB), and expression of programmed death receptor 1 ligand (PD‐L1). Materials and Methods Tumor and blood samples from 637 Chinese patients with NSCLC were collected for targeted panel sequencing. Genomic alterations, including single nucleotide variations, insertions/deletions, copy number variations, and gene rearrangements, were assessed and TMB was computed. TMB‐high (TMB‐H) was defined as ≥10 mutations/Mb. PD‐L1 positivity was defined as ≥1% tumor cells with membranous staining. Genomic data and ICI outcomes of 240 patients with NSCLC were derived from cBioPortal. Results EGFR‐sensitizing mutations, ALK, RET, and ROS1 rearrangements were associated with lower TMB and PD‐L1+/TMB‐H proportions, whereas KRAS, ALK, RET, and ROS1 substitutions/indels correlated with higher TMB and PD‐L1+/TMB‐H proportions than wild‐type genotypes. Histone‐lysine N‐methyltransferase 2 (KMT2) family members (KMT2A, KMT2C, and KMT2D) were frequently mutated in NSCLC tumors, and these mutations were associated with higher TMB and PD‐L1 expression, as well as higher PD‐L1+/TMB‐H proportions. Specifically, patients with KMT2C mutations had higher TMB and PD‐L1+/TMB‐H proportions than wild‐type patients. The median progression‐free survival (PFS) was 5.47 months (95% CI 2.5–NA) in patients with KMT2C mutations versus 3.17 months (95% CI 2.6–4.27) in wild‐type patients (p = 0.058). Furthermore, in patients with NSCLC who underwent ICI treatment, patients with TP53/KMT2C co‐mutations had significantly longer PFS and greater durable clinical benefit (HR: 0.48, 95% CI: 0.24–0.94, p = 0.033). TP53 mutation combined with KMT2C or KRAS mutation was a better biomarker with expanded population benefit from ICIs therapy and increased the predictive power (HR: 0.46, 95% CI: 0.26–0.81, p = 0.007). Conclusion We found that tumors with different alterations in actionable target genes had variable expression of PD‐L1 and TMB in NSCLC. TP53/KMT2C co‐mutation might serve as a predictive biomarker for ICI responses in NSCLC. Implications for Practice Cancer immunotherapies, especially immune checkpoint inhibitors (ICIs), have revolutionized the treatment of non‐small cell lung cancer (NSCLC); however, only a proportion of patients derive durable responses to this treatment. Biomarkers with greate