Abstract 1771P
Background
With the revolutionary progress of immune checkpoint inhibitors (ICIs) achieved in NSCLC, identifying patients benefiting from ICIs becomes critical and urgent. The associations of genomic alterations in protein tyrosine phosphatases receptor-type (PTPRs) and ICIs responses are unknown.
Methods
Whole-exome sequencing (WES) of 73 advanced NSCLC tumors sampled before anti-PD-(L)1therapy were carried out with corresponding clinical data collected as a discovery cohort. Three cohort of 1920 NSCLC patients with WES or target sequencing data of tumor tissue derived DNA or ctDNA and relevant clinical data were used to validate. The LUAD cohort in TCGA was used for analyzing the potential anti-tumor immunologic mechanisms.
Results
Among all PTPRs, PTRPD mutation in non-squamous NSCLC (ns-NSCLC) patients brought longer PFS (324 vs 63 days, HR=0.36, p= 0.015) and higher ORR (p=0.010) in discovery cohort. In validation cohort-1 (n=377), ns-NSCLC patients with tissue PTPRD mutations had favorable PFS (9.10 vs 4.33 months, HR=0.62, p=0.018) and ORR (p=0.013). In validation cohort-2 (n=406), ns-NSCLC patients with tissue PTPRD mutations had favorable OS (over 40 vs 11.94 months, HR=0.57, p=0.011). In validation cohort-3 (n=1137), ns-NSCLC patients with ctDNA PTPRD mutations had longer PFS (6.97 vs 2.73 months, HR=0.63, p=0.028) and higher ORR (p=0.047). Moreover, it was deleterious mutations in phosphatase domains (phosphatase-mut), rather than other mutations (other-mut), that were responsible of PTPRD’s prediction efficiency. In addition, in validation cohort-3, ctDNA phosphatase-mut was also a predictive biomarker identifying patients benefiting more from ICIs than chemotherapy (interaction P for PFS=0.0506, for OS=0.04). Univariate and multivariate regression analysis revealed phosphatase-mut was independent on PD-L1 expression and TMB to predict. In silico analysis based on TCGA LUAD cohort discovered enhanced anti-tumor immunity in phosphatase-mut patients.
Conclusions
Tissue or ctDNA PTPRD phosphatase domain deleterious mutations functioned as a both prognostic and predictive biomarker predicting clinical outcomes of ICIs in ns-NSCLC patients.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
This work was supported by National Key Research and Development Project 2019YFC1315700; NSFC Key Program [81630071]; NSFC General Program (81871889, 81972905); AiyouFoundation (KY201701).
Disclosure
All authors have declared no conflicts of interest.