P2.04-22 Programmed Death 1-Mrna Expression Predicts Benefit to Anti-PD1 Monotherapy in a Prospective Cohort of Advanced NSCLC

Background: Immune checkpoint inhibitors (ICIs) have shown remarkable antitumor effects in non-small cell lung cancer (NSCLC), however only a subset of patients respond.Genomic alterations (GAs) detected by targeted next-generation sequencing (NGS) is increasingly used in clinical practice, but its correlation with recognized immune biomarkers and predictive value for ICIs response in NSCLC is unclear.Method: FFPE tumor and matched blood samples of 637 NSCLC patients (84 squamous cell and 553 non-squamous cell) were collected for targeted NGS panel sequencing from December 2017 to January 2019.GAs including single nucleotide variations, short and long insertions/deletions, copy number variations and gene rearrangements were assessed.TMB high (TMB-H) was defined as 10 muts/Mb.Positive PD-L1 expression was defined as 1% of tumor cells with membranous staining (22C3/28-8, DAKO).Genomic data and ICIs treatment outcome from a 240 NSCLC patient cohort was derived from cBioPortal (MSKCC, J Clin Oncol 2018).Result: In 637 NSCLC patients, the prevalence of PD-L11% was 26.5% and the median TMB was 4.6 muts/Mb (IQR, 2.3-10).Recurrent TP53, KRAS, LRP1B and KEAP1 mutations were significantly correlated with higher TMB (p value).TP53, KRAS and KEAP1 mutations were significantly enriched in the TMB-H/PD-L1+ subset while STK11 mutations were enriched in TMB-H/PD-L1-subset (p value).KMT2C, also known as MLL3, belongs to the mixed-lineage leukemia (MLL) family of histone methyltransferases and its GAs was found in 5% of our cohort.Tumors with KMT2C and TP53 co-mutations (co-MUT) had a significantly higher TMB (15.1 muts/Mb) than TP53/KMT2C single-MUT (8.7 muts/Mb) and TP53/KMT2C co-WT (3.1 muts/Mb) tumors.Moreover, TMB-H/PD-L1+ subset was enriched in KMT2C and TP53 co-MUT (25%) comparing to TP53/KMT2C single-MUT (14.7%) and TP53/ KMT2C co-WT (3.3%) tumors.Survival analysis from public clinical trials confirmed that patients with TP53/KMT2C co-MUT had remarkable clinical benefit to ICIs in both progression free survival (PFS) and durable clinical benefit (DCB).The median PFS was 7.3, 4.2 and 2.5 months for TP53/KMT2C co-MUT, TP53/KMT2C single-MUT and TP53/KMT2C co-WT patients, respectively (p¼0.0032).TP53/KMT2C co-MUT was an independent variable of PFS (TP53/KMT2C co-MUT vs. TP53/KMT2C co-WT, HR: 0.47, 95%CI: 0.25-0.89,p¼0.0199).Furthermore, TP53 with KMT2C or KRAS co-MUT expanded the patient population benefiting from ICIs (mPFS ¼ 7.2 months, p¼0.00042;DCB ¼ 51.2%, p¼ 0.0195). Conclusion:This study provides evidence that TP53/KMT2C co-MUT may serve as a predictive biomarker for ICIs in NSCLC.GAs detected by targeted NGS could illuminate insight for immunotherapy.