998P - Investigating the potential relationship between KRAS mutations and immunotherapeutic biomarkers in lung cancer (LC)

Background

Previous reports have found that LC patients (pts) with KRAS mutations (KRAS^m) respond well to immunotherapy (IT). However, their relationship with IT biomarkers is not clear. Here, we retrospectively investigated the KRAS^m and co-mutation characteristics and their relationship with IT biomarkers in a Chinese LC cohort and TCGA data.

Methods

Our cohort data were from OncoPanscan^TM (Genetron Health) based sequencing, in which the KRAS^m LC data (N=1,890) were used to analyze TMB and PD-L1. KRAS^m LC data (N=156) from TCGA were used to analyze TMB. Co-mutations were also analyzed.

Results

In our and TCGA cohorts, the KRAS^m was focused on exon 2 with mutation rate 93.49% and 96.79% respectively, and the three most prevalent mutations were G12C (31.43%, 37.18%), G12D (19.26%, 12.18%) and G12V (19.10%, 23.08%). In addition, there was a small fraction of G12R/Y/F/L in our data, while not in TCGA. We then analyzed the distribution of KRAS mutations in TMB high (≥10 muts/Mb) and PD-L1 high (TPS≥50%) samples. 41.39% (125/302) of our data had TMB high, while only 27.52% (41/149) in TCGA. The most common KRAS mutation in both was G12C (36.00%, 46.34%; respectively), followed by G12V (22.4%, 17.07%). 22.69% (103/454) of our data had PD-L1 high, with the most prevalent KRAS mutations G12V (33.01%) and G12C (31.07%). 20.42% (39/191) of our samples had both PD-L1 and TMB high, with the two most prevalent KRAS mutations G12C (35.9%) and G12V (25.64%). These results supported that KRAS G12C/V was associated with higher TMB and PD-L1, maybe resulting a benefit from IT. Previous reports have found that KRAS^mTP53^m cases could benefit from IT. 55.2% (69/125) and 65.85% (27/41) of TMB high cases respectively in our and TCGA cohorts were KRAS^mTP53^m. KRAS^mTP53^m cases accounts for 61.17% (63/103) of PD-L1 high pts, moreover, 64.1% (25/39) of patients in our data were TMB^highPD-L1^high. Thus, the close relationship between KRAS^mTP53^m and TMB high and PD-L1 high, may account for the benefit of IT in these pts.

Conclusions

KRAS^m, especially KRAS_G12C or KRAS^mTP53^m, was tightly associated with higher TMB and PD-L1. It may be a positive predictive biomarker for IT in LC patients.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Institute of Cancer and Basic Medicine, Chinese Academy of Sciences.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.