Detection of circulating KRAS4A and KRAS4B isoforms in patients with metastatic lung adenocarcinoma treated with pembrolizumab or chemotherapy plus pembrolizumab by liquid biopsy: Clinical impact and association with circulating PD-L1

Abstract 2206P Background Pre-clinical studies indicate that the KRAS pathway enhances the stability and expression of PD-L1. We investigated the expression of the circulating mRNA (cmRNA) levels of KRAS4A and KRAS4B isoforms and their possible impact on progression-free survival (PFS) of patients with metastatic lung adenocarcinoma treated with Pembrolizumab (P) by liquid biopsy. Methods Patients with metastatic lung adenocarcinoma without driver mutations undergoing P or P plus chemotherapy (PC) were prospectively accrued to analyze KRAS4A, KRAS4B and PD-L1 cmRNA levels by liquid biopsy. Receiver operating characteristic curves (ROC) calculated the Youden index to define the optimum cut-off values for binary classification of patients and PFS analysis. Both the KRAS isoforms were also studied for association with the PD-L1 cmRNA levels. RT-PCR is the method used for expression analysis. Results In 56 fully assessable patients, 28 received P and 28 patients PC. Patients with high (H) KRAS4A cmRNA and HKRAS4B cmRNA levels showed significantly better PFS than patients classified with low (L). The median PFS of patients with H KRAS4A cmRNA and H KRAS4B cmRNA levels was 29 months (95% CI 22-29 months) and 24 months (95% CI 13-29 months), respectively. The median PFS of patients with L KRAS4A cmRNA and L KRAS4B cmRNA expression was 12 months (95% CI 6-15 months) and 12 months (95% CI 5-20 months), respectively. H KRAS4A cmRNA retained a significant positive association with PFS in the multivariate model. The mean expression values of PD-L1 cmRNA levels were significantly higher in patients with H KRAS4A cmRNA and H KRAS4B cmRNA levels. Moreover, an exploratory analysis in treatment subgroups found a positive association between H KRAS4A cmRNA and H KRAS4B cmRNA levels with PFS in patients treated with P. Conclusions Our results suggest the KRAS4A isoform deserves further investigation as a potential marker for defining patients who may benefit the most from immune checkpoint inhibitors therapy. Progresses in this field are desirable to improve personalized cancer immunotherapeutic strategies.