2206P - 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

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.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

FanoAteneo (non-profit association), Italy.

Disclosure

All authors have declared no conflicts of interest.