KRAS and LKB1 mutation conferring prognostic and predictive role on liquid biopsy in advanced NSCLC

Liquid biopsy (LB) is a feasible tool able to detect genomic alterations in cancer at baseline and also as a longitudinal monitoring to identify resistance mutations. In patients (pts) with mNSCLC, when tissue biopsy remains a difficult procedure, LB might be crucial for therapeutical options, especially in the immunotherapy (IO) and target therapy era. The aim of this bicentric study is to assess the prognostic value of LB in mNSCLC. Data from mNSCLC with any gene alteration/PD-L1 expression were collected at Istituto Nazionale Tumori of Milan and Policlinico Universitario of Naples. Liquid biopsy was performed by 73-gene Guardant360® CDx / 29-gene Archer® LiquidPlex™panels. Effects of circulating genomic alterations on Overall Survival (OS) (from 4-stage diagnosis to death/last FUP) were assessed using Cox proportional hazard model cell free. Kaplan-Meier curves were performed to assess OS between IO and non-IO treatments arms. Of 488 pts underwent LB, most were male (56.9%), former smoker (46.3%), with adenocarcinoma (73.6%) and PD-L1 > 1% (55.6%). 301/488 patients (62.6%) were treated with IO alone or in combination with chemotherapy, in first (47.0%) or second line (102 – 29.2%). In 133 (32.1%) cases, LB was performed at IO baseline, while in 101 (24.5%) cases at IO progression. Among the most relevant genes, STK11+/LKB1+ confers the worst OS (HR for OS 2.12 months, CI 95% 1.26 – 3.56; p = 0.005), regardless treatments. LKB1+/KRAS+ have a poorer OS than LKB1-/KRAS- (OS: 13 vs 24 m, HR 2.34 95% IC 1.19 – 4.61) and LKB1-/KRAS+ (OS: 13 vs 34 m HR 2.99 95% IC 1.36-6.54). When analyzing the effect of KRAS on IO and non-IO arms, KRAS-/IO have the best prognosis compared to KRAS+/non-IO which have the worst prognosis, while KRAS+/IO seems to have a similar prognosis to KRAS-/non-IO pts (HR 0.82 95% IC 0.43 – 1.58). Results reported on LB confirmed previous reports on tissue: STK11+ pts, have the worst prognosis regardless treatments. KRAS+ compare to STK11+/KRAS+ pts and STK11-/KRAS- pts seems to have the best prognosis. IO seems to play a relevant role on survival regardless KRAS status, in fact when using IO the negative prognostic effect of KRAS+ pts decreases and becomes similar to KRAS-/non-IO pts.