1989PWNT pathway mutations (APC/CTNNB1) and immune checkpoint inhibitors (ICI) response in metastatic non-small cell lung cancer (NSCLC) patients

Abstract Background WNT pathway mutations (mut) are uncommon in NSCLC. Recent preclinical studies suggest that APC/CTNNB1 mut induce immune resistance in lung adenocarcinoma but how they may impact on immunotherapy response in the clinics remains unclear. Objective: our aim is to describe the clinical outcomes - Overall survival (OS) and progression-free-survival (PFS) and response rate (RR) - of a metastatic NSCLC cohort with APC/CTNNB1 mut treated with immunotherapy. Methods We selected those patients with metastatic NSCLC and APC or CTNNB1 mut detected through Amplicon-Seq (tissue), Foundation (plasma), Guardant (plasma) or exome sequencing (tissue) performed from 2014 to 2018. Results Incidence of APC/CTNNB1 mut in NSCLC in our hospital has been 1,26% and 0,7% respectively by Amplicon-Seq (tissue) and 10.4% and 1.04% respectively by exome sequencing (tissue). We identified 27 patients with APC (81%) or CTNNB1 (19%) mutations. The median age of the patients was 59 years (44-74), 72% of them were male and most frequent histology was adenocarcinoma (66%). Fifteen of the patients received ICI, 27% as a first line treatment and 47% as a second line. Interestingly, 1 patient had EGFR mut (exon 19 and 20) and 4 patients had KRAS mut. Median OS of the whole cohort from date of diagnosis was 24.5 months (CI95% 13.7-NA). Median OS was 23.5 months (CI95% 10.4-NA) for those patients who harboured CTNNB1 mut and 57.3 months (CI95% 13.7-NA) for those patients with APC mut (HR 1.8, CI95% 0.32-10, p = 0.5). Median PFS with ICI was 6.6 months (CI95% 0.9-NA). Median PFS was 0.7 months (CI95% 0.5-NA) for those patients with CTNNB1 mut and 8.9 months (CI95% 1.8-NA) with APC mut (HR 6.7, CI95% 1.1-41, p = 0.04). None of the 2 CTNNB1 mut patients responded to ICI, while RR in the APC mut cohort was 30% (4 out of 13). Conclusions In our cohort, APC mut did not show to impair clinical outcomes. Few CTNNB1 mut cases hinder conclusive analyses. Correlation with other predictive biomarkers such as tumor mutation burden and PDL1 expression is ongoing. Legal entity responsible for the study Vall d´Hebron Institute of Oncology (VHIO). Funding Grant from: Carlos III Institute of Health, Madrid, Spain: PI14/01248 and PI17/00938. Disclosure P. Iranzo: Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Advisory / Consultancy, Travel / Accommod