P45.11 Co-occurring CDKN2A/B Alteration Is Associated With Worse Survival Outcomes in Advanced ALK-Positive Non-Small Cell Lung Cancer

Abstract

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have demonstrated promising activity in ALK-positive (ALK+) non-small cell lung cancer (NSCLC). However, co-occurring genetic alterations, especially those occurring downstream of tumor initiation oncogenes, may influence the efficacy of target therapies. This study analyzed whether co-occurring alterations influence survival outcomes to second-generation anti-ALK therapy in metastatic ALK+ NSCLC patients. From March 2018 to February 2020, in a single center, we analyzed prospectively 44 tumor specimens of patients with metastatic ALK+ NSCLC. Those tumor samples with positive immunohistochemistry, assessed by D5F3 assay, underwent genotyping using the Next-Generation Sequencing platform (Foundation One CDx). Progression-free survival (PFS) and overall survival (OS) were estimated for the total cohort and main commutations. Forty-two patients were analyzed, mean age was 52.5±10.7 years, females in 59.5%, never smokers in 73.8%, and ECOG PS (0-1) in 90.5%. The lung adenocarcinoma subtype was observed in 97.5% of tumor samples, and the predominant solid pattern was the most frequently reported in 23.8%. All patients received a second-generation ALK-TKI in the first or second-line, 82.5% and 17.5%, respectively. Alectinib, brigatinib, and ceritinib were administered in 79%, 13.1%, and 7.9% of the cases. EML4-ALK 3a/b variant was the most common (47.6%), followed by variant 1 in 38.1%. The median PFS in the overall cohort was 22.3 months. No significant differences were observed in the progression-free intervals according to the distinct variants, neither when the variable was dichotomized (3a/b variant vs. others). The most frequent co-occurrent alterations were TP53 (23.8%) and CDKN2A/B (14.3%). Loss of the CDKN2A/B gene was the most common genetic aberration (83.3%) within this subgroup. Among patients with co-current CDKN2A/B alterations, median PFS was significantly shorter than CDKN2A/B wild-type patients (9.3 vs. 28.2 months), p=0.047. The median PFS was shorter in patients harboring a commutation in TP53; however, this difference was not significant (10.7 vs. 22.8 months), p=0.147. The presence of CDKN2A/B co-occurring alteration was correlated significantly with higher baseline serum carcinoembryonic antigen (CEA) levels (p=0.008), and other EML4-ALK fusion variants rather than 3a/b (p=0.02). After adjusting for confounding variables, CDKN2A/B co-occurring alterations remained strongly associated with poorer PFS outcomes. Co-occurring genetic alterations in CKN2A/B confers a poor prognosis in patients treated with a second-generation ALK-TKI in metastatic ALK+ NSCLC patients. The loss of the CDKN2A/B gene was the most frequent alteration seen in this subgroup of patients.