Impact of Concurrent Genomic Alterations on Clinical Outcomes in Patients With ALK-Rearranged NSCLC

Introduction Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have shown promising activity against advanced ALK-rearranged non-small cell lung cancer (NSCLC). However, co-occurring genetic alterations, such as CDKN2/B or TP53, may negatively affect the efficacy of targeted therapies. Patients and Methods From December 2017 to December 2022, this study cohort analyzed Next-Generation Sequencing data of 116 patients with metastatic ALK-rearranged NSCLC from five Latin-American cancer centers. Clinicopathological and molecular features were associated with clinical outcomes and risk of brain metastasis in patients with and without concurrent somatic alterations. Results All patients (n=116) received a second-generation ALK-TKI, and alectinib was selected in 87.2% of cases. Co-alterations occurred in 62% of the cases; the most frequent were TP53 mutations (27%) and CDKN2A/B loss (18%). Loss of CDKN2A/B was associated with an increased risk of brain metastasis, with a cumulative incidence of 33.3% versus 7.4%. Compared with patients without co-alterations, patients with concurrent CDKN2A/B loss (n=21) had a shorter median PFS [10.2 vs. 34.2 months; p<0.001] and OS [26.2 vs. 80.7 months; p<0.001]. In the multivariate analysis, co-occurring CDKN2A/B loss was associated with poorer PFS and OS, despite the presence of other somatic co-alterations, TP53 mutations, brain metastasis, and ECOG PS. Conclusions This study confirmed the worse prognostic value, which depicted co-occurring alterations in patients with ALK rearrangement. CDKN2A/B loss was significantly associated with worse outcomes and a higher risk of brain metastases. The evidence shown in our study may help select patients with ALK-positive tumors suitable for treatment escalation and closer brain follow-up.