PIK3CA Alterations in NSCLC: Clinical Characteristics of a “Neglected” Population of Oncogene-Addicted Patients

<b>Background/Objectives</b>: Alterations of the phosphatidylinositol 3-kinase catalytic subunit alpha gene (<i>PIK3CA</i>) are identified in approximately 2-4% of non-small cell lung cancer (NSCLC) cases; however, their biological and clinical relevance in NSCLC remains incompletely understood. This study aimed to comprehensively characterize the clinical and molecular features, as well as outcomes, of patients with <i>PIK3CA</i>-altered NSCLC across different disease stages. <b>Methods</b>: We conducted a retrospective multicenter analysis of 62 patients with histologically confirmed early-stage or advanced NSCLC-harboring <i>PIK3CA</i> alterations (mutations and/or gene amplifications) treated between 2015 and 2022 at three Italian institutions. Demographic, clinical, pathological, and molecular variables were systematically collected and analyzed. <b>Results</b>: <i>PIK3CA</i> mutations accounted for the majority of alterations (90.3%), while amplifications represented 9.7%. The most frequent mutations involved exon 9 (66.1%), predominantly E545K and E542K, followed by exon 20 (16.1%). Most patients were current or former smokers, and concomitant oncogenic alterations were detected in 59.7% of cases, most commonly <i>KRAS</i> mutations. A history of prior malignancy was reported in 24.6% of cases. In the metastatic setting, adenocarcinoma histology was associated with significantly longer overall survival (OS) compared with non-adenocarcinoma histologies (18.4 vs. 5.5 months; <i>p</i> = 0.02). Patients with PD-L1-negative tumors demonstrated a numerically longer OS than those with PD-L1-positive tumors; however, this difference did not reach statistical significance (19.1 vs. 5.4 months; <i>p</i> = 0.05). No statistically significant survival differences were observed according to specific <i>PIK3CA</i> mutation subtypes or treatment strategies. <b>Conclusions</b>: <i>PIK3CA</i>-altered NSCLC represents a molecularly heterogeneous and clinically understudied subgroup, frequently characterized by co-occurring oncogenic alterations. In this study, no definitive prognostic or predictive role for PIK3CA alterations could be established. Nevertheless, these findings provide a descriptive real-world characterization of this molecular subset and support the need for validation in larger, prospectively designed, molecularly stratified studies.