PIK3CA-Mutant Non-Small Cell Lung Cancer Refractory to Two Lines of Chemoimmunotherapy: A Case Report

<i>PIK3CA</i> mutations play a critical role in tumorigenesis by driving constitutive activation of the phosphoinositide 3-kinase (PI3K) signaling pathway. These mutations have been identified in a small subset of non-small cell lung cancer (NSCLC), but their clinical significance and response to chemoimmunotherapy remain unclear. A 44-year-old man with a 24-pack-year smoking history presented with hoarseness and exertional dyspnea. Imaging demonstrated an irregular left upper-lobe pulmonary nodule consistent with the primary lesion, along with metastatic involvement of the left frontal lobe, cervical-mediastinal lymph nodes, right kidney, and lumbar vertebrae. Endobronchial ultrasound-guided transbronchial needle aspiration of the station 4R lymph node confirmed adenosquamous carcinoma. Molecular analysis revealed a <i>PIK3CA</i> E545K mutation without coexisting oncogenic driver alterations. The programmed cell death ligand 1 tumor proportion score indicated low expression (1-9%). Despite first-line carboplatin, nab-paclitaxel, and pembrolizumab followed by second-line carboplatin, pemetrexed, nivolumab, and ipilimumab, the disease progressed rapidly, and the patient died four months after diagnosis. This case illustrates that isolated <i>PIK3CA</i>-mutant NSCLC can be highly refractory to conventional chemoimmunotherapy, including regimens incorporating a cytotoxic T-lymphocyte-associated antigen 4 inhibitor. Further clinical investigation of PI3K-targeted therapies is warranted to establish effective treatment strategies for <i>PIK3CA</i>-mutant NSCLC.