Optimization of First-Line Treatment Options in HER2-Altered Lung Adenocarcinoma: A Real-World Study.

OBJECTIVES: HER2 alterations are identified in 2%-4% of lung adenocarcinoma, indicating poor clinical outcomes. Chemotherapy alone (C) or in combination with bevacizumab (BC), immune checkpoint inhibitors (IC), or both (IBC) are standard options in the first-line setting; however, optimal therapy and beneficiary populations remain unclear. METHODS: Patients with Stage IV HER2-altered lung adenocarcinoma from four cancer centers in China were retrospectively analyzed. The patients received C, BC, IC, or IBC as the first-line treatments. Clinical outcomes, including progression-free survival (PFS) and overall survival (OS), were evaluated. The tumor immune microenvironment (TIME) characteristics were analyzed to explore the beneficiary populations with different treatments. RESULTS: IBC treatment generated the longest mPFS and OS among four schemes. Subgroup analyses showed that IBC resulted in longer PFS in patients with brain or bone metastases compared to IC. IBC generated significant benefits in younger patients, nonsmokers, and those with oligometastases versus BC. In patients with low density of PD-1(+)CD8(+) T-cells or high density of CD163(+) macrophages in the TIME, IBC treatment resulted in the longest PFS, followed by BC treatment. CONCLUSIONS: IBC treatment generated optimal efficacy as first-line therapy for HER2-altered lung adenocarcinoma. Patients with low PD1(+)CD8(+) T-cell or high CD163(+) macrophage infiltration benefited more from IBC treatment.