VEGF-A blockade overcomes liver metastases resistance to chemoimmunotherapy in patients with advanced non-squamous NSCLC
Matthieu Roulleaux-Dugage, Andrey Yurchenko, Sergey Nikolaev, Barzin Nabet, Stéphanie Corgnac, Céline Anquetil, Minu K Srivastava, Velimir Gayevskiy, Virginia McNally, Laura Mezquita, Jean-Luc Perfettini, Severine Mouraud, Christophe Massard, Benjamin Besse, Yohann Loriot, Aurelien Marabelle, Nathalie Chaput, Edouard AuclinPurpose
Liver metastases (LMs) confer resistance to immune checkpoint blockade in advanced non-squamous non‐small cell lung cancer (ns‐NSCLC), likely through an immunosuppressive tumor microenvironment (TME). We hypothesized that vascular endothelial growth factor (VEGF)-A blockade, by remodeling the immunosuppressive TME, could restore the benefit of chemoimmunotherapy in LM+ patients. Here, we report the first comparative analysis of chemoimmunotherapy with and without bevacizumab specifically in this population.
Experimental design
Data were analyzed from the phase III IMpower130 and IMpower150 trials in treatment‐naïve, EGFR/ALK-wild‐type patients with ns‐NSCLC. Treatment arms included chemotherapy (CT), CT plus atezolizumab (CT+immunotherapy (IT)), CT plus bevacizumab (CT+antiangiogenic (AA)), and CT+IT+ AA, with LM as a stratification factor. Survival outcomes were assessed by Kaplan-Meier estimates and multivariate Cox regression analyses. Bulk and single‐cell RNA sequencing data were used to characterize the LM TME.
Results
Among 1,713 patients, 236 (13.8%) presented with LMs. In IMpower130, LM+ patients derived no overall survival (OS) benefit from CT plus IT (CT+IT) compared with CT alone (HR for OS: 1.05; 95% CI 0.63 to 1.73). In contrast, in IMpower150, the addition of bevacizumab to CT+IT (CT+IT+ AA) significantly improved progression-free survival (PFS; HR: 0.49) and OS (HR: 0.52) in LM+ patients—an effect not observed in patients without LM. Baseline transcriptomic exploratory analyses from IMpower150 revealed a myeloid-enriched, lymphocyte-depleted TME. Single-cell RNA sequencing further demonstrated VEGF-A/VEGFR-1/2 crosstalk between macrophages and endothelial cells, as well as an autocrine VEGF-A/VEGFR-1 loop within macrophages.
Conclusion
The addition of bevacizumab to chemoimmunotherapy was associated with improved survival in ns‐NSCLC specifically in patients with LMs. These hypothesis-generating findings suggest that the benefit may stem from disruption of VEGF-A-driven immunosuppressive signaling in the liver, but require prospective confirmation.