A Study of Combining Cabozantinib and Atezolizumab for Advanced/Metastatic NSCLC (Cabatezo-1)

For metastatic/advanced non-small cell (NSCLC) patients who do not have targetable mutations, the combination of chemotherapy with immunotherapy targeting the programmed death-1 and its ligand (PD-1/L1) is now a standard of care. In addition, recent studies also demonstrated that immunotherapy doublet using anti-PD-1 agent nivolumab and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) agent ipilimumab could be another valid option. However, largely due to the immunosuppressive tumor microenvironment, the therapeutic response remains suboptimal in NSCLC patients with PD-L1 tumor proportion score (TPS) lower than 1% (aka PD-L1 negative). For example, the objective response rate (ORR) in KEYNOTE-189 was 32.3% using pembrolizumab plus chemotherapy, and only 27.3% in Checkmate 227 study using nivolumab and ipilimumab, in the PD-L1 negative population. These observations necessitate the search for novel combinations to benefit our PD-L1 negative NSCLC patients. The investigators hypothesize that the combination of cabozantinib and atezolizumab is such an innovative strategy based on the following rationales: 1) cabozantinib is a multi-kinase inhibitor, and some of the targets, for example the vascular endothelial growth factor (VEGF) pathway is notorious to confer immune suppressive tumor microenvironment. In fact, our previous study has demonstrated that anti-VEGF synergizes anti-PD-1 in preclinical model. Consistent with this, cabozantinib has been shown to increase tumor infiltrative cytotoxic CD8+ T cells, reduce immune suppressive T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs), as well as activate anti-tumor innate immunity in multiple solid tumors; 2) at the animal level, cabozantinib was found synergistic with anti-PD-1 agents to elicit anti-tumor immune response; and 3) more importantly, at the human level, the combination of cabozantinib with atezolizumab was found safe in Cohort 7 of the phase 1b COSMIC-021 study and achieved 27% ORR in previously immunotherapy-treated NSCLC - suggesting a potentially higher efficacy if such combination is to be used in the 1st line setting. The investigators therefore propose here the combination of cabozantinib and atezolizumab to be used as the 1st line treatment for advanced/metastatic NSCLC with negative PD-L1 expression.