Osteosarcoma is an aggressive and highly metastatic cancer in both dogs and humans. Gefitinib, a small molecule receptor tyrosine kinase inhibitor that targets Epidermal Growth Factor Receptor (EGFR), approved as a first-line treatment for human metastatic non-small cell lung carcinoma (NSCLC) that contain specific EGFR mutations, has also been shown to improve survival in non-EGFR mutated NSCLC when intercalated with traditional cytotoxic chemotherapy. This potential EGFR-independent effect may occur in part through the effects of gefitinib on other molecular targets, including the serine/threonine kinase Receptor-Interacting Protein kinase 2 (RIPK2), which is expressed on many immune cells, including macrophages. In experimental models of osteosarcoma, perioperative gefitinib has been shown to reduce metastatic burden through RIPK2 and macrophage dependent mechanism. Based on these results, we predict that the addition of gefitinib to SOC will show clinical benefit in canine osteosarcoma, thereby setting a precedent for the evaluation of such combinations in clinical trials involving human patients.