Cancer‐related deaths are caused principally by recurrence and metastasis arising from residual disease, whose therapeutic responses has been suggested to be substantially different from primary tumors. However, experimental animal models designed for evaluating the therapeutic responses of residual disease are mostly lacking. To overcome this deficiency, we have developed a preclinical model that recapitulates the progression for advanced nonsmall cell lung cancer (NSCLC). An archived Lewis lung carcinoma mouse tumor, propagated only through serial in vivo transplantation and never adapted to cell culture, was stably labeled using lentivirus‐encoded biomarkers, consistently expressed through an RNA polymerase II promoter. Labeled tumors were inoculated into syngeneic immunocompetent mice to ensure superior tumor–host interactions. Primary tumors were resected on reaching a predetermined size, followed by treatment in a setting akin to postsurgical first‐line adjuvant chemotherapy and routine imaging to monitor the progression of pulmonary metastasis. We discovered that efficacious treatment, instead of reducing disease growth rates, significantly prolonged disease‐free survival and overall survival. As in the clinic, cisplatin‐based regimes were more effective in this model. However, the response of metastases to specific agents could not be predicted from, and often opposed, their effects on subcutaneous “primary” tumors, possibly due to their distinct growth kinetics and host interactions. We here introduce a clinically relevant model of residual metastatic disease that may more accurately predict the therapeutic response of recurrent, metastatic disease.