Despite the addition of immune checkpoint blockade to first-line chemotherapy, the prognosis for patients with small cell lung cancer (SCLC) is still devastating. For the subset of SCLC with somatostatin receptor (SSTR) overexpression, radiopharmaceutical therapy (RPT) might be an effective future treatment option. Methods: Here, we present the case of a heavily pretreated stage IV SCLC patient showing an exceptional response to SSTR-directed RPT. A comprehensive translational work-up consisting of histopathologic, immunohistochemical, and molecular pathology analyses at different time points during treatment and especially of lesions with discordant tracer uptake was performed. Results: Besides a promising response to RPT, interesting signs of clonal dynamics under therapy and, most importantly, SSTR downregulation of some lesions as a potential evasion mechanism to SSTR-directed RPT could be identified. Conclusion: This unique investigation for a clinical–molecular understanding of novel treatment paradigms in SCLC may provide the basis for future treatment designs.