Background <p>Breast and gastrointestinal (GI) cancers remain leading causes of cancer-related mortality worldwide, particularly in the metastatic setting, where therapeutic options are limited, and drug resistance inevitably develops. This study aims to evaluate the feasibility and safety of [¹⁷⁷Lu]Lu-FAPI-2286 in patients with breast and GI cancers.</p> Methods <p>In this retrospective, single-center, observational analysis, we evaluated the safety, tolerability, and preliminary efficacy of [¹⁷⁷Lu]Lu-FAPI-2286 in 14 patients with advanced metastatic breast (<i>n</i> = 10) and GI (<i>n</i> = 4) malignancies who had exhausted standard therapies. Adverse events were graded per CTCAE. Clinical response was assessed by evaluating symptomatic outcomes and biochemical markers, and radiographic assessment was performed using post-therapy imaging.</p> Results <p>The cohort (median age 46.5 years) was heavily pre-treated, with extensive bone, liver, and lung metastases. [¹⁷⁷Lu]Lu-FAPI-2286 was generally well tolerated; hematologic toxicity included Grade 3 anemia in two patients and one case of Grade 4 thrombocytopenia. Two patients experienced transient post-administration pain flares. Symptomatic pain relief was reported in four patients (28.6%), particularly among those with predominant bone metastases. Onset occurred approximately one week after therapy and lasted up to one month between cycles. Radiographic outcomes showed stable disease (SD) in 28.6% and progressive disease (PD) in 21.4% of evaluable patients; however, 50% of patients could not be evaluated radiographically due to rapid clinical decline. Median follow-up was 3.25 months (range: 2-17.5 months).</p> Conclusions <p>In this study, [¹⁷⁷Lu]Lu-FAPI-2286 demonstrated feasibility and an acceptable safety profile, with meaningful palliative benefits in a subset of patients. No objective responses were observed, and the primary benefit was palliative.</p>