Background: Survival of patients with metastatic renal cell carcinoma (mRCC) has improved with targeted therapies, but they are rarely curative and often result in therapeutic resistance. Cabozantinib is an oral, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) as well as MET and AXL, known to influence tumor growth, metastasis, and angiogenesis. Aged fragile patients are not usually included in clinical trials and efficacy and tolerability of available treatments in this population are unknown. The aim of this trial is to evaluate safety and efficacy of cabozantinib in aged patients with mRCC. Methods: Pilot open-label, multicenter study that includes previously untreated fragile (G8 scale < 14 points and one or two reversible deficiencies in ADL-activities in daily life- or CISR-G grade 2 comorbidities or weight loss of 5-10% during the last 3 months) patients > 70 years old with histological or cytological diagnosis of mRCC, ECOG 0-2 and adequate organ function. Patients received cabozantinib 40 mg p.o. once daily until unacceptable toxicity or other reasons for treatment discontinuation. Dose can be escalated to 60 mg if 40 mg is considered tolerated and can be reduced to 20 mg if 40 mg is considered not tolerated. Results: Twenty patients are included in this interim analysis, 9 of them are still under treatment. Median age was 78 years, 70% were men and 68% had ECOG 0 and metastatic disease at diagnosis. None of them received radiotherapy. 55% of pts were vulnerable according to G8 score, 5% had grade 3 comorbidities according to CIRS-G scale, 20% had a score < 3 in mini-COG test, 100% had score < 10 in Gijon's social-familial evaluation scale, 25% were vulnerable according to Vulnerable Elders Survey 13 (score ≥3) and 45% were frail and at risk of disability according to Short Physical Performance Battery (score < 10). Median duration of treatment was 3.3 months (max. 20.4). In none of the patients was the dose escalated to 60 mg/d and in 7 patients was the dose reduced to 20 mg/d. Of the 12 patients evaluable for response, 2 achieved partial response and 7 stable disease, with a clinical benefit rate of 75%. Most frequent toxicities (all grades) were: asthenia (30%), diarrhea (25%), mucosal inflammation (15%), dysgeusia (15%) and hypothyroidism (15%). Reported grade 3 toxicities were thrombocytopenia, pyrexia and hypertension (5%). Two patients stopped study treatment due to toxicity: perforated ischemic colitis and skin toxicity. Conclusions: Safety profile in aged people is similar of that observed in previous studies. The frequency of toxicities is slightly lower than expected in this aged fragile population, probably because the patients received treatment at a dose of 40 mg/d, lower than the approved dose. Clinical trial information: NCT04134390.