Active therapy or best supportive care after disease progression to both nivolumab and cabozantinib in metastatic renal cell carcinoma: The BEYOND study (Meet-Uro 19).
Authors: Giorgione Roberta , Santini Daniele , Stellato Marco , Basso Umberto , Bimbatti Davide , Palmieri Valeria Emma , Doni Laura , Antonuzzo Lorenzo , Bersanelli Melissa , Buti Sebastiano , De Giorgi Ugo , Galli Luca , Sbrana Andrea , Conca Raffaele , Carella Claudia , Naglieri Emanuele , Mini Enrico , Pignata Sandro , Procopio Giuseppe , Roviello Giandomenico 
Published: March 2021

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Background: Nivolumab is approved in the second or further line of treatment for patients with metastatic renal cell carcinoma (mRCC); cabozantinib is approved in a similar setting of patients. Unfortunately, no evidence is currently available regarding the best treatment option after disease progression to both nivolumab and cabozantinib. The aim of this study is to compare the treatment choices after progression to nivolumab and cabozantinib including patients followed in best supportive care (BSC) or active therapy. Methods: In this retrospective observational study, we selected 42 patients from 8 Italian cancer centers. Enrolled patients had progressed to both nivolumab and cabozantinib and subsequently referred to active treatment or BSC. Primary endpoint of the study was the OS of patients on active treatment versus BSC. Secondary endpoints were ORR, PFS and OS of patients on active treatment who received sorafenib versus everolimus. Results: The median age was 65 years, 76.2% were male. The majority of patients had undergone nephrectomy (78.6%), had clear cell histology (83%) and were at intermediate-poor risk at the diagnosis (85.7%). The most frequent site of metastatic disease in the general population and in patients referred to BSC was the lung (73.8% and 88.9%, respectively). For patients referred to active treatment, the most frequent site of metastasis was bone (70.8%). Sunitinib (71.4%), nivolumab (64.3%), and cabozantinib (54.7%) were the most commonly used drugs in the I, II and III lines of treatment, respectively. After progression to both nivolumab and cabozantinib 42.9% of patients were referred to BSC, while 57.1% received active treatment (28.6% everolimus, 16.7% sorafenib, 4.8% sunitinib, 4.8% IL2-HD, 2.4% lenvatinib + everolimus). Median OS was 13 (95% CI: 4-NR) and 3 months (95% CI: 2-4) in patients on active treatment versus BSC ( p=0.001). Patients treated with sorafenib had better disease control when compared with those treated with everolimus (SD 71.4% versus 16.7%, PD 14.3% versus 58.3%; p=0.03), but no significant advantage in terms of PFS (5 versus 3 months, 95% CI: 2-6 versus 2-5; p= 0.5) and OS (NR versus 13 months, 95% CI: 3-NR versus 2-NR; p=0.2) was observed. Conclusions: After treatment with both nivolumab and cabozantinib, when possible, the choice of an active treatment seems to produce an OS advantage when compared with BSC. However, although sorafenib seems to demonstrate better results, we cannot indicate which is the drug of choice, as no significant advantage was shown in terms of OS or PFS from the comparison between sorafenib and everolimus. The limitations of this study are given by the size of the sample examined and its retrospective nature. Further studies are needed to confirm whether active treatment choice is associated with improved OS.