Cabozantinib (Cabo) beyond progression improves survival in advanced renal cell carcinoma patients: The CABEYOND study (Meet-Uro 21).
Authors: Procopio Giuseppe , Mennitto Alessia , Di Maio Massimo , Zattarin Emma , Maruzzo Marco , De Giorgi Ugo , Santini Daniele , Buti Sebastiano , Casadei Chiara , Soraru' Mariella , Di Lorenzo Giuseppe , Messina Carlo , Mucciarini Claudia , Roviello Giandomenico , Buttigliero Consuelo , Stellato Marco , Sepe Pierangela , Pignata Sandro , De Braud Filippo G. , Verzoni Elena 
Published: March 2021

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Background: The multikinase inhibitor cabozantinib (Cabo) is an effective treatment option for metastatic renal cell carcinoma (mRCC). However, data on the optimal sequencing of Cabo and other available therapies are lacking. In particular, the strategy of continuing Cabo administration after disease progression (PD) has never been investigated yet. In light of its ability of inhibiting MET and AXL, which are implied in VEGFR acquired resistance, the hypothesis of a prolonged efficacy in slowing tumor growth, despite first radiological PD, is worth to be investigated. Methods: We conducted a retrospective multicenter study of mRCC patients (pts) treated with oral Cabo as second or subsequent line between 2014 and 2020 in 11 Italian Oncology units. Our study population included pts treated beyond RECIST first PD due to the clinical benefit and tolerance to therapy demonstrated. As a control group we analyzed pts treated with other therapies (thyrosin-kinase inhibitors (TKIs), everolimus, nivolumab or other) after first radiological PD with Cabo. Our aim was to evaluate the post-progression outcome according the two treatment strategies: Cabo beyond PD or other subsequent therapy. Results: 89 pts were included in the analysis: 45 pts received Cabo beyond PD and 44 another therapy: 22 pts nivolumab, 7 everolimus, 6 sorafenib and the others lenvatinib plus everolimus, sunitinib, HD-IL2, pazopanib or axitinib. The median age of all pts was 61.6 years (22.7-83.2) and 77.5% were male. 40.4% and 31.5% of pts had received one or two prior treatment lines, respectively; the remaining 28.1% received Cabo > 3 line. At Cabo start, 83.9% were intermediate-poor risk according IMDC score (77.8% in CABO beyond PD and 90.5% in the control group) and the most common metastatic sites were lung (76.4%), lymph nodes (69.7%), bone (56.2%), liver (30.3%) and brain (14.8%). The objective response rate to Cabo before PD was significantly higher in pts continuing Cabo beyond PD than in those who were treated with other after first radiological PD (46.7% vs 25%, p = 0.03) and a longer but not statistically significant PFS was observed (median 8.1 vs 5.9 months, p = 0.377). Moreover, the median number of prior therapy lines was significantly higher for pts who were treated with Cabo beyond PD than other (2 vs 1, p = 0.016). Median duration of treatment with Cabo beyond PD was 6.4 months. In addition, continuing Cabo beyond PD was associated with a significantly better post-progression overall survival (OS) than switching to other therapy at PD (median OS 16.9 vs 13.2 months, Hazard Ratio 0.66, 95%CI 0.48 – 0.92, p = 0.011). Conclusions: This study showed a longer post-progression OS in pts continuing Cabo beyond PD than in those who switched to another therapy. With the limitations of a retrospective analysis, this is the first evidence suggesting that maintaining Cabo beyond PD is an effective strategy in pts with mRCC.