VEGF-TKI Outcomes in Metastatic Renal Cell Carcinoma According to Prior Immune Checkpoint Inhibitor or VEGF-TKI: A Scoping Review and Exploratory Analysis

<b>Background/Objectives</b>: Most patients with metastatic renal cell carcinoma (mRCC) progress on first-line immune checkpoint inhibitor (ICI). Subsequent vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) is standard. Due to the rapid evolution in treatment landscape, data directly comparing outcomes of VEGF-TKI following ICI versus VEGF-TKI alone are limited. This scoping review aimed to explore whether VEGF-TKI following prior ICI is associated with improved outcome, potentially reflecting a treatment sequence effect. <b>Methods</b>: PubMed/MEDLINE and ClinicalTrials.gov were searched systematically to identify phase 2/3 prospective clinical trials that investigated VEGF-TKI in patients who had progressed after ≥1 therapy published from 2004. Included studies were summarised by prior therapy and reported outcomes. Data from subgroups/arms were extracted and weighted overall response rate (ORR), progression free survival (PFS) and overall survival (OS) calculated for patients pretreated with VEGF-TKI versus ICI. An exploratory, hypothesis generating analysis was performed comparing outcomes between patients who received prior VEGF-TKI only or ICI-based therapy. <b>Results</b>: In total, 17 clinical trials were included: 2538 patients had prior VEGF-TKI (15 subgroups/arms) and 724 prior ICI-based therapy (11 subgroups/arms). In prior VEGF-TKI, weighted mORR was 8% (IQR 6-16%) versus 28% (IQR 20-41%) post-ICI. Weighted mPFS was 3.9 m (IQR 3.6-5.4) with prior VEGF-TKI versus 8.3 m (IQR 7.4-10.3) in prior ICI group. Weighted mOS was 15.2 m (IQR 11.1-16.6) versus 22.1 m (IQR 10.9-22.1) with prior ICI. <b>Conclusions</b>: Improved outcomes in ICI pretreated population in this exploratory analysis suggests ongoing biological benefit of ICI therapy. As prospective 2L randomised studies are not feasible, we conclude that VEGF therapy in pretreated mRCC is at least as good, if not better, since the introduction of 1st line ICI.