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

## TL;DR

This study explores how prior immunotherapy affects the effectiveness of VEGF inhibitors in treating advanced kidney cancer, suggesting better outcomes when immunotherapy is used first.

## Contribution

The study provides exploratory evidence that prior immunotherapy may improve outcomes when followed by VEGF inhibitors in metastatic renal cell carcinoma.

## Key findings

- Patients pretreated with immunotherapy had higher response rates and longer survival when treated with VEGF inhibitors.
- The study suggests a potential treatment sequence effect favoring immunotherapy followed by VEGF inhibitors.
- Outcomes after immunotherapy were significantly better than after prior VEGF inhibitors alone.

## Abstract

In this review we looked at clinical trials involving patients with advanced kidney cancer (metastatic renal cell carcinoma) who were treated with targeted therapies known as VEGF inhibitors. These drugs are often used after the first treatment stops working. We compared outcomes between patients who had received prior immunotherapy versus those who received only prior VEGF-inhibitor. Our findings suggest that patients who were previously treated with immunotherapy may respond better to VEGF-inhibitor, which may be due to the lasting effects of immunotherapy even after the treatment has been stopped. While our study cannot prove this, it highlights a trend and the need for further research into the best way to sequence treatments for kidney cancer.

Background/Objectives: 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. Methods: 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. Results: 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. Conclusions: 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.