Background: Emerging agents blocking the PD-1 pathway show activity and may transform the current treatment landscape of mccRCC. The aim of this study was to evaluate the efficacy and safety of VEGFR -TKI therapy after PD-1 treatment. Methods: Patients (pts) with mccRCC treated with PD-1 monotherapy or in combination - with either cytotoxic T-lymphocyte antigen 4(CTLA4) inhibitor (PD1/CTLA4) or TKI (PD-1/VEGFR-TKI) - who subsequently received VEGFR-TKI, were retrospectively reviewed. The efficacy end points were objective response rate (ORR) and progression-free survival (PFS) stratified by type of prior PD-1 regimen. Safety by type and PD-1 exposure was also evaluated. Results: 63 patients were included, 84% of pts had at least one VEGFR-targeted therapy prior to PD-1-based therapy. The ORR for VEGFR -TKI therapy (68%, 17%, 14% and 1% pts received axitinib, pazopanib, sunitinib and sorafenib, respectively) after any PD-1 combination was 27% (17/63 PR). An additional 26 (41%) pts achieved SD. The median PFS (mPFS) was 6.9 months (mo) (95%, CI: 3.7 to 10.1). In the analysis by type of prior PD-1 therapy, there was a trend toward a higher ORR in pts who had prior therapy with PD1 monotherapy or PD1/CTLA4 therapy 33% versus 14% for pts previously treated with PD-1/VEGFR-TKI therapy (p = 0.094). The mPFS was longer in those pre-treated with PD-1 monotherapy or PD-1/CTLA4 therapy: 8.3 mo (95%, CI: 4.0-12.7) compared to those who previously received PD-1/VEGFR-TKI combinations: 6.4 mo (95%, CI: 3.9-8.8); p = 0.049. The most common adverse events (AEs) (all grades/g3-4) were asthenia (69%/11%), hypertension (41%/2%) and diarrhea (30%/0%). One patient experienced grade-2 immune-related colitis during VEGFR-TKI therapy. Conclusions: The efficacy and safety of VEGFR-TKIs after PD-1 treatment was demonstrated in this retrospective study. The response rate was lower and the mPFS shorter in those pts who received prior PD-1 in combination with VEGFR-TKI. PD-1 exposure does not seem to influence the safety of subsequent VEGFR-TKI treatment compared to historical control and immune-related AEs were rare.