Systemic therapy for advanced clear cell renal cell carcinoma after discontinuation of immune-oncology and VEGF targeted therapy combinations

Abstract

Background: Several phase 3 studies reported positive results for combinations of Immune-Oncology (IO) and Vascular Endothelial Growth Factor (VEGF) targeted therapies in patients with metastatic clear cell Renal Cell Carcinoma (ccRCC). However, there are limited data on outcomes to systemic therapy after IO-VEGF combinations.

Methods: A retrospective analysis was performed on patients with metastatic ccRCC treated at the Memorial Sloan Kettering Cancer Center and Cleveland Clinic who initiated systemic therapy post IO-VEGF including combinations with VEGF receptor (VEGFR) tyrosine kinase inhibitors (IO-TKI) and combinations with the anti-VEGF monoclonal antibody bevacizumab (IO-Bev). The study objectives were to evaluate the objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) on systemic therapy post IO-VEGF. RECIST v1.1 criteria were used to determine radiological responses and progression. Survival estimates were evaluated with the Kaplan-Meier methods and the log-rank test from the start of systemic therapy post IO-VEGF to the event of interest.

Results: A total of fifty-nine patients were treated post discontinuation of IO-VEGF regimens which included IO-Bev (n = 35; 59%) and IO-TKI (n = 24; 41%). Fifty-eight patients (98%) received IO-VEGF regimens as part of a clinical trial. Subsequent therapies included cabozantinib (n = 22; 37%), axitinib (n = 18; 31%), pazopanib (n = 4; 7%), lenvatinib and everolimus (n = 4; 7%), mTOR inhibitor monotherapy (n = 3; 5%), axitinib and dalantercept (n = 2; 3%), sunitinib (n = 1; 2%), sorafenib (n = 1; 2%), and treatment with agents on unreported clinical trials (n = 4; 7%). Patients treated on unreported clinical trials were excluded from the efficacy analysis. Post IO-VEGF, the ORR was 25% and median PFS was 12.0 months (95% CI, 8.2-24.5). Median OS was 24.5 months (95% CI, 12-NE) and 12 months OS rate was 63.3% (95% CI, 48.6-74.9). We observed no differences post IO-VEGF OS when comparing IO- TKI vs IO-Bev (Log-rank p = 0.73).

Conclusions: Post IO-VEGF, most patients received VEGFR-TKIs. In this setting, VEGFR-TKIs demonstrated clinical activity and remain a viable option for salvage therapy after progression on IO-VEGF.

Keywords: IO combinations; Immune-oncology; RCC; Survival; VEGF.

Fig. 1

Kaplan Meier curve estimating PFS for 55 patients from the next line of systemic therapy for kidney cancer after discontinuation of IO-VEGF. Median PFS was 12 months (95% CI, 8.2–24.5) and 12-month PFS probability was 49.6% (95% CI, 33.2–64.0). Median follow up time for progression-free survivors was 8.5 months (range: 0, 30). PFS (Progression Free Survival), IO-VEGF (Immune-Oncology and Vascular Endothelial Growth Factor targeted therapy)

Fig. 2

Kaplan Meier curve estimating OS for 55 patients from the next line of systemic therapy for kidney cancer after discontinuation of IO-VEGF. Median OS was 24.5 months (95% CI, 12.0– NE) and 12-month OS probability was 63.3% (95% CI, 48.6–74.9). Median follow up time for survivors was 18 months (range: 0, 44). OS (Overal Survival), IO-VEGF (Immune-Oncology and Vascular Endothelial Growth Factor targeted therapy)

Fig. 3

Kaplan Meier curve comparing OS for 55 patients from the next line of systemic therapy for kidney cancer after discontinuation of IO-VEGF by prior received IO-TKI vs. IO-Bev with no statistical difference between the groups (Log-rank p = 0.73). OS (Overall Survival), IO-VEGF (Immune-Oncology and Vascular Endothelial Growth Factor targeted therapy), IO-TKI (IO-Tyrosine Kinase Inhibitor), IO-Bev (IO-Bevacizumab)

Fig. 4

Kaplan Meier curve comparing OS for 55 patients from the next line of systemic therapy for kidney cancer after discontinuation of IO-VEGF by subsequent therapy: Cabozantinib vs. Axitinib vs. Other agents with no statistical difference among the three (Log-rank p = 0.25). OS (Overall Survival), IO-VEGF (Immune-Oncology and Vascular Endothelial Growth Factor targeted therapy)