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.

Lenvatinib with or Without Everolimus in Patients with Metastatic Renal Cell Carcinoma After Immune Checkpoint Inhibitors and Vascular Endothelial Growth Factor Receptor-Tyrosine Kinase Inhibitor Therapies

“…Limited trial data exist on the efficacy of VEGFR-TKIs or cabozantinib after progression on ICIs. In three real-world studies, second-line VEGFR-TKIs, including cabozantinib, had similar or improved efficacy after disease progression on ICIs, compared with the post-VEGFR-TKI setting [18][19][20]. Cabozantinib is a multitarget TKI that inhibits VEGFR1-3, MET, AXL, RET, ROS1, TYRO3, MER, KIT, and FLT3 and is approved in the first-line and subsequent-line settings for mRCC based on results from the CABOSUN and METEOR trials, respectively [21][22][23][24].…”

Effect of systemic therapies or best supportive care after disease progression to both nivolumab and cabozantinib in metastatic renal cell carcinoma: The Meet‐Uro 19BEYOND study

“…This is partially due to the exclusion of heavily pre‐treated patients from most clinical trials, which are predominantly arranged in the 1 and 2 L settings. The 4 L setting has not been extensively investigated and these data are mostly from retrospective studies, which do not include patients who progressed to both nivolumab and cabozantinib 4,5,16,17,22–25 …”

Antiangiogenic Properties of Axitinib versus Sorafenib Following Sunitinib Resistance in Human Endothelial Cells—A View towards Second Line Renal Cell Carcinoma Treatment

“…Accordingly, Deuker et al has not seen major differences in the efficacy of several TKIs after an immunotherapy-based combination regimen [ 12 ]. Overall survival of patients treated with axitinib or sorafenib, subsequent to discontinuing an ICI-TKI regimen or sunitinib therapy, was similar [ 13 , 14 ]. In contrast, others have attested to better results with axitinib, instead of sorafenib, as a second line option [ 7 , 15 ].…”