PMID- 27059553 OWN - NLM STAT- MEDLINE DCOM- 20171227 LR - 20231005 IS - 1569-8041 (Electronic) IS - 0923-7534 (Print) IS - 0923-7534 (Linking) VI - 27 IP - 7 DP - 2016 Jul TI - Safety and clinical activity of vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitors after programmed cell death 1 inhibitor treatment in patients with metastatic clear cell renal cell carcinoma. PG - 1304-11 LID - 10.1093/annonc/mdw160 [doi] AB - BACKGROUND: Emerging agents blocking the programmed cell death 1 (PD-1) pathway show activity in metastatic clear cell renal cell carcinoma (mRCC). The aim of this study was to evaluate the efficacy and safety of vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)-tyrosine kinase inhibitor (TKI) therapy after PD-1 inhibition. PATIENTS AND METHODS: Patients with mRCC treated with anti-PD-1 antibody (aPD-1) monotherapy or in combination (with VEGFR-TKI or ipilimumab) that subsequently received VEGFR-TKI were retrospectively reviewed. The efficacy end points were objective response rate (ORR) and progression-free survival (PFS) stratified by the type of prior PD-1 regimen. Safety by the type and PD-1 exposure was also evaluated. RESULTS: Seventy patients were included. Forty-nine patients received prior therapy with immune checkpoint inhibitors (CPIs) alone and 21 had combination therapy of aPD-1 and VEGFR-TKI. Overall, ORR to VEGFR-TKI after PD-1 inhibition was 28% (19/68) and the median PFS was 6.4 months (mo) (4.3-9.5). ORR to VEGFR-TKI after aPD-1 in combination with VEGFR-TKI was lower than that in patients treated with VEGFR-TKI after CPI alone (ORR 10% versus 36%, P = 0.039). In the multivariable analysis, patients treated with prior CPI alone were more likely to achieve an objective response than those treated with aPD-1 in combination with VEGFR-TKI (OR = 5.38; 95% CI 1.12-26.0, P = 0.03). There was a trend toward numerically longer median PFS in the VEGFR-TKI after the CPI alone group, 8.4 mo (3.2-12.4) compared with 5.5 mo (2.9-8.3) for those who had VEGFR-TKI after aPD-1 in combination with VEGFR-TKI (P = 0.15). The most common adverse events (AEs) were asthenia, hypertension, and diarrhea. CONCLUSIONS: The efficacy and safety of VEGFR-TKIs after PD-1 inhibition were demonstrated in this retrospective study. The response rate was lower and the median progression-free survival was shorter in those patients who received prior PD-1 in combination with VEGFR-TKI. PD-1 exposure does not seem to significantly influence the safety of subsequent VEGFR-TKI treatment. CI - (c) The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com. FAU - Nadal, R AU - Nadal R AD - The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore. FAU - Amin, A AU - Amin A AD - Department of Oncology, Levine Cancer Institute, Charlotte. FAU - Geynisman, D M AU - Geynisman DM AD - Fox Chase Cancer Center-Temple University Health System, Philadelphia. FAU - Voss, M H AU - Voss MH AD - Department of Oncology, Memorial Sloan Kettering Cancer Center, New York. FAU - Weinstock, M AU - Weinstock M AD - Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston. FAU - Doyle, J AU - Doyle J AD - Fox Chase Cancer Center-Temple University Health System, Philadelphia. FAU - Zhang, Z AU - Zhang Z AD - The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore. FAU - Viudez, A AU - Viudez A AD - The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore. FAU - Plimack, E R AU - Plimack ER AD - Fox Chase Cancer Center-Temple University Health System, Philadelphia. FAU - McDermott, D F AU - McDermott DF AD - Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston. FAU - Motzer, R AU - Motzer R AD - Department of Oncology, Memorial Sloan Kettering Cancer Center, New York. FAU - Rini, B AU - Rini B AD - Department of Hematology and Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, USA. FAU - Hammers, H J AU - Hammers HJ AD - The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore hhammer2@jhmi.edu. LA - eng GR - P30 CA008748/CA/NCI NIH HHS/United States GR - R01 CA140917/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160407 PL - England TA - Ann Oncol JT - Annals of oncology : official journal of the European Society for Medical Oncology JID - 9007735 RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) RN - 0 (Protein Kinase Inhibitors) RN - 0 (VEGFA protein, human) RN - 0 (Vascular Endothelial Growth Factor A) RN - 9HW64Q8G6G (Everolimus) RN - EC 2.7.10.1 (Receptors, Vascular Endothelial Growth Factor) RN - W36ZG6FT64 (Sirolimus) SB - IM CIN - Nat Rev Urol. 2016 Jun;13(6):301. PMID: 27142126 MH - Adult MH - Aged MH - Carcinoma, Renal Cell/*drug therapy/genetics/pathology MH - Clinical Trials as Topic MH - Disease-Free Survival MH - Everolimus/administration & dosage MH - Female MH - Humans MH - Male MH - Middle Aged MH - Neoplasm Metastasis MH - Programmed Cell Death 1 Receptor/antagonists & inhibitors/*genetics MH - Protein Kinase Inhibitors/*administration & dosage/adverse effects MH - Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors/*genetics MH - Sirolimus MH - Vascular Endothelial Growth Factor A/antagonists & inhibitors PMC - PMC6276905 OTO - NOTNLM OT - PD-1 inhibitor OT - ipilimumab OT - nivolumab OT - renal cell carcinoma OT - vascular endothelial growth factor receptor-tyrosine kinase inhibitor EDAT- 2016/04/10 06:00 MHDA- 2017/12/28 06:00 PMCR- 2017/07/01 CRDT- 2016/04/10 06:00 PHST- 2015/12/05 00:00 [received] PHST- 2016/03/29 00:00 [accepted] PHST- 2016/04/10 06:00 [entrez] PHST- 2016/04/10 06:00 [pubmed] PHST- 2017/12/28 06:00 [medline] PHST- 2017/07/01 00:00 [pmc-release] AID - S0923-7534(19)35688-1 [pii] AID - mdw160 [pii] AID - 10.1093/annonc/mdw160 [doi] PST - ppublish SO - Ann Oncol. 2016 Jul;27(7):1304-11. doi: 10.1093/annonc/mdw160. Epub 2016 Apr 7.