title: 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.
abstract: 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 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore.
authors.forename: R
authors.initials: R
authors.lastname: Nadal
authors.affiliation: Department of Oncology, Levine Cancer Institute, Charlotte.
authors.forename: A
authors.initials: A
authors.lastname: Amin
authors.affiliation: Fox Chase Cancer Center-Temple University Health System, Philadelphia.
authors.forename: D M
authors.initials: DM
authors.lastname: Geynisman
authors.affiliation: Department of Oncology, Memorial Sloan Kettering Cancer Center, New York.
authors.forename: M H
authors.initials: MH
authors.lastname: Voss
authors.affiliation: Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston.
authors.forename: M
authors.initials: M
authors.lastname: Weinstock
authors.affiliation: Fox Chase Cancer Center-Temple University Health System, Philadelphia.
authors.forename: J
authors.initials: J
authors.lastname: Doyle
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore.
authors.forename: A
authors.initials: A
authors.lastname: Viudez
authors.affiliation: Fox Chase Cancer Center-Temple University Health System, Philadelphia.
authors.forename: E R
authors.initials: ER
authors.lastname: Plimack
authors.affiliation: Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston.
authors.forename: D F
authors.initials: DF
authors.lastname: McDermott
authors.affiliation: Department of Oncology, Memorial Sloan Kettering Cancer Center, New York.
authors.forename: R
authors.initials: R
authors.lastname: Motzer
authors.affiliation: Department of Hematology and Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, USA.
authors.forename: B
authors.initials: B
authors.lastname: Rini
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore hhammer2@jhmi.edu.
authors.forename: H J
authors.initials: HJ
authors.lastname: Hammers
mesh_terms: D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002986:Clinical Trials as Topic; D018572:Disease-Free Survival; D000068338:Everolimus / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics*; D020123:Sirolimus; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D047428:Protein Kinase Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068338:Everolimus; D040262:Receptors, Vascular Endothelial Growth Factor; D020123:Sirolimus
keywords: PD-1 inhibitor; ipilimumab; nivolumab; renal cell carcinoma; vascular endothelial growth factor receptor–tyrosine kinase inhibitor