title: Safety and Efficacy of Nivolumab in Patients With Metastatic Renal Cell Carcinoma Treated Beyond Progression: A Subgroup Analysis of a Randomized Clinical Trial.
abstract: OBJECTIVE
  Response patterns with immunotherapy may differ from those of other treatments. This warrants further investigation because some patients may benefit from continued immunotherapy beyond Response Evaluation Criteria in Solid Tumors (RECIST)-defined first progression.
  
  
  OBJECTIVE
  To evaluate the safety and potential benefit of treatment with nivolumab, a programmed cell death 1 immune checkpoint inhibitor, beyond investigator-assessed first progression in patients with metastatic renal cell carcinoma (mRCC).
  
  
  METHODS
  Subgroup analysis of a blinded, randomized, multicenter, phase 2 dose-ranging trial initiated May 31, 2011, including patients with clear-cell mRCC previously treated with antiangiogenic therapy. Data cutoffs for this subgroup analysis were May 15, 2013, for progression-free survival and objective response rate and March 5, 2014, for overall survival and duration of response. In this analysis, patients treated beyond first progression received their last dose of nivolumab more than 6 weeks after RECIST-defined progression, and patients not treated beyond first progression discontinued nivolumab before or at RECIST-defined progression.
  
  
  METHODS
  Nivolumab 0.3, 2, or 10 mg/kg intravenously every 3 weeks.
  
  
  METHODS
  Safety and efficacy of nivolumab treatment.
  
  
  RESULTS
  Of 168 patients (median [range] age, 61 [37-81] years; 72% male) randomized to nivolumab, 154 experienced progression (36 were treated beyond first progression, 26 were treated beyond first progression for ≤6 weeks, and 92 were not treated beyond first progression), 13 were treated and did not experience progression, and 1 was not treated. Prior to first progression, the RECIST-defined objective response rate was 14% (5 patients) and 16% (15 patients), and median progression-free survival was 4.2 (95% CI, 2.8-5.5) and 2.6 (95% CI, 1.5-3.9) months in patients treated and not treated beyond progression, respectively. Following initial progression, 25 (69%) patients treated beyond progression experienced subsequent tumor reduction or stabilization in target lesion size. The incidence of treatment-related adverse events was higher in patients treated beyond progression (n = 29 [81%]) vs those not treated beyond progression (n = 61 [66%]); however, after adjusting for length of treatment exposure, incidence was lower in patients treated beyond progression (322.9 vs 518.7 incidence rate/100 patient-years for patients treated vs not treated beyond progression).
  
  
  CONCLUSIONS
  In this subgroup analysis, a proportion of patients who continued treatment beyond RECIST-defined first progression demonstrated sustained reductions in tumor burden or stabilization in the size of target lesions, with an acceptable safety profile. Further analysis will help define the clinical benefit for patients with mRCC treated with nivolumab beyond progression.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT01354431.
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Saby
authors.initials: S
authors.lastname: George
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Motzer
authors.affiliation: Department of Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Hammers
authors.affiliation: Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor.
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Redman
authors.affiliation: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Kuzel
authors.affiliation: Department of Medicine, University of Washington and Fred Hutchinson Cancer Research Center, Seattle.
authors.forename: Scott S
authors.initials: SS
authors.lastname: Tykodi
authors.affiliation: Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Plimack
authors.affiliation: Global Biometric Sciences, Bristol-Myers Squibb, Princeton, New Jersey.
authors.forename: Joel
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Global Clinical Research, Bristol-Myers Squibb, Princeton, New Jersey.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Waxman
authors.affiliation: Department of Hematology and Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio.
authors.forename: Brian I
authors.initials: BI
authors.lastname: Rini
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000556:secondary; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D000077594:Nivolumab; D066066:Response Evaluation Criteria in Solid Tumors; D015996:Survival Rate; D047368:Tumor Burden
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000077594:Nivolumab