title: The high-dose aldesleukin "select" trial: a trial to prospectively validate predictive models of response to treatment in patients with metastatic renal cell carcinoma.
abstract: OBJECTIVE
  High-dose aldesleukin (HD IL2) received FDA approval for the treatment of metastatic renal cell carcinoma (MRCC) in 1992, producing a 14% objective response rate (ORR) and durable remissions. Retrospective studies suggested that clinical and pathologic features could predict for benefit. The Cytokine Working Group conducted this prospective trial to validate proposed predictive markers of response to HD IL2.
  
  
  METHODS
  Standard HD IL2 was administered to prospectively evaluate whether the ORR of patients with mRCC with "good" predictive pathologic features based on an "integrated selection" model [ISM (e.g., clear-cell histology subclassification and carbonic anhydrase-9 (CA-9) IHC staining] was significantly higher than the ORR of a historical, unselected population. Archived tumor was collected for pathologic analysis including tumor programmed death-ligand 1 (PD-L1) expression.
  
  
  RESULTS
  One hundred and twenty eligible patients were enrolled between June 11 and September 7; 70% were Memorial Sloan Kettering Cancer Center (New York, NY) intermediate risk, 96% had clear cell RCC, and 99% had prior nephrectomy. The independently assessed ORR was 25% (30/120, 95% CI, 17.5%-33.7%, P = 0.0014; 3 complete responses, 27 partial responses) and was higher than a historical ORR. Thirteen patients (11%) remained progression free at 3 years and the median overall survival was 42.8 months. ORR was not statistically different by ISM classification ("good-risk" 23% vs. "poor-risk" 30%; P = 0.39). ORR was positively associated with tumor PD-L1 expression (P = 0.01) by IHC.
  
  
  CONCLUSIONS
  In this prospective, biomarker validation study, HD IL2 produced durable remissions and prolonged survival in both "good" and "poor-risk" patients. The proposed ISM was unable to improve the selection criteria. Novel markers (e.g., tumor PD L1 expression) appeared useful, but require independent validation.
authors.affiliation: Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston, Massachusetts. dmcdermo@bidmc.harvard.edu.
authors.forename: David F
authors.initials: DF
authors.lastname: McDermott
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Su-Chun
authors.initials: SC
authors.lastname: Cheng
authors.affiliation: Brigham and Women's Hospital, Dana-Farber/Harvard Cancer Center, Boston, Massachusetts.
authors.forename: Sabina
authors.initials: S
authors.lastname: Signoretti
authors.affiliation: University of Washington, Seattle, Washington.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Margolin
authors.affiliation: Loyola University, Stritch School of Medicine, Chicago, Illinois.
authors.forename: Joseph I
authors.initials: JI
authors.lastname: Clark
authors.affiliation: Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sosman
authors.affiliation: Our Lady Of Mercy Medical Center, New York, New York.
authors.forename: Janice P
authors.initials: JP
authors.lastname: Dutcher
authors.affiliation: Indiana University, Simon Cancer Center, Indianapolis, Indiana.
authors.forename: Theodore F
authors.initials: TF
authors.lastname: Logan
authors.affiliation: Providence Cancer Center, Earle A. Chiles Research Institute, Portland, Oregon.
authors.forename: Brendan D
authors.initials: BD
authors.lastname: Curti
authors.affiliation: Dartmouth-Hitchcock Medical Center, Norris Cotton Cancer Center, Dartmouth, New Hampshire.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Ernstoff
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Leonard
authors.initials: L
authors.lastname: Appleman
authors.affiliation: Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Michael K K
authors.initials: MK
authors.lastname: Wong
authors.affiliation: Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Nikhil I
authors.initials: NI
authors.lastname: Khushalani
authors.affiliation: Lawrence and Memorial Hospital, Waterford, Connecticut.
authors.forename: Leslie
authors.initials: L
authors.lastname: Oleksowicz
authors.affiliation: Karmanos Cancer Institute, Detroit, Michigan.
authors.forename: Ulka N
authors.initials: UN
authors.lastname: Vaishampayan
authors.affiliation: Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston, Massachusetts.
authors.forename: James W
authors.initials: JW
authors.lastname: Mier
authors.affiliation: Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston, Massachusetts.
authors.forename: David J
authors.initials: DJ
authors.lastname: Panka
authors.affiliation: Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston, Massachusetts.
authors.forename: Rupal S
authors.initials: RS
authors.lastname: Bhatt
authors.affiliation: Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston, Massachusetts.
authors.forename: Alexandra S
authors.initials: AS
authors.lastname: Bailey
authors.affiliation: Department of Urology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Bradley C
authors.initials: BC
authors.lastname: Leibovich
authors.affiliation: Department of Urology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Eugene D
authors.initials: ED
authors.lastname: Kwon
authors.affiliation: University of California Los Angeles Medical Center, Santa Monica, California.
authors.forename: Fairooz F
authors.initials: FF
authors.lastname: Kabbinavar
authors.affiliation: University of California Los Angeles Medical Center, Santa Monica, California.
authors.forename: Arie S
authors.initials: AS
authors.lastname: Belldegrun
authors.affiliation: Cedars-Sinai's Samuel Oschin Comprehensive Cancer Institute, West Hollywood, California.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Figlin
authors.affiliation: University of California Los Angeles Medical Center, Santa Monica, California.
authors.forename: Allan J
authors.initials: AJ
authors.lastname: Pantuck
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Meredith M
authors.initials: MM
authors.lastname: Regan
authors.affiliation: Georgetown-Lombardi Cancer Center, Washington, D.C.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Atkins
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage / Q000031:analogs & derivatives*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D011994:Recombinant Proteins / Q000008:administration & dosage; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D007376:Interleukin-2; D011994:Recombinant Proteins; C082598:aldesleukin