title: High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801.
abstract: OBJECTIVE
  Vaccine alternatives to high-dose interferon alfa-2b therapy (HDI), the current standard adjuvant therapy for high-risk melanoma, are of interest because of toxicity associated with HDI. The GM2 ganglioside is a well-defined melanoma antigen, and anti-GM2 antibodies have been associated with improved prognosis. We conducted a prospective, randomized, intergroup trial to evaluate the efficacy of HDI for 1 year versus vaccination with GM2 conjugated to keyhole limpet hemocyanin and administered with QS-21 (GMK) for 96 weeks (weekly x 4 then every 12 weeks x 8).
  
  
  METHODS
  Eligible patients had resected stage IIB/III melanoma. Patients were stratified by sex and number of positive nodes. Primary end points were relapse-free survival (RFS) and overall survival (OS).
  
  
  RESULTS
  Eight hundred eighty patients were randomized (440 per treatment group); 774 patients were eligible for efficacy analysis. The trial was closed after interim analysis indicated inferiority of GMK compared with HDI. For eligible patients, HDI provided a statistically significant RFS benefit (hazard ratio [HR] = 1.47, P = .0015) and OS benefit (HR = 1.52, P = .009) for GMK versus HDI. Similar benefit was observed in the intent-to-treat analysis (RFS HR = 1.49; OS HR = 1.38). HDI was associated with a treatment benefit in all subsets of patients with zero to > or = four positive nodes, but the greatest benefit was observed in the node-negative subset (RFS HR = 2.07; OS HR = 2.71 [eligible population]). Antibody responses to GM2 (ie, titers > or = 1:80) at days 29, 85, 365, and 720 were associated with a trend toward improved RFS and OS (P2 = .068 at day 29).
  
  
  CONCLUSIONS
  This trial demonstrated a significant treatment benefit of HDI versus GMK in terms of RFS and OS in melanoma patients at high risk of recurrence.
authors.affiliation: Division of Hematology-Oncology and Department of Pathology, Department of Medicine, University of Pittsburgh Cancer Institute Melanoma Center, University of Pittsburgh Medical Center, Pittsburgh, PA 15213-2582, USA. jmk@jiimmy.harvard.edu
authors.forename: J M
authors.initials: JM
authors.lastname: Kirkwood
authors.forename: J G
authors.initials: JG
authors.lastname: Ibrahim
authors.forename: J A
authors.initials: JA
authors.lastname: Sosman
authors.forename: V K
authors.initials: VK
authors.lastname: Sondak
authors.forename: S S
authors.initials: SS
authors.lastname: Agarwala
authors.forename: M S
authors.initials: MS
authors.lastname: Ernstoff
authors.forename: U
authors.initials: U
authors.lastname: Rao
mesh_terms: D000328:Adult; D000368:Aged; D019496:Cancer Vaccines / Q000276:immunology*; D018572:Disease-Free Survival; D005260:Female; D005678:G(M2) Ganglioside / Q000276:immunology*; D006433:Hemocyanins / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D009367:Neoplasm Staging; D011446:Prospective Studies; D011994:Recombinant Proteins; D012503:Saponins; D014611:Vaccination; D018074:Vaccines, Conjugate / Q000276:immunology
chemical_list: D019496:Cancer Vaccines; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D012503:Saponins; D018074:Vaccines, Conjugate; D005678:G(M2) Ganglioside; C078785:saponin QA-21V1; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin