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© 2001 American Society for Clinical Oncology
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/C509801From the 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; Department of Biostatistics, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA; College of Medicine, University of Illinois at Chicago, Chicago, IL; Department of Surgery, Division of Surgical Oncology, University of Michigan, Ann Arbor, MI; Department of Medicine, Division of Hematology-Oncology, Dartmouth-Hitchcock Medical Center, Lebanon, NH; Eastern Cooperative Oncology Group, Boston, MA; and Southwest Oncology Group, San Antonio, TX. Address reprint requests to John M. Kirkwood, MD, Department of Medicine, University of Pittsburgh School of Medicine, Melanoma Center, University of Pittsburgh Cancer Institute, 200 Lothrop St, Pittsburgh, PA 15213-2582; email: jmk{at}jimmy.harvard.edu
PURPOSE: 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). PATIENTS AND 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 CONCLUSION: 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.
PATIENTS WITH stage T4N0M0 (American Joint Committee on Cancer [AJCC] stage IIB) and stage T1-4N1M0 (AJCC stage III) disease are at high risk of recurrence after definitive surgery. These patients, as well as patients with regional nodal recurrences, are candidates for adjuvant therapy and have been the focus of a series of Eastern Cooperative Oncology Group (ECOG) and United States Intergroup studies of the ECOG, together with the Southwest Oncology Group and Cancer and Leukemia Group B. The pivotal ECOG trial E1684 demonstrated that adjuvant therapy with high-dose interferon alfa-2b (IFN  2b; Schering-Plough, Kenilworth, NJ), administered intravenously (IV) for 4 weeks and subcutaneously (SC) for 48 weeks, significantly prolongs relapse-free survival (RFS) and overall survival (OS) compared with observation in high-risk melanoma patients (stage IIB and III).1 Given these data, high-dose IFN2b (20 megaunits [MU]/m2/d IV x 5 days a week for 4 weeks and 10 MU/m2 SC three times per week [TIW] x 48 weeks) was approved as adjuvant therapy for high-risk melanoma by the United States Food and Drug Administration (FDA) in 1995. This regimen is currently the standard of care for adjuvant therapy of high-risk melanoma patients treated off-protocol and the reference standard for evaluation of alternative modalities such as vaccines in current United States cooperative group trials. Given the toxicities associated with HDI,1-5 alternative regimens have been widely investigated. Vaccines are an attractive alternative to HDI because, theoretically, they can induce an antitumor immune response that may protect against relapse, and they are associated with minimal toxicity. A variety of vaccine strategies have been investigated and fall into two general categories. Polyvalent vaccines, including allogeneic or autologous tumor cells,6-12 tumor cell lysates,13,14 and shed antigens,15,16 can potentially present a myriad of antigenic targets to the immune system, thereby stimulating multiple antibody and T-cell responses. Tumor cell vaccines have been reported to induce occasional objective tumor regressions in patients with metastatic disease,8,9,11,12 and retrospective studies have suggested that disease outcome may be correlated with antibody and delayed-type hypersensitivity responses to some vaccines10 and to complement-dependent cytotoxicity.17 A series of molecularly defined melanoma antigens, including gangliosides and peptides, can elicit either antibody and/or T-cell responses, respectively. These molecules represent more focused and reproducible vaccine candidates compared with polyvalent cell-derived vaccines. The ganglioside GM2 is a serologically well-defined melanoma antigen and the most immunogenic ganglioside expressed on melanoma cells.18,19 Studies conducted at Memorial Sloan-Kettering Cancer Center have demonstrated that administration of GM2 in combination with Bacillus Calmette-Guérin (BCG) induced immunoglobulin (Ig)M anti-GM2 antibodies in the majority of patients and that these antibody responses were correlated with improved RFS and OS in AJCC stage III melanoma patients.20,21 Subsequently, a variety of GM2 vaccine formulations have been studied, and a commercial vaccine preparation has been selected, consisting of GM2 coupled to keyhole limpet hemocyanin (KLH) and combined with the QS-21 adjuvant22; this formulation is hereafter referred to as the GMK vaccine (Progenics Pharmaceuticals, Inc, Tarrytown, NY). Immunization of melanoma patients with the GMK vaccine has been shown to induce high titers of IgM antibodies in more than 80% of patients as well as IgG antibodies that had not been previously observed with GM2 plus BCG.22 These induced anti-GM2 antibodies have been reported to mediate complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity of melanoma cell lines in vitro.22-24
On the basis of these data, we initiated Intergroup trial E1694 to evaluate the efficacy and safety of the GMK vaccine in comparison with high-dose IFN
Patient Selection Eligible patients had histologically proven stage IIB/III primary melanoma of cutaneous origin, clinically detected nodal metastasis arising from an unknown primary, or a first clinically detectable nodal recurrence, without evidence of systemic metastases (T4N0, T1 to 4pN1cN0, TxcN1, or T1 to 4cN1 primary or recurrent). This corresponds to T4a/bN0M0, and any TN1 to 3a/bM0 in the revised AJCC stage groupings.25 Patients with deep primary lesions (> 4.0 mm Breslow depth) with microscopic satellite lesions within 2 cm of the primary tumor were eligible; however, T4 patients with gross SC invasion or grossly apparent satellite lesions were not eligible. If there was no clinical evidence of lymph node metastasis, patients were not required to undergo lymphadenectomy. These patients were randomized within 56 days of wide excision of the primary tumor (minimum 1-cm margins) or of lymphadenectomy. Patients with histologically or clinically detected regional lymph node metastasis received wide local excision with a minimum margin of 1 cm and complete lymphadenectomy within 56 days of randomization. The definition of nodal involvement required the identification of tumor cells by routine stains, and neither positive immunohistochemical stains nor positive reverse transcriptase polymerase chain reactions alone were considered sufficient evidence of tumor involvement for study entry.
Eligible patients had normal organ function, no significant medical or psychiatric comorbidity, and an ECOG performance status of 0 or 1. Patients who had received prior adjuvant radiotherapy, chemotherapy, or immunotherapy, or for whom IFN
Patients were stratified by sex and according to the number of positive nodes at lymphadenectomy (zero, one, two to three, or
Treatment
In the GMK arm, a permanent 50% dose reduction was implemented for any occurrence of grade 3 toxicity. Patients with recurrence or persistence of grade 3 toxicity for two additional doses or with grade 4 toxicity at any time were removed from the study. Dose reduction in the IFN 2b arm was performed in accordance with the common toxicity criteria established by the National Cancer Institute Cancer Treatment Evaluation Program.26 If criteria dictating dose modification were met, then treatment was withheld until recovery from toxicity. Treatment was resumed with a 33% dose reduction after the first treatment interruption for toxicity; a 66% dose reduction was required after a second treatment interruption for toxicity. Dose re-escalation was not attempted. Any patient who required a third treatment interruption for toxicity was removed from the study.
Study Design
The study design was based on a cure-rate model and involved two primary comparisons (RFS and OS) for the GMK vaccine versus high-dose IFN
At the recommendation of the independent Data Safety Monitoring Committee, based on the third interim analysis in April 2000 (corresponding to the milestone of 58% relapse events and 41% of death events), E1694 was unblinded in June 2000, before reaching the originally stipulated event goals, and at that time, the results were disclosed to all investigators and participants. This decision was based on early stopping rules, which used an O’Brien-Fleming upper boundary, in case GMK was superior to high-dose IFN The database was subsequently augmented with data obtained from a review of each patient’s chart. Information was evaluated on the type of lymph node assessment performed in each case (ie, SLN biopsy, elective or therapeutic lymph node dissection, or clinical evaluation) and the extent of lymph node involvement found at the original pathologic evaluation (ie, number of lymph nodes containing microscopic v macroscopic disease). These data were collected retrospectively; therefore, some data were missing.
Statistical Analysis
Patient Characteristics The trial accrued 880 patients from June 1996 to October 1999, and 774 patients (88%; 389 in the GMK arm and 385 in the IFN 2b arm) were eligible for the efficacy and safety interim analysis in April 2000. As of December 31, 1999, 106 patients (12%) were ineligible because of protocol violations, including inappropriate stage of disease (n = 36), interval more than 70 days from biopsy (n = 21), inappropriate or undocumented laboratory values (n = 20), inappropriate surgery (n = 18), prior chemotherapy, radiotherapy, or comorbidity (n = 8), and second malignancy (n = 3). The trial was powered based on an anticipated 10% ineligibility rate. Within the eligible patient population, 37 patients refused assigned therapy and were never treated; however, these patients were included in all efficacy analyses.
Randomization achieved an excellent balance between treatment groups for age, sex, ECOG performance status, and disease stage. Table 1 lists the distribution of known prognostic factors between treatment groups. The majority of patients (approximately 80%) in each arm had an ECOG performance status of 0. Lymph node involvement was documented clinically or pathologically at study entry in 77% of patients; the remaining 23% of patients (101 patients in each treatment group) were classified as node-negative (T4N0). Within the node-negative subset, 29 patients in the GMK arm and 27 patients in the IFN
Impact of IFN 2b Versus GMK on RFS and OSAs of June 2000, when the study was unblinded, there were 249 relapses and 133 deaths (58% and 41% of the targeted number of events, respectively). Median duration of follow-up was 16 months. Of 774 eligible patients, 151 (39%) of 389 patients treated with GMK and 98 (25%) of 385 patients treated with IFN 2b had experienced relapse. The HR for RFS was 1.47 (P1 = .0015; 95% confidence interval [CI], 1.14 to 1.90) for eligible cases and 1.49 (P1 = .00045) in the ITT analysis in favor of IFN2b ( Table 3), indicating nearly a 50% decrease in the hazard of relapse for patients treated with IFN2b compared with GMK. Because these P values for RFS crossed the protocol-specified constant lower boundary (as well as a symmetric O’Brien-Fleming lower boundary) for study termination, the study was closed at that time. A Cox regression analysis adjusting for sex, ECOG performance status, nodal status, and age demonstrated a similar RFS benefit (P2 = .0027 for eligible patients; P2 = .0007 in the ITT analysis) for patients treated with IFN2b therapy versus GMK (Table 3). The Kaplan-Meier estimates of RFS in the eligible population are shown in Fig 2; the median RFS was 22.5 months in the GMK arm and was not reached in the IFN2b arm. The estimated 2-year RFS rate for eligible cases was 62% in the IFN2b arm versus 49% in the GMK arm.
High-dose IFN 2b therapy also demonstrated a significant OS benefit compared with GMK. There were 81 deaths in the GMK arm and 52 deaths in the IFN2b arm. The HR for OS was 1.52 (P1 = .009; 95% CI, 1.07 to 2.15) for eligible cases and 1.38 (P1 = .023) in the ITT analysis in favor of IFN2b (Table 3), indicating a 52% increase in the hazard of death for eligible patients treated with GMK compared with the reference agent IFN2b. The Cox regression analysis, adjusting for prognostic variables, also demonstrated a significant survival advantage associated with IFN2b therapy in both the eligible and ITT populations (Table 3). The Kaplan-Meier estimates of OS for the eligible population are shown in Fig 3; the median OS was not reached in either treatment group. The estimated 2-year OS rate for eligible cases was 78% in the IFN2b arm versus 73% in the GMK arm.
The Kaplan-Meier estimates of RFS and OS based on the ITT analysis are shown in Fig 4 and are quite similar to the estimates based on eligible patients.
Subset Analysis Analysis of the hazard of relapse and death in each stratification group by the number of positive lymph nodes demonstrated the superiority of IFN 2b over GMK in all nodal subsets ( Table 4). Kaplan-Meier estimates of RFS by treatment group for each nodal subset are shown in Fig 5. Patients with no nodal metastasis (n = 202) had the greatest reduction in the risk of relapse and death. A two-sided log-rank test adjusting for number of positive nodes demonstrated that node-negative patients treated with IFN2b had a statistically significant RFS benefit compared with patients treated with GMK (P2 = .015 for eligible patients and P2 = .012 in the ITT analysis). The two-sided log-rank analysis also demonstrated a significant OS benefit for IFN2b over GMK (P2 = .046) in the eligible node-negative population.
Serologic Correlations With Clinical Outcome in the GMK Arm The proportion of patients in the GMK arm with positive antibody titers (  1:80 by enzyme-linked immunosorbent assay) at day 0, 29, 85, and 365 is listed in Table 5. The majority of assessable patients (88%) had an IgM response at the day 29 evaluation (actual day drawn, days 7 to 36), and the frequency of this primary immune response decreased thereafter but was still evident at day 365. An IgG response was observed in 26% of patients at the day 29 evaluation, and the proportion of responding patients increased to 50% by day 365. Evaluation of anti-GM2 antibody responses to GMK demonstrated that patients with IgG and IgM titers 1:80 had improved RFS and OS compared with nonresponders by Kaplan-Meier estimates, although the trend toward improved OS only approached marginal significance (P2 = .068) for patients with IgG or IgM titers 1:80 at day 29.
Safety Summary The most common grade 3 and 4 adverse events (per World Health Organization criteria) reported in this trial are listed in Table 6. The most common toxicities associated with IFN 2b included fatigue, cytopenias, elevation of liver enzymes, and neurologic symptoms. The majority of adverse events were of grade 3 severity. Among patients in the IFN2b arm, 45 (10%) of 440 patients discontinued treatment because of adverse events, and there were no treatment-related deaths. As of June 2000, 101 patients had completed a full year of IFN2b therapy, and 128 patients were continuing on therapy. On the basis of a recent analysis, as of February 2001, the number of treatment delays and dose reductions owing to toxicity or any reason are listed in Table 7. Injection site reactions were the most common grade 3 adverse events reported in the GMK arm; no patients discontinued treatment because of adverse events.
Intergroup trial E1694 is the largest adjuvant trial for resected high-risk melanoma yet reported. This trial was designed to test the efficacy of the GMK ganglioside vaccine for 2 years versus high-dose IFN 2b for 1 year, which is the current FDA-approved standard of care. A randomized controlled trial of GM2 combined with BCG conducted at the Memorial Sloan-Kettering Cancer Center demonstrated a trend toward an RFS benefit for GM2/BCG versus BCG alone21 and provided the clinical rationale for comparing the improved GMK vaccine against high-dose IFN2b in a large randomized trial. Although the GMK vaccine was well tolerated, the results reported here demonstrate that high-dose IFN2b significantly improved RFS and OS compared with GMK vaccination. There was no evidence of any adverse effect of GMK on RFS or OS; in fact, the trend toward improved outcome for patients with positive IgM and IgG titers suggests that GMK may have provided some clinical benefit to responding patients. In any case, the outcome for patients on the GMK arm seemed to be no worse than for similar patients receiving observation, based on comparison with the observation arm of previous adjuvant trials.1,2 The absence of an observation arm in E1694 prevents a direct comparison of GMK with observation.
The RFS benefit of high-dose IFN
The survival benefit demonstrated in E1694 (HR = 1.52) was consistent with the reduction in relapse rate, suggesting that RFS and OS are linked. In contrast, Intergroup trial E1690 failed to demonstrate an OS benefit associated with high-dose IFN
An analysis of RFS and OS in all three trials (E1684, E1690, and E1694), based on the estimated 2-year survival rates, indicated that the benefit associated with IFN
Analysis of the impact of high-dose IFN
The greatest impediment to the more widespread use of high-dose IFN
The key to further improvement in the efficacy and therapeutic index of immunotherapy for melanoma lies in understanding the mechanism of the antitumor effects of IFN
In summary, E1694 has confirmed the RFS and OS benefit of high-dose IFN
Supported by Eastern Cooperative Oncology Group grant no. NIH CA 39229-16 and R03 grant no. CA75950-02. We gratefully acknowledge the contributions of the many investigators from ECOG, the Southwest Oncology Group, Cancer and Leukemia Group B, M.D. Anderson Cancer Center, and Memorial Sloan-Kettering Cancer Center who enrolled patients on this trial, and officially acknowledge P.Y. Liu, who contributed the early stopping rules that were adopted for this intergroup effort.
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ABSTRACT
INTRODUCTION
