Journal of Clinical Oncology, Vol 19, Issue 9
(May), 2001: 2370-2380
© 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/C509801
By John M. Kirkwood,
Joseph G. Ibrahim,
Jeffrey A. Sosman,
Vernon K. Sondak,
Sanjiv S. Agarwala,
Marc S. Ernstoff,
Uma Rao
From 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
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ABSTRACT
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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  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 1:80) at days 29, 85, 365, and 720 were associated with a trend toward improved RFS and OS (P2 = .068 at day 29).
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.
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INTRODUCTION
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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 IFN2b (FDA-approved regimen) as adjuvant therapy in resected high-risk melanoma patients. The primary objective was to determine whether GMK was superior to high-dose IFN2b with respect to RFS and OS. The study was also designed to determine the correlation of preexisting and vaccine-induced IgM and IgG antibodies with RFS and OS.
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PATIENTS AND METHODS
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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 IFN2b therapy was medically contraindicated were ineligible. Patients younger than 18 years of age and pregnant or lactating women were ineligible. Women of child-bearing potential and sexually active men were required to use reliable contraceptive means during and for 18 months after treatment discontinuation. All patients provided informed written consent.
Patients were stratified by sex and according to the number of positive nodes at lymphadenectomy (zero, one, two to three, or four). Patients who did not undergo lymphadenectomy were stratified with the N0 group. Sentinel lymph node (SLN) biopsy was permitted if it met established criteria. Any patient with a positive SLN was required to undergo a complete lymphadenectomy to be eligible.
Treatment
Patients were randomly assigned 1:1 by the ECOG operations office to the two treatment groups: (A) 1 mL of GMK vaccine administered via a deep SC injection on days 1, 8, 15, and 22, then every 12 weeks (weeks 12 to 96); or (B) high-dose IFN2b, 20 MU/m2/d IV 5 days/wk x 4 weeks followed by 10 MU/m2 SC TIW x 48 weeks ( Fig 1). The vaccine was administered using a 25-gauge needle with rotation of the injection site. Self-administration of the SC doses of IFN2b was pursued after the first 4 weeks of 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 IFN2b 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
Patients were monitored for toxicity weekly during the first month on study and for toxicity and disease status at 1- to 3-month intervals during the first year. Patients were monitored every 4 months in the second year and every 6 months in subsequent years. Criteria for determining treatment effect were relapse-free interval and survival time from study entry. The sites of all recurrences were documented with attention to regional nodal relapse. Histologic and cytologic confirmation of relapse was attempted in all cases. A serologic assessment of the anti-GM2 antibody titer was conducted on serum collected at baseline, day 29, day 85, and at 6, 9, 12, 18, and 24 months after vaccination with GMK using an enzyme-linked immunosorbent assay. Antibody responses were correlated with outcome at predefined threshold titers of 1:40 and 1:80.21
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 IFN2b, which is the active reference agent; the goal was to determine whether GMK was superior to IFN2b using RFS and OS as the primary end points. Each comparison was conducted with a one-sided type 1 error rate of 0.025, for an overall type 1 error rate of 0.05. The sample size was established to detect a 15% relative difference in median time-to-event among noncured patients and a 10% absolute difference in cure rate, ensuring 86% power to detect changes in the relapse-free rate and 80% power to detect changes in overall survival rate between treatment groups. Target accrual was set at 851 patients, and three interim analyses were planned at approximately 25%, 50%, and 75% of statistical information. The final analysis was planned at 100% of statistical information for both end points, which was anticipated to be approximately 2 years after completion of accrual. Accrual was completed on October 14, 1999.
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 IFN2b, and a fixed lower boundary, defined as inferiority of GMK compared with high-dose IFN2b at a constant lower boundary of 1.645 for RFS at each interim analysis. This fixed lower boundary was used for safety reasons to stop the trial early with high probability in the event that GMK acted essentially as placebo. This boundary is equivalent to choosing a one-sided significance level of 5% at each interim analysis.
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
Efficacy comparisons between the GMK and IFN2b arms were performed using one-sided log-rank test statistics as specified in the original protocol based on eligible and intent-to-treat (ITT) populations. The probability of RFS and OS were estimated by the Kaplan-Meier method.27 The HR for relapse or death was calculated using a Cox proportional hazards regression model after adjustment for stage of disease and number of involved nodes using two-sided statistics. Additional regression analyses adjusting for ulceration and microscopic versus macroscopic lymph node involvement were also conducted. Throughout we have defined HR to denote the ratio of the hazard of an event (relapse or death) for the GMK arm relative to that of the IFN2b arm; therefore, an HR of more than 1 indicates that the risk of relapse or death was greater in the GMK arm than in the IFN2b arm.
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RESULTS
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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 IFN2b 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 IFN2b arm underwent SLN biopsy (28% total); more than two thirds of T4N0 patients were not surgically staged ( Table 2). The largest subgroup of patients (41%) had one involved lymph node, 21% of patients had two to three involved lymph nodes, and 14% of patients had four involved lymph nodes (Table 1). The proportion of patients with microscopic versus macroscopic lymph node metastases was well balanced between stratification groups and treatment groups (Table 2); 44% of patients in the IFN2b arm and 49% in the GMK arm had micrometastases only (Table 1). Approximately one third of patients had confirmed ulceration of their primary tumor, and 36% patients had recurrent disease at study entry (Table 1).
Impact of IFN2b Versus GMK on RFS and OS
As 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 IFN2b 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 IFN2b 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 IFN2b 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 IFN2b 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.
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DISCUSSION
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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 IFN2b 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 IFN2b has been reported previously in three adjuvant melanoma trials (ECOG 1684, Intergroup trial E1690/S9111/C9190, and ECOG 2696),1,2,28 and the current trial is now the fourth and largest trial to demonstrate this benefit. The RFS benefit of high-dose IFN2b was consistent and highly significant both in the eligible (HR = 1.47) and the ITT (HR = 1.49) populations. Moreover, these HRs for RFS derived from the comparison of GMK versus IFN2b in E1694 were nearly identical to those derived from the comparison of observation versus IFN2b in the original pivotal trial of high-dose IFN2b (HR = 1.44) and in E1690 (HR = 1.28).1,2 Most importantly, E1694 has also demonstrated a significant improvement in OS, both in the eligible and ITT populations. The highly significant benefit of IFN2b compared with GMK with respect to both the RFS and OS end points forced the closure and unblinding of the study at a median follow-up of 16 months.
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 IFN2b, possibly because patients originally assigned to observation frequently crossed over to receive IFN2b salvage therapy when they experienced treatment failure in regional nodes.2 A follow-up analysis of sites of relapse and salvage therapy in the current trial is being conducted.
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 IFN2b improved with each successive trial. The estimated 2-year RFS rate in each of the high-dose IFN2b arms was 48% in E1684, 52% in E1690, and 62% in E1694. Likewise, the estimated 2-year OS rate was 63% in E1684, 71% in E1690, and 77% in E1694. This difference is most likely to have resulted from differences in the patient populations enrolled in these studies. The patient populations in E1690 and E1694 contained a greater proportion of node-negative patients (25% and 23%, respectively, compared with only 11% in E1684) and a smaller proportion of patients with recurrent disease (51% and 36%, respectively, compared with 61% in E1684). As micro- versus macrometastatic disease was not a captured in the earlier trials, and patients were not stratified in the earlier trials based on number of positive nodes, it is impossible to compare the patient populations in these three trials based on those criteria.
Analysis of the impact of high-dose IFN2b by risk group was also performed in E1694 and provides another basis for comparison across several ECOG studies of adjuvant IFN2b. Patients enrolled in E1694 were stratified based on the number of positive lymph nodes, which has been shown to be the most powerful prognostic factor for patients with nodal metastases.29 Trial E1694 demonstrated the greatest benefit, and the only independently statistically significant benefit, in the node-negative subset. In contrast, E1684 demonstrated the greatest RFS benefit of high-dose IFN2b among patients presenting with one positive lymph node (P2 = .001; Smith et al, unpublished data), whereas in Intergroup trial E1690, the subset with the greatest RFS benefit, and the only one that achieved independent statistical significance, was the group of patients with two to three positive nodes (P2 = .02).2 In E1684, the node-negative subgroup was small and there was a disproportionate number of cases with ulceration of the primary tumor among patients assigned to IFN2b, which confounded further analysis. Taken together, these results suggest that the RFS benefit of IFN2b may, in fact, be stage-independent, and the relative risk of relapse is reduced to a similar degree across the subgroups evaluated in these trials. At present there is little evidence to suggest that the benefit of IFN2b therapy differs in patients with microscopic versus macroscopic disease. The ongoing Sunbelt melanoma trial is addressing this question.
The greatest impediment to the more widespread use of high-dose IFN2b remains the tolerability and patient acceptance of this regimen. The toxicities associated with high-dose IFN2b are well documented and have been the impetus behind efforts to find alternative, more specific, and less toxic immunologic therapies. In this trial, as in previous trials, there was a fairly high incidence of grade 3 toxicity, including neurologic toxicity; however, neither the incidence nor severity of adverse events observed in this trial was substantially different from that observed in the previous cooperative group trials. The proportion of patients requiring dose reductions was comparable to that observed in E1684 and lower than that observed in E1690; there have not been any changes in the treatment guidelines or the dose-reduction practices of investigators using this regimen. Although toxicity remains an issue with high-dose IFN2b, the associated adverse events are largely manageable with appropriate supportive care. Using current dose-modification guidelines (adopted after two treatment-related deaths occurred early in E1684), more than 700 patients have been safely treated with high-dose IFN2b in multicenter trials without any fatal events reported. Antipyretics, nutritional and fluid support, antidepressants, and a variety of other supportive interventions intended to relieve symptoms are currently being routinely applied or investigated in patients receiving 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 IFN2b as well as of vaccines. Small studies have suggested that IFN may modulate dendritic cell function and maturation and is associated with infiltration of CD4+ T cells into melanoma tumors in responding patients; moreover, the degree of CD4+ T-cell infiltration has been shown to significantly correlate with tumor regression and clinical outcome.30,31 Vaccine trials with defined peptide and protein antigens are now in progress to dissect the role of relevant T-cell subsets.32-42 These studies will ultimately provide a more rational foundation for combinations of IFN2b and vaccines.
In summary, E1694 has confirmed the RFS and OS benefit of high-dose IFN2b that was first demonstrated by E1684 as reported in 1996.1 Patients treated with GMK had an RFS and OS comparable to patients on observation in prior adjuvant trials, suggesting that a response to GMK was not deleterious. The significant prolongation of RFS and OS demonstrated by high-dose IFN2b in resected high-risk melanoma remains unrivaled by any other drug, cytokine, or vaccine modality that has been prospectively tested in rigorous, multicenter, randomized, controlled trials. Recent data demonstrating the feasibility of combining IFN2b with vaccines such as GMK,28 and pending data from multicenter trials combining IFN2b with several peptide vaccines as well as polychemotherapy plus interleukin-2, promise to expand the role of IFN2b in the treatment of melanoma.
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ACKNOWLEDGMENTS
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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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Submitted January 3, 2001;
accepted March 9, 2001.
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TOP
ABSTRACT
INTRODUCTION
