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High-Dose Interferon Alfa-2b Does Not Diminish Antibody Response to GM2 Vaccination in Patients With Resected Melanoma: Results of the Multicenter Eastern Cooperative Oncology Group Phase II Trial E2696

From the University of Pittsburgh Medical Center, University of Pittsburgh Cancer Institute Melanoma Center, Department of Medicine, Division of Hematology-Oncology, Pittsburgh, PA; Dana-Farber Cancer Institute, Department of Biostatistical Science, and Beth Israel Deaconess Medical Center, Division of Hematology/Oncology, Boston, MA; Winship Cancer Institute, Emory University Medical School, Atlanta, GA; Progenics Pharmaceuticals, Inc, Tarrytown; and Memorial Sloan-Kettering Cancer Center, New York, NY.

Address reprint requests to John M. Kirkwood, MD, Professor and Vice Chairman, Department of Medicine, University of Pittsburgh School of Medicine, Director, Melanoma Center, University of Pittsburgh Cancer Institute, 200 Lothrop St, Pittsburgh, PA 15213-2582; email: jmk{at}jimmy.harvard.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: High-dose interferon alfa-2b (IFN2b) is the only established adjuvant therapy of resectable high-risk melanoma. GM2-KLH/QS-21 (GMK) is a chemically defined vaccine that is one of the best developed of a range of vaccine candidates for melanoma. A single-institution phase III trial conducted at Memorial Hospital served as the impetus for an intergroup adjuvant E1694/S9512/C509801 trial, which recently completed enrollment of 880 patients. To build on the apparent benefit of IFN2b in resectable high-risk American Joint Committee on Cancer (AJCC) stage IIB or III melanoma, this phase II study was designed to evaluate the combination of GMK and IFN2b. The E2696 trial was undertaken to evaluate the toxicity and other effects of the established adjuvant high-dose IFN2b regimen in relation to immune responses to GMK and to evaluate the potential clinical and immunologic effects of the combined therapies.

PATIENTS AND METHODS: This trial enrolled 107 patients with resectable high- or very high–risk melanoma (AJCC stages IIB, III, and IV).

RESULTS: The results demonstrate that IFN2b does not significantly inhibit immunoglobulin M or G serologic responses to the vaccine and that the combination of high-dose IFN2b and GMK is well tolerated in this patient population.

CONCLUSION: Cox analysis of the results of the combination with IFN2b show improvement in the relapse-free survival of patients with very high–risk melanoma (including those with resectable M₁ disease).

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
THE RISK OF RELAPSE for patients with resected melanoma depends on the thickness of the primary lesion (Breslow depth) and whether regional lymph nodes are involved with the tumor (American Joint Committee on Cancer [AJCC] stage III, or node-positive). The Eastern Cooperative Oncology Group (ECOG) has defined high-risk melanoma as primary melanoma with a Breslow depth greater than 4 mm, or any primary melanoma associated with regional lymph node metastasis. For this group of patients, mature multicenter clinical trial data from ECOG trial E1684 in 287 patients has demonstrated a statistically significant relapse-free survival (RFS) and overall survival advantage for patients treated with high-dose interferon alfa-2b (IFN2b) for 1 year. These results led to Food and Drug Administration approval of this regimen as the first adjuvant therapy of high-risk melanoma and provided the basis for a second trial undertaken in the intergroup setting (E1690/S1906/C9190), which has recently been reported.¹ The toxicity of this regimen has been considerable and an impediment to its universal adoption for all patients with resected high-risk melanoma. A series of investigations of less toxic and potentially more specific whole-cell, derivative, and chemically defined vaccine approaches to adjuvant therapy has therefore been undertaken. One of these approaches has focused on the gangliosides. The gangliosides are sialated glycolipid molecules that are highly expressed in melanoma, among which the GM2 ganglioside has been found to be the most immunogenic. Improved RFS has been reported for patients with circulating anti-GM2 antibodies in studies of the European Organization for Research and Treatment of Cancer in France,² the University of California, Los Angeles,³ and Memorial Hospital, New York.⁴ These latter studies culminated in a trial of vaccination with the ganglioside GM2 given with bacillus Calmette-Guerin vaccine as an immunologic adjuvant versus bacillus Calmette-Guerin vaccine alone, which demonstrated a trend toward improved RFS for the combination arm. The failure to achieve statistical significance in this study has been attributed to the small size of the trial (122 subjects) and to the fact that there was an imbalance in baseline native anti-GM2 antibodies between the treatment arms.⁴ The potential therapeutic benefit of this chemically defined vaccine and its relative lack of toxicity have provided the impetus for further exploration of GM2 conjugated with various carriers and given with adjuvants for potential multicenter studies. The most effective of the conjugated GM2 vaccines was GM2-KLH, and the most effective adjuvant was QS21 (GMK; Progenics Pharmaceuticals, Tarrytown, NY). The intergroup phase III adjuvant trial E1694/S9512/C has tested the efficacy of this vaccine compared with high-dose IFN2b. To prepare for large-scale trials of IFN-vaccine combinations, a phase II evaluation of the GMK vaccine and IFN2b has been pursued in E2696. E2696 is a randomized evaluation of the following: GMK vaccination given concurrently with IFN2b; GMK given alone for 1 month (four doses), followed by the addition of IFN2b; and GMK vaccination alone ( Fig 1). The goals of this trial were to determine whether there were any adverse interactions of the combination in terms of the antibody response to GMK assessed over the interval of 1 year and to evaluate the toxicity and therapeutic efficacy of the combined-modality therapy. A population of patients at higher risk for recurrence than previously targeted in cooperative group adjuvant trials was planned for this study, including resected stage IV (M1). We report here the findings of this trial.

View larger version (28K): [in this window] [in a new window]   Fig 1. Randomization schema. Abbreviations: IV, intravenous; sc, subcutaneous.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

Patients were excluded from the study if they had any prior systemic anticancer therapy, including immune modulators; had concomitant autoimmune or malignant diseases; required anti-inflammatory immunosuppressive or antihistaminic drugs, including any corticosteroids; had undergone splenectomy; had a history of heart disease higher than New York Heart Association class 2; had organic brain syndrome, neuropathy, or active infection; or had a history of severe allergic reaction to shellfish. Women of childbearing potential and sexually active men were counseled to use an accepted and effective method of contraception while on treatment and for 18 months afterward. All patients gave written informed consent to participate.

Treatment Arms
All eligibility criteria were reviewed before patients were assigned to one of the three treatments (Fig 1). IFN2b was administered by using the dose and schedule previously tested in E1684, E1690, and E1694 trials.⁵ The induction phase consists of a daily intravenous infusion (Monday through Friday) of 20 megaunits/m² for 4 weeks. Afterward, patients were maintained on a dosage of 10 megaunits/m² administered as a subcutaneous injection three times weekly for up to 48 weeks. For both the induction and maintenance phases, the IFN2b dose was held and then restarted at a 33% dose reduction if severe toxicity (grade 3 or 4) was observed. A second decrease of 33% of the original dosage was also specified for recurrent severe toxicity. Patients who developed severe toxicity despite these dose reductions were taken off the study.

GMK was administered as a subcutaneous injection on weeks 1, 2, 3, 4, 12, 24, and 36. Each dose contained 30 µg of GM2 and 100 µg of QS21. If patients developed grade 3 toxicity associated with the vaccination, the dose was decreased by 50%.

Patients were assigned randomly through the ECOG Statistical Center Data Management Office via telephone to one of three treatment arms (Fig 1). In arm A, patients received both IFN2b and GMK vaccine starting on day 1. Patients assigned to arm B also received both IFN2b and GMK, but the IFN2b was started on week 5, after four weekly vaccinations with GMK. We hypothesized that if IFN2b acutely inhibited the anti-GM2 response, patients in arm B might escape this inhibitory effect. Patients in arm C received GMK alone without any IFN2b.

Patients who were assigned to arms A or B but who could not tolerate IFN2b were allowed to stay on the study and continue to receive the GMK vaccine. Patients who developed recurrent melanoma were removed from the study unless the melanoma could be completely resected and the patient did not require or receive any other systemic therapy. To be considered assessable, patients had to receive at least four GMK vaccinations.

Clinical and Immunologic Assessments
Before treatment, patients underwent a physical examination and radiologic imaging of the chest. Patients with either stage IV disease or abnormal liver functions were also required to have an abdominal computed tomography scan. Additional radiologic imaging was performed at the discretion of the investigator. Patients also had a complete blood cell count (CBC), liver function tests, creatinine/blood urea nitrogen (BUN), and an ECG. Women of childbearing potential had a serum beta human chorionic gonadotropin test.

While patients were on the induction phase of the IFN2b treatment, they were examined weekly. During the maintenance phase of IFNa2b treatment, patients were evaluated three times monthly, then every 3 months. CBC, liver functions, and creatinine/BUN were evaluated at each visit. Radiologic imaging of the chest was repeated every 3 months or more frequently if clinically indicated. Overall survival was defined as the time from randomization to death of any cause for all patients. RFS was the time from randomization to recurrence of disease or to death without recurrence.

Patients assigned to arm C (no IFN2b) were evaluated with a physical examination, CBC, liver function tests, creatinine/BUN, and radiologic imaging of the chest every 3 months. Toxicity was scored according to the common toxicity criteria of the National Cancer Institute.

Anti-GM2 Antibody Response Measurement
Serum for assay of immunoglobulin (Ig) M and IgG anti-GM2 titers was collected before treatment and at 12 time points representing the times of vaccines 4 through 7, and 2 weeks after vaccines 4 through 7. A final serum sample was collected at week 52. Anti-GM2 antibodies were measured by enzyme-linked immunoadsorbent assay as previously reported, both in laboratories at Progenics, Inc and in the Melanoma Center of the University of Pittsburgh Cancer Institute, by using reported methods.⁶

Biostatistics
The primary end point of this study was the anti-GM2 antibody response. The anti-GM2 response was measured in terms of IgM and IgG isotypes repetitively over time, and titers above 1:40 were classified as serologic responses. Previous experience has correlated the presence of an anti-GM2 titer of 1:40 with an improved RFS.⁶ Because all but five patients gave antibody responses at this threshold, analyses are also reported at the more stringent threshold of 1:80.

The main comparisons of statistical interest were between IFN2b and GMK given concurrently (arm A) or given sequentially beginning 1 month after initiation of GMK (arm B) in relationship to GMK alone (arm C). The combinations of GMK and IFN2b (A and B) were considered worthy of further investigation if the antibody response observed in either was at least 70% of the response to the GMK vaccine given alone. The study was designed to have an 80% power to detect the difference between a serologic response rate of 95% in GMK vaccine-only (arm C) and 66.5% in the GMK- IFN2b combination arms A or B with a one-sided Fisher’s exact test at alpha = 0.05. A difference of 35% in the rate of toxicity of arms C and A or B was capable of being detected with at least an 80% power. In the final statistical analysis, comparisons of the number of toxic events in arm A versus C and arm B versus C were carried out with Fisher’s exact test. Comparisons of toxicity and immune response for all three treatment arms were made with the Kruskal-Wallis test. The same tests were used for pairwise comparisons of the treatment arms and comparisons across all treatment arms for serologic response.

Although relapse and death were not primary end points of the study, the distributions of overall survival and RFS were estimated by using the method of Kaplan and Meier.⁷ Median survival and RFS were estimated with these curves. The distribution of RFS for each treatment arm when stratified by serologic response was also calculated with the Kaplan-Meier method. Differences in the estimated survival distribution were calculated by using the log-rank test. Prognostic factors for RFS were explored with Cox proportional hazards models.⁸ Initial results obtained from an analysis at 14.9 months⁹ were updated with a reanalysis at 23.9 months, including all events as of April 2000.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Population
One hundred seven patients were accrued to the study; all were assessable for serologic response and toxicity. The patient characteristics are listed in Table 1. The three arms were well-balanced for age, stage, sex, site of primary tumor, and the time from complete resection until accrual onto the study.

Previous studies have suggested that anti-GM2 titers 1:40 correlate with improved RFS.⁶ Eight patients (8%) had pretreatment anti-GM2 titers 1:40; this is consistent with the literature, in which 5% of stage III melanoma patients have shown pre-existing anti-GM2 antibodies.⁶ These eight patients were equally distributed among the three treatment arms. After immunization, eight patients did not make anti-GM2 IgM titers 1:40, and eight did not make IgG titers 1:40. However, only three patients on the trial did not make either IgM or IgG anti-GM2 antibodies at a titer 1:40 ( Table 3). There was no difference in antibody response rate among the three treatment arms at a threshold of 1:40. With a more stringent titer threshold of 1:80, 90% of patients developed IgM anti-GM2 antibodies, and 92% developed IgG anti-GM2 antibodies. Only five patients failed to make either IgM or IgG anti-GM2 antibodies at a titer 1:80. There was also no difference in antibody response rate across the three treatment arms at this titer threshold.

View this table: [in this window] [in a new window]   Table 3. Antibody Response: Maximum Titer of IgM or IgG 1:80 (1:40)

Results of serologic analyses performed at the Progenics and the University of Pittsburgh Melanoma Center laboratories were similar in all regards, with the single exception of the median time to peak IgG titer. This was found at week 16 with the data from the Pittsburgh laboratory and at week 14 with the data from the Progenics laboratory.

We conclude that for both IgM and IgG responses, there was no difference between treatment arms in the percentage of antibody responders over the period of the trial (either at a titer threshold of 1:40 or 1:80); nor were there differences in the median titers at week 4 or week 14, or the peak titers among the three treatment arms. The data support the conclusion that coadministration of IFN2b does not affect the anti-GM2 antibody response induced by vaccination with the GMK ganglioside vaccine.

RFS and Overall Survival
The majority of the statistical analyses were performed on RFS, because the median time of follow-up was only 23.9 months and the primary end point of this study was immunologic. Although no attempt was made to stratify the patients for prognostic variables, the three arms were well balanced for stage, sex, site of primary tumor, and time from resection to registration. Progressive disease was noted in 15 patients in arm A, 13 in arm B, and 19 in arm C. Kaplan-Meier median overall survival estimates were not reached for any treatment group. The median RFS time for arm C was 14.85 months (95% confidence interval [CI], 5 to 29 months), and for arm B it was 30.72 months (95% CI, 27 to 53 months), whereas the median RFS was not reached for arm A ( Fig 2).

View larger version (21K): [in this window] [in a new window]   Fig 2. RFS for all 3 arms.

Serologic Response and Survival
The relationship of serologic response to disease outcome was examined, because earlier studies had shown anti-GM2 response to be of favorable prognostic significance.^3,6 The maximum IgM or IgG antibody responses and the serologic response at day 29 (week 4) and week 14 were compared with RFS and overall survival by treatment arm. The greatest number of relapses and deaths was observed in arm C (GMK without IFN2b), but this analysis is limited because of the small size of this phase II study and consequent few events at the follow-up of 23.9 months. Analysis of RFS was performed to determine whether patients who developed a serologic response to GM2 may have had a lesser benefit associated with IFN2b. The Kaplan-Meier curves for this analysis (data not shown) do not suggest a difference in RFS benefit obtained with the addition of IFN2b for patients who developed an IgM or IgG antibody response compared with those in the trial overall. There is no evidence that patients exhibiting serologic response derived any less benefit from IFN2b therapy than those without serologic response.

Toxicity
There were no treatment-related deaths and only five grade 4 toxic events, all occurring on treatment arms that included IFN2b. The most common severe (grade 3) toxic events were liver enzyme elevation (n = 22), granulocytopenia (n = 21), and fatigue (n = 16). Table 5 shows the distribution of the worst grade 3 or 4 toxicities ( grade 3). A Kruskal-Wallis test comparing the distributions of toxicities across all treatment arms showed that patients in arm C experienced significantly fewer toxicities (P < .0001). Comparisons of toxicity of combined therapy versus GMK alone (arms A v C and arms B v C) were also found to be highly statistically significant by using Fisher’s exact test. Arm C was significantly less toxic than arms A and B. The P value for both tests was less than .0001.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

The analyses of the toxic and therapeutic effects of the combinations were secondary goals in this phase II trial. Of interest, significant differences were observed for the toxicity and disease outcome of the IFN2b combination arms of this phase II trial. Treatment with GMK alone (arm C) was associated with significantly fewer grade 3 or higher toxicities than either arm A or B. Conversely, the RFS for patients treated with IFN2b and GMK in either combination was significantly better than for the control arm (GMK only). Among serologic responders, the benefit of IFN2b was still apparent, suggesting that the benefits of GMK and those of IFNs occur through separate, noncompetitive mechanisms. It is more difficult to evaluate the benefit of GMK in relation to IFN2b in this trial because no control arm receiving IFN2b or observation alone was included. The intergroup trial E1694 has recently shown the superiority of IFNb over GMK in stage IIB and III melanoma at a median follow-up of 16 months, because this study was closed by the data and safety monitoring board of ECOG.¹⁰ This is the subject of a separate communication now in preparation.

In summary, this trial has demonstrated several new findings important in relation to the adjuvant therapy of melanoma. First, we have shown that IFN2b does not abrogate or hinder antibody IgM or IgG response to the glycolipid GM2 antigen, independently tested in two laboratories. Second, the study has shown that the toxicity of the combination is increased but tolerable in the majority of subjects. Third, a Cox regression analysis of these data suggest that high-dose intravenous and subcutaneous IFN2b added to GMK reduces the relapse rate among high- to very high–risk melanoma patients, including those with resected regional or distant metastatic disease. This raises issues regarding the broader applicability of IFN2b beyond the scope of more narrowly defined node-confined and deep primary disease addressed in trials E1684, E1690, and E1694. Two different schedules of IFN2b combined with the GMK vaccine were tested, and for most comparisons there is no clear distinction between the two schedules. The results of E2696 prepare a foundation for vaccine-IFN2b combinations and argue for more extensive evaluation of combined-modality therapy for melanoma. Such combinations would logically include protein and peptide antigens for which the effects of IFN2 on antigen-presenting cell function may improve immunologic as well as clinical response. These are currently in progress in ECOG.

	ACKNOWLEDGMENTS

 
Supported by Eastern Cooperative Oncology Group Main Institution National Institutes of Health grant no. U10:CA39229-15.

We would like to acknowledge the excellent protocol coordination of S. Donnelly, RN, and L. Stover, RN, at the University of Pittsburgh Melanoma Center, and data management of Carol Tate at ECOG Operations Office, Boston, MA. We acknowledge the unrestricted grant to ECOG from Dr Craig Tendler of Schering Plough Research Institute and the provision of the vaccine for this trial by Drs Robert Israel and Paul Maddon of Progenics, Inc. Finally, we acknowledge the excellent administrative and secretarial assistance of B. Mislanovich.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Kirkwood JM, Ibrahim JG, Sondak VK, et al: High- and low-dose interferon alfa-2b in high-risk melanoma: First analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol 18: 2444-2458, 2000[Abstract/Free Full Text]

2. Portoukalian J, Zwingelstein G, DoréJ-F, et al: Studies of ganglioside fraction extracted from human malignant melanoma. Biochimie 58: 1285-1287, 1976[Medline]

3. Jones PC, Sze LL, Liu PY, et al: Prolonged survival for melanoma patients with elevated IgM antibody to oncofetal antigen. J Natl Cancer Inst 66: 249-254, 1981

4. Yohn JJ, Lyons MB, Norris DA: Cultured human melanocytes from black and white donors have different sunlight and ultraviolet A radiation sensitivities. J Invest Dermatol 99: 454-459, 1992[Medline]

5. Kirkwood JM, Strawderman MH, Ernstoff MS, et al: Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: The Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 14: 7-17, 1996[Abstract]

6. Livingston PO, Wong GYC, Adluri S, et al: Improved survival in stage III melanoma patients with GM2 antibodies: A randomized trial of adjuvant vaccination with GM2 ganglioside. J Clin Oncol 12: 1036-1044, 1994[Abstract/Free Full Text]

7. Kaplan EL, Meier P: Nonparametric estimation of incomplete observations. J Am Stat Assoc 53: 457-481, 1958

8. Cox DR: Regression models and life tables (with discussion). J R Stat Soc (B) 34: 187-220, 1972

9. Chapman PB, Morrissey D, Ibrahim J, et al: Eastern Cooperative Oncology Group phase II randomized adjuvant trial of GM2-KLH + QS21 (GMK) vaccine ± high dose interferon- 2b (HD IFN) in melanoma (MEL). Proc Am Soc Clin Oncol 18: 538a, 1999 (abstr 2078)

10. Kirkwood JM, Ibrahim J, Sondak VK, et al: Relapse-free and overall survival are significantly prolonged by high-dose IFN2b (HDI) compared to vaccine GM2-KLH with QS21 (GMK, Progenics) for high-risk resected stage IIB-III melanoma: Results of the intergroup phase III study E1694/S9512/C509801. 25th ESMO Congress, 2000.

Submitted August 2, 2000; accepted November 14, 2000.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kirkwood, J. M. Articles by Chapman, P. B. Search for Related Content PubMed PubMed Citation Articles by Kirkwood, J. M. Articles by Chapman, P. B. Social Bookmarking                            What's this?