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Update on the EORTC 18991 trial with pegylated interferon

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Regarding stage III melanoma, approximately 20% of patients with microscopic disease and no ulceration do not survive after 5 years. Of patients with at least 4 palpable nodes and ulceration, 70% will not live 5 years (Table 1).¹

AJCC 5-Year Survival by Lymph Node Tumor Burden and Tumor Ulceration (Stage III)

Source: Balch CM, et al. J Clin Oncol. 2010;28:2452-2459.

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Studies have shown that adjuvant therapy improves overall survival (OS) and relapse-free survival (RFS). For example, meta-analyses suggest interferon (IFN) therapy results in improvements in OS of approximately 11% (Table 2).^2,3 Important questions have arised regarding which patients would benefit, which dose is optimal, and which regimen should be implemented.

Table 2. Meta-analyses of Interferon

Source: Wheatley K, et al. Cancer Treat Rev. 2003;29:241-252; Mocellin S, et. al. J Natl Cancer Inst. 2010;102:493-501.

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Pegylated interferon (PEG-IFN) α-2b provides another adjuvant therapy option for high-risk melanoma patients. Derivatization of protein-based therapeutics with polyethylene glycol (pegylation) can often improve pharmacokinetic and pharmacodynamic properties of the proteins, which can improve efficacy and minimize dosing frequency. PEG-IFN α-2b is formed by attachment of a 12-kilodalton mono-methoxy polyethylene glycol (PEG) to the IFN α-2b protein.⁴ Compared with high-dose IFN (HDI), which is usually administered in higher doses, daily or 3 times a week, PEG-IFN α-2B can be administered once a week. When the kinetics of PEG-IFN α-2b is compared with that of HDI, what is observed is that the plasma peak levels of the 2 regimens are different. However, the areas under the curve of the 2 regimens are similar, indicating that PEG-IFN α-2B is a high-dose regimen that is administered subcutaneously for 5 years compared with 1 year (Eggermont AM, personal communication; Figure 1).

Figure 1. Pharmacokinetics Maintenance: Role in Efficacy and Tolerability

The areas under the curve for HDI and PEG-IFN a-2b are similar, indicating that PEG-IFN a-2b is a high-dose regimen that can be administered for 5 years compared with 1 year.
Source: Eggermont AM, personal communication.

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PEG-IFN α-2b was approved by the FDA in March 2011 as Sylatron (Schering Corporation) for the treatment of patients with melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection including complete lymphadenectomy.⁵

European Organisation for Research and Treatment of Cancer (EORTC) 18991

The approval of PEG-IFN α-2b was based on the results of a single trial, EORTC 18991. EORTC 18991 was an open-label, multicenter trial enrolling 1,256 patients who had been adequately surgically resected for their primary cutaneous melanoma and affected regional lymph nodes. Patients were randomized 1:1 to receive either PEG-IFN α-2b or observation for a 5-year period. PEG-IFN α-2b was administered at 6 μg/kg/week for 8 weeks, followed by 3 μg/kg/week for the remainder of the treatment.

In the EORTC 18991 trial, the adverse events associated with PEG-IFN α-2b were similar to those associated with HDI, such as fatigue, liver toxicity, and depression (Table 3).⁶ However, 40% to 50% of study participants reported grade 3 and grade 4 adverse events in the EORTC 18991 trial, compared with approximately 80% who reported these types of adverse effects in the E1684 trial examining 1-year HDI.⁷ Thus, it appears PEG-IFN α-2b is associated with fewer adverse events than HDI. Discontinuation was still an issue with PEG-IFN α-2b, as approximately 40% of patients stopped treatment due to toxicity.

Table 3. Adverse Events (%)

Source: Eggermont AM, et al. Lancet. 2008;372:117-126.

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The efficacy of PEG-IFN α-2b in the intent-to-treat (ITT) population of EORTC 18991 was analyzed in 2007, at a median follow-up of 3.8 years,⁶ and in 2011, at a median follow-up of 7.6 years.⁸ The primary efficacy endpoint, RFS, was defined as the time to the earliest of local or regional recurrence, distant metastases, or death. At 3.8 (3.2-4.2) years median follow-up, 328 recurrence events had occurred in the PEG-IFN α-2b group compared with 368 in the observation group (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.71-0.96; P = .011). The estimated median RFS was 34.8 months (95% CI, 26.1-47.4) and 25.5 months (95% CI, 19.6-30.8) in the PEG-IFN α-2b and observation arms, respectively. Evaluation at 7.6 years of follow-up indicated that RFS remained stable in the PEG-IFN α-2b group (HR, 0.87; 95% Cl, 0.76-1.00; P = .05).

Following 525 deaths, there was no difference in OS between the PEG-IFN α-2b and the observation arms (HR, 0.98; 95% CI, 0.82-1.16; P = .78) at 3.8 years of follow-up, which remained consistent at 7.6 years of follow-up (HR, 0.96; 95% Cl, 0.82-1.11; P = .57).^6,8 Distant metastasis-free survival (DMFS) of patients in the PEG-IFN α-2b group was not significantly different from that of the observation group at 3.8 years of follow-up (HR, 0.88; 95% Cl, 0.75-1.03; P = .11) or at 7.6 years of follow-up (HR, 0.93; 95% Cl, 0.81-1.07; P = .33). Thus, effic­acy analysis indicates that PEG-IFN α-2b resulted in a significant benefit compared with observation with respect to RFS, but not with respect to OS or DMFS. Importantly, the benefit associated with RFS remained stable through 7.6 years of follow-up.⁸

Subgroup analysis: Tumor burden

In order to determine which patients are most likely to benefit from treatment with PEG-IFN α-2b, subgroup analyses were performed in EORTC 18991 at 7.6 years of follow-up. Randomization was stratified for microscopic (N1) versus macroscopic (N2) nodal involvement, number of nodes, and ulceration of the primary tumor site.⁸

When comparing patients in the N1 population (positive sentinel lymph node) with those in the N2 population (palpable lymph node), a significant difference in RFS was observed with PEG-IFN α-2b compared with observation in the stage III-N1 population (HR, 0.82; 99% CI, 0.61-1.10; P = .08). In contrast, there was no significant difference in RFS associated with PEG-IFN α-2b in the stage III-N2 population (HR, 0.89; 99% CI, 0.71-1.13; P = .21; Figure 2).⁸

Figure 2. N1 Versus N2: RFS

PEG-IFN a-2b led to a significant improvement in RFS compared with observation in the stage III-N1 population, but not in the stage III-N2 population.
Source: Eggermont AM, et al. Presented at: American Society of Clinical Oncology Annual Meeting; June 3-7, 2011; Chicago, IL; Abstract 8506b. Accessed September 5, 2011.

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Regarding DMFS, a benefit was observed with PEG-IFN α-2b in the N1 population, but the difference between the 2 groups was not significant (HR, 0.86; 99% Cl, 0.63-1.17; P = .22). Again, there was no difference between PEG-IFN α-2b and observation regarding DMFS in the stage III-N2 population (HR, 0.96; 99% Cl, 0.76-1.22; P = .66). There was no significant difference in OS between the PEG-IFN α-2b group and the observation group in either the N1 (HR, 0.86; 99% Cl, 0.62-1.21; P = .26) or N2 (HR, 1.00; 99% Cl, 0.78-1.29; P = .97) populations.⁸

These results were supported in a retrospective analysis, when comparing EORTC 18991 data with another EORTC study, EORTC 18952. The EORTC 18952 study involved 1,388 patients with resected stage IIb or III melanoma who were randomized to observation or to intermediate doses of IFN α-2b (induction with 10 million units 5 times a week for 4 weeks, followed by maintenance with either 10 million units 3 times weekly for 12 months or 5 million IU 3 times weekly for 24 months).⁹ In patients with stage IIb melanoma, the HR for OS was 0.63. In patients with stage III-N1 in the EORTC 18952 trial, the OS HR was 0.88; it was 0.86 in the same stage patients in EORTC 18991. In patients with stage III-N2, the OS HR was 1.03 in EORTC 18952; it was 1.00 in the same stage patients in EORTC 18991. Thus from a sample size of 2,500 patients from these 2 trials, it appears that patients with a lower tumor burden are more likely to benefit from IFN therapy.

Subgroup analysis: Ulceration

The effects of ulceration on treatment efficacy were also examined in a subgroup analysis of EORTC 18991.⁸ Among patients that were sentinel lymph node-positive (N1) plus ulceration, a significant benefit regarding RFS was observed in the PEG-IFN α-2b group compared with observation (HR, 0.72; 99% Cl, 0.46-1.13; P = .06). Interestingly, PEG-IFN α-2b was also associated with a significant improvement in DMFS (HR, 0.65; 99% Cl, 0.41-1.04; P = .02) and OS (HR, 0.59; 99% Cl, 0.35-0.97; P = .006) in this population. In the PEG-IFN α-2b group, the median OS was > 9 years, compared with 3.7 years in the observation group.⁸

Results of the EORTC 18952 trial coincide with the findings of EORTC 18991. There were appreciable differences in OS in both IFN treatment arms compared with observation in patients with stage III-N1 plus ulceration. The hazard ratios were 0.68 (99% Cl, 0.38-1.21; P = .08) and 0.48 (99% Cl, 0.27-0.85; P = .001) for the groups receiving IFN for 13 months and 25 months, respectively.⁹

A combined analysis of these 2 trials confirmed the improvements in OS (HR, 0.58; 95% CI, 0.43-0.78; P = .0003) and DMFS (HR, 0.59; 95% CI, 0.45-0.77; P = .001) associated with PEG-IFN α-2b in patients with stage IIb or III-N1 plus ulceration (Figure 3). No significant improvements in OS (HR, 1.11; 95% CI, 0.80-1.56; P = .53) or DMFS (HR, 0.96; 95% CI, 0.72-1.29; P = .80) were observed in patients with stage IIb and III-N1 without ulceration in these trials.⁸

Figure 3. Stage IIB-N1 and III-N1

No significant improvements in OS were observed in patients with stage IIB-N1 and III-N1 without ulceration.
Source: Eggermont AM, et al. Presented at: American Society of Clinical Oncology Annual Meeting; June 3-7, 2011; Chicago, IL; Abstract 8506b. http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=83141. Accessed September 5, 2011.

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This benefit of PEG-IFN α-2b was lost in the N2 population with ulceration in these trials.⁸ The HR associated with RFS was 0.83 (95% CI, 0.64-1.08; P = .15) in patients with stage III-N2 plus ulceration and 0.96 (95% CI, 0.79-1.18; P = .70) in patients with stage III-N2 without ulceration. Similar results were observed for OS in patients with (HR, 0.89; 95% CI, 0.68-1.17; P = .41) and without (HR, 1.10; 95% CI, 0.87-1.38; P = .42) ulceration. Therefore, ulceration does not seem to play a role in the susceptibility of patients to IFN when a higher stage of tumor burden is reached. Reasons for these differences are currently not well-understood.

The EORTC meta-analysis examined the effects of IFN on OS in patients with ulceration, without ulceration, and whose ulceration status was unknown. Results demonstrated that the effect on OS was strongest in patients with ulceration (Table 4).⁸ Thus, there is evidence that patients with ulceration have a different biology that might be more affected by IFN.

Table 4. Overall Survival Stratified by Ulceration

Source: Eggermont AM, et al. Presented at: American Society of Clinical Oncology Annual Meeting; June 3-7, 2011; Chicago, IL; Abstract 8506b. http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=83141. Accessed September 5, 2011.

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Results of the EORTC trials regarding ulceration have been corroborated in a post hoc analysis of the SUNBELT trial.¹⁰ In this analysis, a total of 1,769 patients were analyzed (1,311 without ulceration, 458 with ulceration) with a median follow-up of 71 months. Ulceration was associated with significantly worse disease-free survival (DFS) and OS in both node-negative and node-positive patients. Kaplan-Meier analysis of node-negative and node-positive patients by ulceration status revealed that the only significant impact of IFN was improved DFS in the ulcerated node-positive patients (P = .0169). IFN therapy had no significant impact on OS regardless of ulceration status, however. On multivariate analysis, IFN treatment was a significant independent predictor of DFS among ulcerated patients (odds ratio, 0.51; 95% CI, 0.30-0.83; P = .0053), but not among patients without ulceration.

Conclusions

In conclusion, PEG-IFN α-2b has been shown to result in a significant and sustained benefit on RFS, but not on DMFS and OS. Furthermore, there is a clear stage-dependent benefit, as patients with stage III-N1 disease experienced greater benefit in terms of RFS and trend for DMFS and OS, while patients with stage III-N2 did not experience a benefit with PEG-IFN α-2b in regards to any endpoints. Importantly, patients with ulcerated primary sentinel node-positive stage III disease displayed a significant benefit with regard to all endpoints. The role of ulceration has been confirmed in the EORTC 18952 and 18991 trials, the SUNBELT trial, and a meta-analysis. However, results of the SUNBELT trial did not demonstrate that ulceration was significantly associated with response to IFN regarding OS, while the EORTC trials did. The role of ulceration in susceptibility to PEG-IFN α-2b will be further examined in EORTC 18081, a randomized phase 3 trial of patients with stage II ulcerated primary melanoma > 1 mm. Patients will be randomized to receive either PEG-IFN α-2b for 2 years or observation.

References

1. Balch, CM, Gershenwald JE, Soong SJ, et al. Multivariate analysis of prognostic factors among 2,313 patients with stage III melanoma: Comparison of nodal micrometastases versus macrometastases. J Clin Oncol. 2010;28(14):2452-2459.
2. Wheatley K, Ives N, Hancock B, Gore M, Eggermont A, Suciu S. Does adjuvant interferon-alpha for high-risk melanoma provide a worthwhile benefit? A meta-analysis of the randomised trials. Cancer Treat Rev. 2003;29(4):241-252.
3. Mocellin S, Pasquali S, Rossi CR, Nitti D. Interferon alpha adjuvant therapy in patients with high-risk melanoma: A systematic review and meta-analysis. J Natl Cancer Inst. 2010;102(7):493-501.
4. Youngster S, Wang YS, Grace M, Bausch J, Bordens R, Wyss DF. Structure, biology, and therapeutic implications of pegylated interferon alpha-2b. Curr Pharm Des. 2002;8(24):2139-2157.
5. US Food and Drug Administration. Peginterferon alfa-2b. http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm249263.htm. Accessed September 1, 2011.
6. Eggermont AM, Suciu S, Santinami M, et al; EORTC Melanoma Group. Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: Final results of EORTC 18991, a randomised phase III trial. Lancet. 2008;372(9633):117-126.
7. Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: The Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996;14(1):7-17.
8. Eggermont AM, Suciu S, Santinami M, et al. EORTC 18991 phase III trial: Long-term adjuvant pegylated interferon-α2b (PEG-IFN) versus observation in resected stage III melanoma: Long-term results at 7.6-years follow-up. Presented at: American Society of Clinical Oncology Annual Meeting; June 3-7, 2011; Chicago, IL. Abstract 8506b. http://www.asco.org/ascov2/Meetings/Abstracts?vmview=abst_detail_view&confID=102&abstractID=83141. Accessed September 5, 2011.
9. Eggermont AM, Suciu S, MacKie R, et al; EORTC Melanoma Group. Post-surgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): Randomised controlled trial. Lancet. 2005;366(9492):1189-1196.
10. McMasters KM, Edwards MJ, Ross MI, et al. Ulceration as a predictive marker for response to adjuvant interferon therapy in melanoma. Ann Surg. 2010;252(3):460-465.