Ipilimumab (Yervoy) is a fully human monoclonal antibody that blocks the negative T-cell regulator cytotoxic T-lymphocyte antigen 4 (CTLA-4) and has improved overall survival for patients with unresectable or metastatic melanoma in two phase III studies.^1,2 Based upon these results, ipilimumab was tested in the adjuvant setting for patients with resected, stage III melanoma.

A Closer Look at EORTC 18071

The European Organisation for Research and Treatment of Cancer (EORTC) 18071 trial—reported in The Lancet Oncology by Alexander ­Eggermont, MD, and colleagues³ and reviewed in this issue of The ASCO Post—was a double-blinded, randomized-controlled trial where patients with resected stage III cutaneous melanoma (lymph node involvement > 1 mm) received ipilimumab (10 mg/kg every 3 weeks for four doses and then every 3 months for up to 3 years) or placebo. The study’s primary endpoint was recurrence-free survival as assessed by an independent review committee. Dr. ­Eggermont first reported the trial’s results at the 2014 ASCO Annual Meeting.

The study met its primary recurrence-free survival endpoint. Ipilimumab conferred a recurrence-free survival benefit (median recurrence-free survival of 26.1 months, 95% confidence interval [CI] = 19.3–39.3) for ipilimumab vs 17.1 months (95% CI  = 13.4–21.6) for placebo (hazard ratio = 0.75, 95% CI = 0.64–0.90, P = .0013). No overall survival information has yet been presented.

The investigators should be congratulated for the conduct of this large study involving 951 patients treated in 19 countries worldwide and demonstrating, for the first time, a benefit for ipilimumab in the adjuvant setting. Nonetheless, several important questions remain about adjuvant ipilimumab, particularly when considering this trial’s results against other standard melanoma adjuvant approaches such as interferon alfa-2b (Intron A) and observation.

Longer Follow-Up and Further Study Needed

As demonstrated by the primary endpoint results of EORTC 18071, adjuvant ipilimumab improves recurrence-free survival, but whether ipilimumab improves overall survival in this context remains unknown. Many treating physicians consider demonstration of an overall survival benefit to be a particularly critical endpoint in an adjuvant trial testing any agent that could cause side effects. Pegylated and high-dose interferon, standard adjuvant melanoma treatment options, have improved recurrence-free survival compared with observation.^4-6 Yet controversies over interferon’s long-term overall survival benefit and side-effect profile have limited its unanimous use.

With longer follow-up, all are hopeful that an overall survival benefit will emerge for ipilimumab administered as an adjuvant therapy. However, since ipilimumab is a standard treatment for patients with recurrent melanoma, many patients in the placebo group who experience disease recurrence will subsequently receive ipilimumab, possibly affecting interpretations of overall survival differences between the study arms. If there is ultimately no overall survival difference, it would likely be reasonable to reserve ipilimumab treatment for patients upon relapse. In subsequent analyses of this study, it will be important to consider the number of relapsing patients who receive subsequent ipilimumab.

In EORTC 18071, adjuvant ipilimumab was administered at a high dose of 10 mg/kg, approximately three times the current U.S. Food and Drug Administration–approved dose of 3 mg/ kg. It remains unclear whether the dose of ipilimumab is related to efficacy. A phase III trial is testing ipilimumab at 10 mg/ kg vs 3 mg/kg in patients with unresectable or metastatic melanoma. Another phase III trial, Eastern Cooperative Oncology Group (ECOG) 1609, is testing ipilimumab 10 mg/kg vs ipilimumab 3 mg/kg vs high-dose interferon in the adjuvant setting and will provide additional information on the relevance of the dose of ipilimumab to therapeutic outcome. The ECOG 1609 trial will also be the first to report the efficacy of ipilimumab vs high-dose interferon.

In the EORTC 18071 trial, adverse events led to discontinuation of treatment in 52% of patients receiving ipilimumab, with 40% discontinuing ipilimumab before the end of the initial 12-week dosing period (before maintenance dosing). Although this may seem to be a high number, the clinical significance of this discontinuation rate remains completely unknown, since the likelihood of benefit from ipilimumab is not clearly related to the amount of treatment received.

The specific side effects related to ipilimumab in this study (diarrhea, rash, hepatitis, endocrinopathy) were generally similar to those seen in prior trials of patients with unresectable or metastatic melanoma, and most side effects resolved within 4 to 8 weeks with immunosuppressive agents such as steroids. Of note were five ipilimumab treatment-related deaths (1%). Four of these five patients received steroid immunosuppression, and one received antitumor necrosis-alpha therapy. Whether these deaths could have been prevented with alternative immunosuppressive management remains unknown, but they serve as a reminder that patients receiving ipilimumab require significant clinical attention.

As newer immunotherapeutic agents such as those targeting the programmed cell death 1 (PD-1) receptor (nivolumab [Opdivo] and pembrolizumab [Keytruda]) demonstrate success in the metastatic setting,^7,8 their potential efficacy as adjuvant therapies remains of great interest. Clinical trials examining adjuvant pembrolizumab vs placebo (NCT02362594) and nivolumab vs ipilimumab (NCT02388906) have been or will soon be initiated for patients with resected melanoma. One potential pitfall to our ultimate understanding of the relative values of specific adjuvant treatments in melanoma will be the varied approaches used in the control arms of the ongoing large adjuvant trials. Some studies use control arms containing regimens such as interferon or ipilimumab, and in other trials, observation remains the control.

Closing Thoughts

The positive recurrence-free survival data for ipilimumab in the EORTC 18071 study are encouraging, yet additional follow-up, including overall survival data, is necessary to assess the true value of ipilimumab in the adjuvant setting. In the meantime, enrollment of patients into ongoing clinical trials testing new approaches in the adjuvant treatment of melanoma, such as anti–PD-1 therapy, is encouraged. ■

Disclosure: Dr. Postow is a consultant for Bristol-Myers-Squibb and Amgen and has received a research grant from Bristol-Myers Squibb.

References

1. Hodi FS, et al: N Engl J Med 363:711-723, 2010.

2. Robert C, et al: N Engl J Med 364:2517-2526, 2011.

3. Eggermont AM, et al: Lancet Oncol 16:522-530, 2015.

4. Eggermont AM, et al: J Clin Oncol 30:3810-3818, 2012.

5. Kirkwood JM, et al: J Clin Oncol 18:2444-2458, 2000.

6. Kirkwood JM, et al: Clin Cancer Res 10:1670-1677, 2004.

7. Robert C, et al: N Engl J Med 372:2521-2532, 2015.

8. Larkin J, et al: N Engl J Med. May 31, 2015 (early release online).