Is Ipilimumab Ready for the Adjuvant Treatment of Melanoma?

Alexander M. Castellino, PhD

April 08, 2015

Ipilimumab (Yervoy, Bristol-Myers Squibb) was the first immunotherapy to change the landscape for metastatic melanoma treatment. Having first been tested in patients who failed to respond to other available treatments, it is now routinely used in the first-line setting for patients with metastatic melanoma. Although not all patients respond to ipilimumab, when responses occur they are durable — lasting longer than 10 years in more than 20% of cases.

With such success in the metastatic setting, researchers have now turned to earlier stages of the disease and are exploring the use of ipilimumab in the adjuvant setting for melanoma patients at high risk for recurrence after surgery.

Initial data suggesting that there is benefit in the adjuvant setting come from an interim analysis of data from the European Organization for Research and Treatment of Cancer (EORTC) 18071 study, published online March 31 in the Lancet Oncology.

EORTC 18071 was conducted in high-risk patients with stage III melanoma who had undergone a complete lymph node dissection. The interim results show that 3-year recurrence-free survival was significantly higher in patients receiving ipilimumab than in those receiving placebo (46.5% vs 34.8%; = .0013). However, overall survival information was not available from this analysis.

In the study, ipilimumab was given at a dose of 10 mg/kg, which is significantly higher than the approved dose of 3 mg/kg in the metastatic setting but is based on data from a dose-ranging phase 2 study (Lancet Oncol. 2010;11:155-164).

The authors contend that although recurrence-free survival is significant, "the risk–benefit ratio of adjuvant ipilimumab at this dose and schedule requires additional assessment based on distant metastasis-free survival and overall survival end points to define its definitive value."

"This was a well-planned, randomized, blinded study that set about answering an important question in adjuvant melanoma," EORTC 18071 coauthor Omid Hamid, MD, director of the melanoma program and chief of clinical research at the Angeles Clinic and Research Institute in Los Angeles, told Medscape Medical News.

"We evaluated what we believed was the right adjuvant treatment. Ipilimumab was shown to provide long-term survival in the metastatic setting. It made sense to take it to the adjuvant setting," he added.

"Having made such dramatic progress in metastatic melanoma with ipilimumab and other new drugs, the next frontier is clearly adjuvant therapy. This study provides the first brick in a bigger wall by showing us that it is at least possible to use new, breakthrough drugs in the adjuvant setting," Vernon K. Sondak, MD, from the Department of Cutaneous Oncology at the Moffitt Cancer Center in Tampa, Florida, who coauthored an accompanying comment with Grant A. McArthur, MB BS, from the Peter MacCallum Cancer Centre in Melbourne, Australia, told Medscape Medical News.

"This EORTC study is the first evidence that ipilimumab may provide clinical benefits to patients in the adjuvant setting, but it is not a home run yet since we do not have the survival data," Dr Sondak said.

Much remains to be learned about ipilimumab in the adjuvant setting of melanoma, he added, such as whether the higher dose is really necessary and how much of an advantage ipilimumab has over interferon.

But "after decades of having only interferon, we may have another option for high-risk patients with melanoma," Dr Hamid told Medscape Medical News.

The EORTC 18071 Study

EORTC 18071 is a phase 3 double-blind placebo-controlled study of 951 patients with stage III cutaneous melanoma who had not received previous systemic therapy. Patients were excluded if metastasis was 1 mm or smaller or was in transit.

After undergoing complete resection with adequate surgical margins and complete regional lymphadenectomy within 12 weeks, 475 patients were randomized to receive ipilimumab and 476 were randomized to receive placebo.

Intravenous infusion of ipilimumab 10 mg/kg or placebo was administered every 3 weeks for four doses (induction therapy), and then every 3 months for up to 3 years (maintenance therapy).

Recurrence-free survival was the primary end point of the study. Overall survival and distant-metastasis-free survival were secondary end points. Both groups were assessed with CT every 3 months for 3 years, and every 6 months thereafter.

Recurrence-free survival was better in the ipilimumab group than in the placebo group at 1 year (63.5% vs 56.1%), at 2 years (51.5% vs 43.8%), and at 3 years (46.5% vs 34.8%).

Patients in the ipilimumab group were 25% less likely to experience melanoma recurrence than those in the placebo group (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.64 - 0.90; = .0013). And median recurrence-free survival was better in the ipilimumab group (26.1 vs 17.1 months).

Toxicity of Adjuvant Ipilimumab 10 mg/kg

It is noteworthy that patients did not receive all planned doses because of the toxicity associated with the dose and schedule of ipilimumab, Dr Sondak explained. Patients in the ipilimumab group received a median of four doses each (range, 1 - 16), which constitutes 3 months of therapy, and those in the placebo group received a median of eight (range, 1 - 16).

Maintenance ipilimumab was administered to 42% of patients, with only 29% of patients receiving seven doses (the equivalent of 1 year of the planned 3 years of treatment).

More patients in the ipilimumab group than in the placebo group discontinued therapy because of adverse events (52% vs 4%). Of these events, 49% were drug-related and 39% led to discontinuation in the first 12 weeks of treatment.

However, discontinuation related to disease recurrence was less common in the ipilimumab group than in the placebo group (28% vs 58%).

Adverse events of any grade were more common in the ipilimumab group than in the placebo group (99% vs 91%), as were grade 3/4 events (54% vs 25%).

"This degree of toxicity seems to be notably more than would be expected with ipilimumab given in the metastatic setting," Drs Sondak and McArthur write.

"Although the higher dose and longer duration of exposure might be partly responsible, lower tumor burden in the adjuvant setting might also result in less suppression of the immune system or less targeting of the immune response towards tumor associated antigens," they add.

Although recurrence-free survival was significant, toxicity issues need to be resolved, Dr Hamid said, noting the five ipilimumab-associated deaths and the fraction of patients for whom the toxicity did not resolve.

Clinical Implications

Anyone who is considering using ipilimumab off-protocol in the adjuvant setting needs to be aware of these data, Dr Sondak told Medscape Medical News. He noted that interferon, which is the current standard of care in the adjuvant setting, might have a similar recurrence-free survival profile but is less toxic.

But Dr Hamid said that interferon is not without controversy. The toxicities are different (fatigue, anorexia, and cognitive dysfunctions are significant with interferon) and the survival benefits are questionable. He indicated that in the future, biomarker analyses might be able to identify patients who will benefit from therapy with ipilimumab.

Dr Hamid pointed out that pegylated interferon was approved on the basis of recurrence-free survival data without any overall survival impact. However, the survival data were known by the US Food and Drug Administration when the decision to approve the product was made.

Given the toxicity and discontinuation rates reported in this study, it might be prudent to save ipilimumab for patients in the metastatic setting, Dr Sondak said. In particular, he noted, he wants to see overall survival data to be sure that the crossover of patients to ipilimumab on relapse isn't as effective as using ipilimumab in the adjuvant setting.

Drs Sondak and McArthur argue that "a large percentage of patients in the placebo group who develop metastatic disease would be expected to receive ipilimumab on relapse."

"If overall survival for the two groups does not differ significantly, it would suggest that reserving ipilimumab for salvage treatment is preferable to exposing all patients to the toxicity (and cost) of adjuvant use," they add.

Ongoing Studies in Adjuvant Melanoma

Because interferon is the current standard-of-care adjuvant therapy, Dr Sondak questioned the use of placebo as the comparator. Other studies might be better designed to determine whether ipilimumab is superior to interferon in the adjuvant setting, and at what dose, he noted.

In EORTC 18071, placebo was chosen as the comparator because of "widespread dissatisfaction with available alternative adjuvant treatments for high-risk patients with stage III melanoma," Dr Sondak explained.

He pointed out that the Eastern Cooperative Oncology Group (ECOG) 1609 study will help determine whether ipilimumab trumps interferon in the adjuvant setting, and whether ipilimumab 10 mg/kg is more effective than ipilimumab 3 mg/kg.

These studies will also address the appropriate length of maintenance therapy — 1 year (ECOG 1609) or 3 years (EORTC 18071), Dr Hamid said.

The ongoing ECOG 1609 (NCT01274338) study being conducted in the United States is comparing high-dose interferon, ipilimumab 10 mg/kg, and ipilimumab 3 mg/kg. After four doses of induction therapy, four maintenance doses of ipilimumab will be administered over 1 year. Recurrence-free survival and overall survival are coprimary end points. The study has completed accrual, and first results are expected in May 2018.

Drs Sondak and Hamid share their enthusiasm for other adjuvant trials in melanoma. "The expectation is riding high on the other immunotherapies — the PD-1 inhibitors, nivolumab, and pembrolizumab — approved in the metastatic setting," Dr Sondak said.

These drugs seem to be less toxic and more effective than ipilimumab, he added.

The phase 3 CheckMate 238 (NCT02388906) study will determine whether nivolumab is better than ipilimumab in the adjuvant melanoma setting. And the phase 3 KEYNOTE-054 (NCT02362594) study will determine whether pembrolizumab is better than placebo in the adjuvant melanoma setting.

In addition, the Southwest Oncology Group S1404 study is designed to compare pembrolizumab with high-dose interferon in the adjuvant treatment of resected stage III and IV melanoma.

"We are excited about these new trials," Dr Sondak told Medscape Medical News. CheckMate 238 and KEYNOTE-054 have not started recruiting patients and are expected to go beyond 2020.

"Although we recognize that there is still a long way to go before ipilimumab or any other checkpoint inhibitor can be deemed standard-of-care adjuvant treatment, [the EORTC 18071] results establish that checkpoint inhibitors can favorably affect the natural history of minimal residual disease, opening the door to expanding trials of these agents beyond melanoma," Drs Sondak and McArthur conclude.

EORTC 18071 was funded by Bristol-Myers Squibb (BMS). Some coauthors report financial relationships with BMS and other pharmaceutical companies, as detailed in the publication. Dr Hamid reports being a consultant, speaker, and/or researcher for BMS and Merck. Dr Sondak reports being a consultant for several pharmaceutical companies, including BMS.

Lancet Oncol. Published online March 31, 2015. Abstract, Comment

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