Ipilimumab may become standard of care for adjuvant melanoma therapy
NEW YORK — Two phase 3 trials currently underway are expected to help answer the provocative question of whether ipilimumab will replace interferon as the standard of care for adjuvant therapy in melanoma, according to a presenter at the HemOnc Today Melanoma and Cutaneous Malignancies meeting.
“We really have a new path forward and a new beginning,” Lynn M. Schuchter, MD, chief of the division of hematology/oncology and C. Willard professor of medicine at Abramson Cancer Center at the University of Pennsylvania, said during a presentation. “I’m hopeful we will advance this therapy further by refining proper patient selection, matching the right biomarkers and modifying toxicities.”
Lynn M. Schuchter
Adjuvant therapy for melanoma typically is offered to patients with high-risk disease, including those with melanomas greater than 4 mm thick and those with node-positive disease.
Interferon is the only FDA-approved treatment for the management of melanoma in the adjuvant setting.
Agents must meet specific standards — including a >10% response rate and a reasonable side-effect profile — in the metastatic setting before they can be considered in the adjuvant setting.
“These are patients who are potentially cured, and we don’t want to have the potential risks of the therapy outweigh the potential benefits,” Schuchter said.
Agents in development for treatment of advanced melanoma include BRAF and MEK inhibitors, combination targeted therapies, ipilimumab (Yervoy, Bristol-Myers Squibb) and PD-1 antibodies.
“Clinical trials are ongoing to look at these strategies in the adjuvant setting,” Schuchter said. “Based upon the principles I just described, these would all qualify. They have much higher response rates than the minimum standard of 10% and they have reasonable toxicity profiles. These are all potential new approaches that could be taken into the adjuvant setting.”
Two randomized clinical trials demonstrated ipilimumab’s activity in patients with stage IV or advanced stage III metastatic disease.
Hodi and colleagues compared ipilimumab 3 mg/kg vs. gp100 peptide vaccine vs. a combination of the two therapies. Results showed patients assigned ipilimumab alone experienced longer median OS than those assigned the vaccine alone (10 months vs. 6 months). The addition of the vaccine to ipilimumab did not yield a survival benefit. Rates of 1-year OS were 46% for ipilimumab alone, 44% for ipilimumab plus gp100, and 25% for gp100 alone.
Robert and colleagues evaluated dacarbazine with or without ipilimumab 10 mg/kg. Results showed an OS advantage for the combination regimen (11.2 months vs. 9.1 months).
“We certainly see many clues from metastatic disease that this could be an active agent in the adjuvant setting,” Schuchter said.
The most common toxicity associated with ipilimumab in the metastatic setting was dermatitis (43.5%), followed by increased ALT/AST levels (about 30%) and colitis diarrhea (about 30%). Grade 3 or grade IV toxicities occurred in about 20% of patients.
“With early detection and early evaluation, we can manage patients through these toxicities,” Schuchter said.
Two phase 3 trials are underway to evaluate ipilimumab in the adjuvant setting among patients with stage IIIA, IIIB or IIIc disease. Patients with ocular or mucosal melanoma were not eligible for either study.
The randomized, double blind EORTC 18701 trial includes 950 patients assigned to ipilimumab 10 mg/kg or observation. Ipilimumab treatment includes four induction doses, followed by maintenance every 12 weeks for a total of 3 years. The primary endpoint is RFS, and OS is a secondary endpoint.
The randomized, double blind Intergroup E1609 trial includes 1,500 patients assigned to one of three treatment arms: ipilimumab 3 mg/kg, ipilimumab 10 mg/kg or high-dose interferon. Ipilimumab treatment includes four induction doses, followed by 1 year of maintenance. The primary endpoints are RFS and OS.
The initial results of the EORTC study are expected to be presented at the ASCO Annual Meeting, scheduled for May 30-June 3 in Chicago.
Schuchter emphasized she does not have information about outcomes of either trial, but she offered her “predictions and hopes.”
She predicted EORTC 18071 will be a positive trial that shows improvement in RFS and OS.
“The hazard ratio for adjuvant [trastuzumab (Herceptin, Genentech)] in breast cancer is around 0.45, so I’m hoping we see something around 0.6 for ipilimumab,” she said.
Schuchter speculated immune adverse events will be a concern and that it will prove difficult to administer 3 years of therapy, particularly at the 10-mg/kg dose.
She predicted ECOG 1609 will be a positive trial that shows improvement in RFS and OS with both ipilimumab doses; however, more successful post-relapse therapy may limit the ability to measure OS benefit. High-dose ipilimumab likely will be marginally better than low-dose ipilimumab, but a higher rate of immune adverse events with the higher dose may cancel out that benefit, Schuchter said.
“This clinical trial, open for accrual, is a critical study,” Schuchter said. “Enrollment on this clinical trial is my preferred approach for patients with stage III melanoma.”
She speculated the recommendation going forward will be ipilimumab 3 mg/kg, with 1 year of maintenance.
“Will ipilimumab become the new standard of care [in the adjuvant setting]? I would say yes, but of course we will have to monitor risk vs. benefit with any of the therapies that we consider,” Schuchter said.
Questions that must be addressed with regard to ipilimumab include which patients will benefit most, as well as which dose and what treatment duration yield optimal outcomes.
Even if ipilimumab becomes the standard of care in the adjuvant setting, it may not fill that role for long, she added.
“There is going to be a PD-1 versus ipilimumab clinical trial,” Schuchter said. “Ipilimumab may become the new standard of care, but I don’t know for how long. PD-1 antibodies are likely to be approved this summer for patients with advanced melanoma. Ultimately, these agents will be explored in the adjuvant setting.”
For more information:
Schuchter LM. Adjuvant therapy of melanoma: Will ipilimumab become the new standard of care? Presented at: HemOnc Today Melanoma and Cutaneous Malignancies; April 11-12, 2014; New York.
Hodi FS. N Engl J Med. 2010;363:711-723.
Robert C. N Engl J Med. 2011;364:2517-2526.
Disclosure: Schuchter reports clinical trial involvement with GlaxoSmithKline and Merck.