NEW YORK — Interferon and ipilimumab are options for the adjuvant treatment of many patients with melanoma, but data are lacking comparing these two agents, according to a speaker at HemOnc Today Melanoma and Cutaneous Malignancies.
Future options may include immunotherapies and targeted therapies, or perhaps no adjuvant therapy at all, according to Sanjiv S. Agarwala, MD, professor of medicine at Temple University School of Medicine, chief of oncology and hematology at St. Luke’s Cancer Center in Bethlehem, Pennsylvania, and a HemOnc Today Editorial Board member.
“Adjuvant therapy is a controversial and tough topic, and we still struggle with the right thing to do for these patients,” Agarwala said during his presentation. “There is a large group between low-risk resectable and advanced unresectable disease, and this group of intermediate-risk patients is still being defined. These patients potentially could benefit from treatment so we can prevent them from becoming those with advanced disease.”
Sanjiv S. Agarwala
Interferon has been the longest-standing option for these patients, but challenges remain interpreting interferon data due to changes in staging classifications and techniques, as well as the multiple schedules and regimens that exist.
Updated efficacy results of ECOG 1684, conducted after a median follow-up of 12.6 years, showed high-dose interferon significantly improved RFS (P = .02) compared with observation.
“Benefit is seen long term and, therefore, this is still a standard regimen that someone can use,” Agarwala said.
However, toxicity and appropriate duration are issues. Approaches to overcome these challenges have been to use a lower dose, a shorter duration of high-dose therapy or pegylated interferon. The ECOG 1697 trial did not show a benefit to the use of interferon only during induction, but EORTC 18991 showed a benefit in RFS (median, 34.8 months vs. 25.6 months; 4-year rate, 45.6% vs. 38.9%), but not OS, with pegylated interferon.
Ulceration also may be a biomarker for interferon benefit, but this is still a hypothesis, Agarwala said.
Ipilimumab (Yervoy, Bristol-Myers Squibb) is an option for stage 3 patients, but data are lacking that compare ipilimumab with active controls, including interferon.
Ipilimumab has demonstrated an RFS (HR = 0.75; 95% CI, 0.64-0.9) and OS (HR = 0.72; 95% CI, 0.58-0.88) benefit compared with placebo.
However, more patients assigned ipilimumab experienced a grade 3 or grade 4 adverse event (54.1% vs. 26.26), which is almost as high as what is observed in metastatic melanoma, Agarwala said.
“This is difficult for patients, and the fact that there were five patients who died on this treatment is a concern,” he added. “In metastatic melanoma, which is aggressive and has a potential for dying, it is perhaps acceptable, but it is certainly not acceptable in the adjuvant setting. This should be used very cautiously and in centers that know how to do it.”
Because anti–PD-L1 agents have improved outcomes over anti–CTLA-4 agents in the metastatic setting, trials are needed to compare these drugs in the adjuvant setting, especially because these agents are associated with less toxicity.
“One thing is very clear, toxicity is low,” Agarwala said. “This makes it much more attractive in the do-no-harm realm, which is extremely important in the adjuvant setting.”
Many trials are underway evaluating different combinations of immunotherapies, and there also trials of targeted therapies for BRAF–positive disease, to help better define the role of these treatments for the adjuvant therapy of melanoma.
Until data from these are available, clinicians must look at the existing data and individualize care, Agarwala said. He also noted the importance of enrolling patients on clinical trials.
However, it is also possible that in future years, researchers will consider abandoning adjuvant therapy all together, Agarwala said.
“We’re making a lot of success in metastatic melanoma, so do we need to subject patients who are potentially cured — and we know the cure rates are getting better and better with new surgical techniques — to adjuvant treatment?” he said. “Our real true success in melanoma is going to be when adjuvant therapy is not an issue anymore, because adjuvant therapy is giving a lot of patients something they did not need, at a high toxicity and a very high expense.
“I will say we have success in melanoma treatment when we no longer have adjuvant therapy, and that’s a day I’m looking forward to,” Agarwala added. – by Alexandra Todak
Agarwala SS. Adjuvant therapy: Past, present and future. Presented at: HemOnc Today Melanoma and Cutaneous Malignancies; March 24-25, 2017; New York.
Disclosure: Agarwala reports no relevant financial disclosures.