Copenhagen, Denmark—Adjuvant immunotherapy with ipilimumab (Yervoy) led to significant improvement in long-term overall survival (OS) among patients with high-risk melanoma, according to results from a 5.3-year follow-up in a randomized clinical trial reported at the 2016 European Society for Medical Oncology Congress and published simultaneously online (Eggermont A, et al. N Engl J Med. 2016 Oct 7. Epub ahead of print).
After undergoing complete resection, patients who received postoperative ipilimumab had a 5-year survival rate of 65.4% compared with 54.4% for patients who received placebo. Recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) were also significantly improved in the ipilimumab arm of the study.
These findings reinforced earlier results from the EORTC 18071 clinical trial, which led to the FDA approval of ipilimumab for the adjuvant use in stage III melanoma.
“The [magnitude of] effect of adjuvant ipilimumab was consistent across all survival end points,” said Alexander Eggermont, MD, Gustave Roussy Institute, Villejuif, France. “We also see for the first time, in palpable nodal disease, that treatment does better than placebo.”
“Of course, the benefit comes at a price in terms of side effects and toxicity. Ipilimumab is not an easy drug to handle, and my recommendation is to keep it in [experienced] centers. It does now present an important option for patients to be treated in the adjuvant setting,” he added.
Ipilimumab is 1 of 3 agents approved in the United States for adjuvant therapy in patients with high-risk melanoma. Interferon and pegylated interferon are the other 2 approved options. Data from the EORTC 18071 clinical trial demonstrated a median RFS of 26.1 months with ipilimumab versus 17.1 months with placebo.
However, EORTC 18071 showed no survival benefit with ipilimumab after a median follow-up of 2.7 years (Eggermont A, et al. Lancet Oncol. 2015;16:522-530). Dr Eggermont reported updated findings from 5.3 years’ median follow-up.
The EORTC 18071 involved 951 patients with stage IIIa-c melanoma that had been completely resected. The patients were randomized to receive ipilimumab 10 mg/kg every 3 weeks for 4 doses or to matching placebo. The primary end point was RFS, and the secondary end points included OS, DMFS, and safety.
The 11% absolute difference in OS translated into a 28% reduction in the hazard for disease progression or death in favor of ipilimumab (P = .001). The median RFS and 5-year RFS were 27.6 months and 40.8%, respectively, with ipilimumab versus 17.1 months and 30.3%, respectively, with placebo (P = .0008). The median DMFS and 5-year DMFS were 48.3 months and 48.3%, respectively, with ipilimumab versus 27.5 months and 38.9%, respectively, with placebo (P = .002).
Overall, toxicity was consistent with previous experience with ipilimumab, and no new or unexpected adverse events were observed.
Treatment with ipilimumab was associated with increased rates of treatment-related adverse events and serious adverse events. The incidence of immune-related grade 3 or 4 adverse events was 41.6%, the most common being hepatic effects (10.9%), diarrhea (9.8%), colitis (7.4%), and endocrine effects (7.8%). Some patients developed endocrine abnormalities, such as hypophysitis, requiring lifelong replacement therapy, said Dr Eggermont.
In the ipilimumab group, fatal adverse events included 3 patients with colitis (including 2 patients with gastrointestinal perforations); 1 patient with myocarditis; and 1 patient with multiorgan failure associated with Guillain-Barré syndrome.
Further emphasizing the beneficial effect of ipilimumab, Dr Eggermont showed a comparison of results in patients with palpable and nonpalpable disease from this clinical trial and from previous placebo-controlled EORTC clinical trials that evaluated conventional and pegylated interferon use in the adjuvant setting.
The analysis showed that the drugs did not improve survival in patients with palpable disease. A similar analysis of EORTC 18071 showed a 20% reduction in the survival hazard among patients with palpable disease who received ipilimumab, although with overlapping confidence intervals.
These study results represent “an important milestone in the treatment of melanoma,” said Olivier Michielin, MD, Personalized Analytical Oncology, CHUV, Lausanne, Switzerland.
“These results open the door for other studies of checkpoint blockade to try and improve cure rates in the advent setting of melanoma, as well as other disease types,” Dr Michielin said.
“The risks and benefits of this option should now be discussed with our patients,” Dr Michielin added. “The toxicity is not negligible, and patients need to be aware of the adverse event profile. The 10-mg/kg regimen used in the trial is associated with potentially severe toxicities and should be reserved for experienced centers.”
