NEW YORK — Patients with high-risk stage III melanoma who received ipilimumab after complete resection demonstrated prolonged RFS compared with patients who received placebo, according to phase 3 study results presented at the HemOnc Today Melanoma and Cutaneous Malignancies meeting.
FDA-approved drugs for the adjuvant therapy of stage III melanoma included interferon alpha-2b and pegylated interferon alpha-2b, according to study background.
Alexander M.M. Eggermont
“There have been different schedules applied, mainly because of the lack of efficacy of interferon in advanced melanoma, so there was no guidance coming out of stage IV disease,” Alexander M. M. Eggermont, MD, PhD, director general of the Gustave Roussy Cancer Campus Grand Paris in France, said during his presentation. “A minority of the patients get a benefit from interferon therapy, which is exactly the reason why the overall outcome for adjuvant interferon therapies is marginal, with usually only an effect on RFS and not OS.”
The current analysis included 951 patients with high-risk, stage III, completely resected melanoma. Eggermont and colleagues randomly assigned patients 1:1 to receive 10 mg/kg ipilimumab (Yervoy, Bristol-Myers Squibb) every 3 weeks followed by maintenance ipilimumab every 3 months for up to 3 years, or placebo.
The median age of patients on the ipilimumab arm was 51 years, and the median age of the placebo arm was 52 years. Sixty-two percent of each cohort were male. The most common disease stage in each arm was IIIB (ipilimumab, 45%; placebo, 43%).
The primary endpoint was RFS. OS, distant metastases-free survival, adverse events and health-related quality of life served as secondary endpoints.
Sixty more patients relapsed in the placebo arm than in the ipilimumab arm (294 vs. 234). Ipilimumab conferred greater rates for RFS at 2 years (51.5% vs. 43.8%) and 3 years (46.5% vs. 34.8%). Overall, ipilimumab was associated with a reduced risk for recurrence (HR = 0.75; 95% CI, 0.64-0.9).
Treatment discontinuation occurred in 91.7% of patients assigned ipilimumab and 83.1% of patients assigned placebo. More patients in the placebo arm discontinued treatment due to disease progression (57.6% vs. 28%), whereas more patients in the ipilimumab arm discontinued due to an adverse event (48.8% vs. 1.7%).
More patients in the ipilimumab arm experienced any-grade gastrointestinal adverse events (46.3% vs. 17.7%), diarrhea (41.4% vs. 16.7%), colitis (15.9% vs. 1.3%), hypophysitis (18.3% vs. 0.4%), and hepatic adverse events (25.1% vs. 4.4%). Time to resolution of grade 2 to grade 4 ipilimumab-associated skin, gastrointestinal and hepatic adverse events ranged from a median of 4 weeks to 5.5 weeks; however, endocrine adverse events took a median of 31 weeks to resolve.
Five patients died due to drug-related adverse events in the ipilimumab arm, three of whom died due to colitis, one due to myocarditis, and one due to Guillain-Barré syndrome.
“Ipilimumab is a drug we know has its own complexities, and this can be handled sufficiently with all the algorithms,” Eggermont said. “However, everyone needs to be very much aware that there were five deaths related to ipilimumab administration.”
Post hoc analyses indicated patients with microscopic stage III disease demonstrated the most significant RFS benefit with ipilimumab (HR = 0.65; 95% CI, 0.45-0.96) followed by patients with macroscopic stage III disease (HR = 0.81; 95% CI, 0.61-1.08).
“This is an important observation because we in our EORTC trials … have never observed a significant impact on patients with palpable nodal disease with any interferon,” Eggermont said.
Researchers conducted additional post hoc analyses of ulcerated primary (n = 400) vs. non-ulcerated primary tumors (n = 501). Among patients with microscopic disease, the HR for RFS associated with ipilimumab for those with ulcerated tumors was 0.53 (95% CI, 0.21-0.9) and for those with non-ulcerated tumors was 0.72 (95% CI, 0.4-1.31). Among patients with macroscopic disease, the HRs were 0.68 (95% CI, 0.44-1.05) for ulcerated tumors and 0.85 (95% CI, 0.57-1.28) for non-ulcerated tumors favoring ipilimumab.
“What we see with ipilimumab is that it shifts to the left for both patient populations, meaning that the benefit of adjuvant ipilimumab benefits both patient populations, but the ulcerated primary biology still favors the major impact of the adjuvant therapy,” Eggermont said.
There was no clinically significant impact of ipilimumab treatment on global health status.
“I have credibility problems with this kind of read out considering the side effects of ipilimumab,” Eggermont said. “I think that what it reflects is that patients were happy that they were having side effects because they knew they were actually getting the drug.”
OS and distant metastases-free survival data were not yet mature at the time of analysis.
“I expect these data to be very consistent with the RFS benefit, if not better, because the late effects of ipilimumab are actually the strength of the molecule, and not necessarily the short-term impact on RFS,” Eggermont said.
Despite these results, researchers await the results of other randomized trials of anti-PD1 agents and combined BRAF inhibitors and MEK inhibitors in this setting, Eggermont said. — by Alexandra Todak
Eggermont AM, et al. Ipilimumab versus placebo after complete resection of stage III melanoma: efficacy, safety and QoL results from the EORTC 18071 phase III trial. Presented at: HemOnc Today Melanoma and Cutaneous Malignancies meeting; April 10-11, 2015, New York.
Disclosure: Eggermont reports consultant fees from Amgen, Bristol-Myers Squibb, GlaxoSmithKline, MedImmune and Merck.