Adjuvant ipilimumab extends survival in stage III melanoma

COPENHAGEN, Denmark — Adjuvant therapy with ipilimumab significantly extended survival compared with placebo among patients who underwent complete resection for stage III melanoma at high risk for relapse, according to phase 3 study results presented at the European Society for Medical Oncology Congress.

However, more than 40% of patients treated with ipilimumab (Yervoy, Bristol-Myers Squibb) experienced grade 3 or grade 4 immune-related adverse events. Five ipilimumab-treated patients died due to immune-related adverse events.

Alexander M.M. Eggermont

“[The survival benefit] comes at the price of side effects and toxicity,” Alexander M.M. Eggermont, MD, PhD, director general of Institut Gustave Roussy in Villejuif, France, said during a press conference. “Ipilimumab is not an easy drug to handle ... but it does represent an important option for patients who are treated in the adjuvant setting.”

A phase 2 trial that evaluated three doses of the anti–CTLA-4 antibody ipilimumab — 0.3 mg/kg, 3 mg/kg and 10 mg/kg — showed the 10-mg/kg dose had the greatest efficacy for treatment of advanced melanoma, despite increased toxicity.

Based on those results, Eggermont and colleagues conducted the phase 3 EORTC 18071 trial to compare the ipilimumab 10 mg/kg with placebo in 951 patients who underwent complete resection of regional lymph node–positive melanoma with a high risk for recurrence.

Researchers enrolled patients from June 2008 through July 2011 at centers in the United States, Europe and Australia.

Investigators randomly assigned patients to ipilimumab (n = 475) or placebo (n = 476) every 3 weeks for four doses, followed by maintenance therapy every 3 months. Treatment continued for up to 3 years, or until disease recurrence or unacceptable toxicity.

RFS served as the primary endpoint. OS, distant metastasis-free survival and safety served as secondary endpoints.

Data released in 2015, based on a median 2.3 years of follow-up, showed ipilimumab significantly extended RFS.

At ESMO, Eggermont presented data based on median follow-up of 5.3 years.

Researchers reported median RFS of 27.6 months (95% CI, 19.3-37.2) in the ipilimumab group and 17.1 months (95% CI, 13.6-21.6) in the placebo group.

More patients assigned ipilimumab achieved 5-year RFS (40.8% vs. 30.3%; HR = 0.76; 95% CI, 0.64-0.89) and 5-year OS (65.4% vs. 54.4%; HR = 0.72; 95.1% CI, 0.58-0.88).

A significantly higher percentage of ipilimumab-treated patients achieved 5-year distant metastasis-free survival (48.3% vs. 38.9%; HR = 0.76; 95.8% CI, 0.64-0.92).

A comparison of data from this trial to historical data of interferon adjuvant therapy showed clear efficacy benefit for ipilimumab in patients with microscopic disease, as well as those with clinically palpable lymph nodes, Eggermont said.

Twice as many patients assigned ipilimumab experienced grade 3 or grade 4 adverse events (54.1% vs. 26.2%). Grade 3 or grade 4 immune-related adverse events occurred in 41.6% of patients assigned ipilimumab and 2.7% of patients assigned placebo.

Most adverse events that occurred among ipilimumab-treated patients were transient, according to researchers. However, five patients (1.1%) assigned ipilimumab died due to immune-related adverse events.

Ipilimumab stimulates the immune system against tumor antigens. However, it had been unclear whether a sufficient number of antigens remained in the adjuvant setting to trigger a response, according to Olivier Michielin, MD, PhD, head of personalized analytical oncology at Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland, who was not involved with the study.

Michielin called this “an important scientific discovery,” but he emphasized “the toxicity is not negligible,” and that patients must be aware of the potential for adverse events.

“This trial represents an important milestone in the treatment of melanoma,” Michielin said. “These results open the door for other studies based on checkpoint blockade to try and improve cure rates in the adjuvant setting of melanoma, as well as other disease types.” – by Mark Leiser

For more information: Eggermont AM, et al. Abstract LBA2_PR. Presented at: European Society for Medical Oncology Congress; Oct. 7-11, 2016; Copenhagen, Denmark.

Disclosure: Bristol-Myers Squibb provided funding for this study. Eggermont reports advisory board roles with Bristol-Myers Squibb and Merck Sharpe & Dohme. Please see the abstract for a list of all other researchers’ relevant financial disclosures.