Alexander Eggermont, MD, PhD
Treatment with ipilimumab (Yervoy) reduced the risk of death by 28% versus placebo in patients with high-risk stage III melanoma, according to updated findings from the phase III EORTC 18071 trial presented at the 2016 ESMO Congress.1
At a median of 5.3 years’ follow-up, the 5-year overall survival (OS) rate was 65.4% with ipilimumab compared with 54.4% in the control arm (HR, 0.72; 95% CI, 0.58-0.88; P
= .001). The recurrence-free survival (RFS) rate at 5 years was 40.8% versus 30.3% (HR, 0.76; 95% CI 0.64-0.89; P
<.001), respectively, and the 5-year distant metastasis–free survival (DMFS) rate was 48.3% versus 38.9%, respectively (HR, 0.76; 95.8% CI, 0.64-0.92; P
“Ipilimumab adjuvant therapy brings a significant improvement of overall survival and has a favorable risk-benefit ratio. It clearly represents a serious option for patients with stage III melanoma,” lead author Alexander Eggermont, MD, PhD, director general of Gustave Roussy Cancer Campus Grand Paris, Villejuif, France, said in statement.
The international, double-blind phase III EORTC 18071 trial included 951 patients with stage III cutaneous melanoma who had adequate resection of lymph nodes. Patients were randomized in a 1:1 ratio to receive ipilimumab at 10 mg/kg (n = 475) or placebo (n = 476) every 3 weeks for 4 doses, then every 3 months for up to 3 years. Patients in the ipilimumab arm received a median of 4 doses (range, 1-16), with 36% remaining on the drug for >6 months.
Treatment was administered until completion of therapy, disease recurrence, or unacceptable toxicity. The primary endpoint was RFS, with OS as a secondary outcome measure.
At a median follow-up of 5.3 years, the median OS was 86.6 months with ipilimumab and was not yet reached in the placebo arm. The median RFS was 27.6 months in the ipilimumab group versus 17.1 months in the control arm. The median DMFS was 48.3 months versus 27.5 months, respectively.
Previously published results from the trial showed that at a median follow-up of 2.74 years, the median RFS was 26.1 months with ipilimumab versus 17.1 months with placebo (HR, 0.75; 95% CI, 0.64-0.90; P
The 3-year RFS rates were 46.5% versus 34.8%, respectively.
At the 5-year follow-up presented at the ESMO congress, there were no new safety signals or deaths in the ipilimumab cohort. Grade 3/4 adverse events (AEs) occurred in 54.1% of the ipilimumab arm compared with 26.2% of the control group. The rates of grade 3/4 immune-related AEs were 41.6% versus 2.7%, respectively.
Grade 3/4 AEs of note in the ipilimumab arm included gastrointestinal (16%), hepatic (11%), and endocrine (8%). In general, it took 4 to 8 weeks to resolve these toxicities. Endocrine events usually took longer than the other events to resolve, with some requiring permanent hormone replacement therapy.
“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,” Olivier Michielin, MD, PhD, head of Personalized Analytical Oncology, CHUV, Lausanne, Switzerland, said in a statement.
In the United States and Europe, ipilimumab (3 mg/kg) has been approved since 2011 for the first-line treatment of patients with advanced melanoma. In October 2015, based on the initial EORTC 18071 results, the US FDA expanded the approval of ipilimumab to include the adjuvant treatment of patients with stage III melanoma with pathologic involvement of regional lymph nodes >1 mm who have undergone complete resection including total lymphadenectomy.
Further commenting on the EORTC 18071 long-term adjuvant data presented at ESMO, Michielin, said, “This was also an important scientific discovery. Ipilimumab works by stimulating the immune system against tumor antigens. In the adjuvant setting, there is microscopic residual disease and, until now, it was not clear if there was a sufficient amount of antigens to trigger a response.”
“This trial represents an important milestone in the treatment of melanoma. 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. We are currently waiting for the results of several trials including EORTC 1325 which is investigating pembrolizumab, a PD-1 checkpoint blocking antibody, compared to placebo in the adjuvant setting,” Michielin added.
- Eggermont AMM, Chiarion-Sileni V, Grob J-J, et al. Ipilimumab (IPI) vs placebo (PBO) after complete resection of stage III melanoma: final overall survival results from the EORTC 18071 randomized, double-blind, phase 3 trial. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA2.
- Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015;16(5):522-530.
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