Yervoy (ipilimumab) reduced risk of death by 28 percent compared to placebo in patients with high-risk stage 3 melanoma, according to updated findings from the phase 3 EORTC 18071 trial presented at the 2016 European Society for Medical Oncology (ESMO) Congress.
At a median of 5.3 years’ follow-up, the five-year overall survival (OS) rate was 65.4 percent with Yervoy compared with 54.4 percent in the control arm. The recurrence-free survival (RFS) rate at five years was 40.8 percent versus 30.3 percent, respectively, and the five-year distant metastasis–free survival (DMFS) rate was 48.3 percent versus 38.9 percent, respectively.
“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 3 melanoma,” lead author Alexander Eggermont, M.D., Ph.D., director general of Gustave Roussy Cancer Campus Grand Paris, Villejuif, France, said in statement.
The international, double-blind phase 3 EORTC 18071 trial included 951 patients with stage 3 cutaneous melanoma who had adequate resection of lymph nodes. Patients were randomized in a 1-1 ratio to receive Yervoy at 10 mg/kg (475 patients) or placebo (476 patients) every three weeks for four doses, then every three months for up to three years. Patients in the Yervoy arm received a median of four doses (range, one-16), with 36 percent remaining on the drug for more than six 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 Yervoy and was not yet reached in the placebo arm. The median RFS was 27.6 months in the Yervoy 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 Yervoy versus 17.1 months with placebo. The three-year RFS rates were 46.5 percent versus 34.8 percent, respectively.
At the five-year follow-up presented at the ESMO congress, there were no new safety signals or deaths in the Yervoy cohort. Grade 3/4 adverse events (AEs) occurred in 54.1 percent of the Yervoy arm compared with 26.2 percent of the control group. The rates of grade 3/4 immune-related AEs were 41.6 percent versus 2.7 percent, respectively.
Grade 3/4 AEs of note in the Yervoy arm included gastrointestinal (16 percent), hepatic (11 percent) and endocrine (8 percent). In general, it took four to eight 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, M.D., Ph.D., head of Personalized Analytical Oncology, CHUV, Lausanne, Switzerland, said in a statement.
In the United States and Europe, Yervoy (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 Yervoy to include the adjuvant treatment of patients with stage 3 melanoma with pathologic involvement of regional lymph nodes greater than 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 Keytruda (pembrolizumab), a PD-1 checkpoint blocking antibody, compared to placebo in the adjuvant setting,” Michielin added.