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Higher-dose ipilimumab linked to better OS, more adverse events in advanced melanoma

Roshini Claire Anthony
03 May 2017

A 10 mg/kg dose of ipilimumab led to significant improvement in overall survival (OS) in individuals with advanced melanoma compared with a 3 mg/kg dose, but was also associated with a higher number of treatment-related adverse events (TRAEs), according to findings of a recent study.

“These data suggest that the proven and approved dose of ipilimumab in the adjuvant setting (10 mg/kg) might be the optimum dose, but toxicity is notable, particularly considering that many patients with stage III melanoma are cured with surgery alone,” said Dr Alexander Menzies and Professor Georgina Long from The University of Sydney, New South Wales, Australia, in a separate editorial. [Lancet Oncol 2017;doi:10.1016/S1470-2045(17)30228-0]

The double-blind, multicentre (87 centres in 21 countries), phase III trial comprised 727 patients (mean age 62 years, 60 and 64 percent male in the 10 mg/kg and 3 mg/kg groups, respectively) with previously treated (56 percent; except with BRAF or immune checkpoint inhibitors) or untreated unresectable stage III or IV melanoma who were randomized to receive four doses of either ipilimumab 10 mg/kg or 3 mg/kg (n=365 and 362, respectively) delivered via intravenous infusion over 90 minutes every 3 weeks. Patients on the 10 mg/kg and 3 mg/kg doses were followed-up for a median 14.5 and 11.2 months, respectively. [Lancet Oncol 2017;doi:10.1016/S1470-2045(17)30231-0]

The median OS was higher in patients given ipilimumab 10 mg/kg compared with those given ipilimumab 3 mg/kg (15.7 vs 11.5 months, hazard ratio [HR], 0.84, 95 percent confidence interval [CI], 0.70–0.99; p=0.04). Progression-free survival (PFS) did not differ between patients in the two groups (median 2.8 months for both, HR, 0.89, 95 percent CI, 0.76–1.40; p=0.16).

“[P]erhaps a higher dose of ipilimumab has differing immunomodulatory effects, with increased frequency of pseudoprogression, or different kinetics of disease progression, or both, or perhaps the activity of subsequent therapy is increased after a higher dose of ipilimumab,” said Menzies and Long, regarding the lack of effect on PFS.

TRAEs of any grade were reported by 79 and 63 percent of patients given the 10 mg/kg and 3 mg/kg doses, respectively. Adverse events leading to treatment discontinuation were also more frequently reported by patients on the 10 mg/kg dose than the 3 mg/kg dose (31 percent vs 19 percent for any-grade and 24 percent vs 12 percent for grade 3–4 events).

A higher number of patients given the 10 mg/kg dose reported serious TRAEs compared with those given the 3 mg/kg dose (37 percent vs 18 percent), with diarrhoea (11 percent vs 6 percent) and colitis (8 percent vs 3 percent) being the most common events reported. There were four and two deaths due to TRAEs reported in the 10 mg/kg and 3 mg/kg groups, respectively.

“Our results should be interpreted in the context of the changing treatment landscape, in which ipilimumab monotherapy is no longer used in the first-line setting for melanoma in most countries where improved drugs that result in increased survival have become available,” said the researchers.

“However, the increased survival benefit of ipilimumab 10 mg/kg compared with 3 mg/kg suggests that the clinical utility of ipilimumab in refractory patients with high unmet medical need could warrant further assessment,” they said. 

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Most Read Articles
Roshini Claire Anthony, 04 Apr 2019

In addition to an intensive weight loss programme, the use of continuous positive airway pressure (CPAP) could improve absolute weight loss in individuals with obesity and obstructive sleep apnoea (OSA), according to a study presented at ENDO 2019.

2 days ago
The ketogenic and Modified Atkin’s diets are effective treatments for children with refractory epilepsy of genetic aetiology, a new study suggests.
4 days ago
Extremely premature neonates who have been exposed to pre-eclampsia in utero are at high risk of developing severe respiratory distress syndrome and severe bronchopulmonary dysplasia, according to a study.
Pearl Toh, 2 days ago
A contraceptive vaginal system (Annovera) releasing a combination of segesterone acetate and ethinyl estradiol (SA/EE) effectively inhibits ovulation up to a year even at low systemic levels of SA, reports a review study presented at ENDO 2019.