TOPLINE: 

In patients with unresectable melanoma, a flipped-dose regimen of 3 mg/kg of nivolumab plus 1 mg/kg of ipilimumab was associated with higher response rates, longer survival, and fewer severe immune-related adverse events vs standard dosing.

METHODOLOGY: 

• Combination immunotherapy with nivolumab and ipilimumab improves survival among patients with advanced melanoma, but standard dosing (NIVO1+IPI3) can cause severe toxicity. After the CheckMate 511 trial found that a flipped-dose regimen (NIVO3+IPI1) reduced adverse events, clinics in some countries implemented the approach. No studies have compared flipped vs standard dosing in a real-world setting.
• In this study, Swedish researchers assessed 399 patients with advanced unresectable melanoma who received either a conventional NIVO1+IPI3 regimen (n = 190; median age, 60 years) or the alternative NIVO3+IPI1 approach (n = 209; median age, 63 years).
• The researchers assessed objective response rate, disease control rate, progression-free survival, overall survival, and the incidence of grade 3-5 immune-related adverse events. Median follow-up was 41 months for the NIVO3+IPI1 group and 53 months for the NIVO1+IPI3 group.
• The NIVO3+IPI1 group had a higher proportion of patients with earlier-stage disease (stage III, M1a-M1b; 42.1% vs 17.9%), whereas the NIVO1+IPI3 group had more patients with brain metastases (M1d; 50.0% vs 21.1%) (P < .001).

TAKEAWAY: 

• The objective response rate was significantly higher in the NIVO3+IPI1 group than in the NIVO1+IPI3 group (48.8% vs 36.9%; P =.016), as was the rate of disease control (60.3% vs 45.8%; P = .004).
• Median progression-free survival was 8.9 months with NIVO3+IPI1 vs 2.7 months with NIVO1+IPI3, while median overall survival was 42.4 months and 14.5 months, respectively.
• After adjustment for baseline factors, NIVO3+IPI1 remained associated with reduced risks of death (adjusted hazard ratio [aHR], 0.59; P < .001) and disease progression (aHR, 0.67; P = .002) compared with conventional dosing.
• The incidence of grade 3-5 immune-related adverse events was significantly lower with NIVO3+IPI1 than with NIVO1+IPI3 (30.6% vs 51.1%; P < .001). Patients who received the flipped-dose regimen were more likely to complete all four doses of combination therapy (57.4% vs 33.7%; P = .005) and more often received maintenance nivolumab therapy (45.5% vs 27.4%; P = .01) than those in the NIVO1+IPI3 group.

IN PRACTICE: 

These findings “raise concerns regarding possible overtreatment with the higher dose of ipilimumab in the traditional NIVO1+IPI3 regimen in advanced melanoma and provide evidence supporting the use of NIVO3+IPI1 as a preferred regimen that may offer both improved efficacy and tolerability,” the authors wrote.

In a press release, Hildur Helgadottir, MD, PhD, of Karolinska Institutet in Stockholm, Sweden, said, “Our results suggest that this lower dosage may enable more patients to continue the treatment for a longer time, which is likely to contribute to the improved results and longer survival.” Continued evaluation of the flipped-dose regimen is needed, the researchers noted, including a comparison against the recently approved combination of nivolumab and relatlimab.

SOURCE: 

The study, led by Karl Björkström, MD, PhD, Karolinska Institutet, Stockholm, Sweden, was published online in JNCI: Journal of the National Cancer Institute.

LIMITATIONS: 

The retrospective design prevents establishment of causality. The treatment groups showed significant differences in baseline characteristics, particularly disease stage distribution and timing of inclusion. Findings on patients in a single country may not be generalizable.

DISCLOSURES: 

The study received support through grants from the Swedish Cancer Society, Region Stockholm, and the Cancer Research Funds of Radiumhemmet. Some authors reported receiving speaker honoraria or research grants and having other ties with various sources. Full disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.