The flipped dose for nivolumab at 3 mg/kg and ipilimumab at 1 mg/kg led to improved response rates and survival findings as well as lower severe immune-related toxicities compared with the standard dose of the immunotherapy combination in patients with advanced unresectable melanoma, according to real-world findings published in the Journal of the National Cancer Institute.
“The results are highly interesting in oncology, as we show that a lower dose of an immunotherapy drug, in addition to causing significantly fewer side effects, actually gives better results against tumors and longer survival,” stated study leader and author Hildur Helgadottir, MD, PhD, Researcher in the Department of Oncology-Pathology at Karolinska Institutet in Solna, Sweden.
Background and Study Methods
When the combination of nivolumab and ipilimumab was approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with advanced melanoma in 2016, patients were administered 1 mg/kg of nivolumab and 3 mg/kg of ipilimumab. Then the CheckMate 511 trial showed that there was improved tolerability with a dosing schedule of nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg. However, this dosing schedule is not yet approved by the FDA.
Researchers explored real-world efficacy and safety data for patients with advanced unresectable melanoma treated with the immune checkpoint inhibition combination of nivolumab and ipilimumab and compared the findings by the doses.
Key Findings
In patients treated with nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg (n = 209), the objective response rate was 48.8% compared with a rate of 36.9% (P = .016) in patients treated with nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg (n = 190). The median progression-free survival with nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg dosing was 9 months in comparison with 3 months with nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg (adjusted hazard ratio [aHR] = 0.67; 95% confidence interval [CI] = 0.53–0.87; P = .002). Patients treated with the flipped dose had a median overall survival of 42 months vs 14 months with the standard dose (aHR = 0.59; 95% CI = 0.44–0.78; P < .001). These trends of lowered risk with the flipped dose were seen across the majority of studied subgroups as well.
Grade 3 to 5 immune-related adverse events were observed in 30.6% of patients treated with the nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg dosing vs 51.1% in those treated with nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg (P < .001).
“The new immunotherapies are very valuable and effective, but at the same time they can cause serious side effects that are sometimes life-threatening or chronic. 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,” Dr. Helgadottir said, who also noted that in Sweden physicians have greater flexibility for choosing doses for their patients than in other countries.
Disclosure: The study was funded by the Cancer Foundation, Region Stockholm, and the Radiumhemmet Research Fund. For full disclosures of the study authors, visit academic.oup.com.
