Researchers at Karolinska Institutet report that using a reduced dose of ipilimumab together with nivolumab in immunotherapy for advanced malignant melanoma was associated with better tumor control and fewer serious side effects than the traditional full-dose combination. In a real-world study of nearly 400 patients with advanced, inoperable skin cancer, response rates and survival times were higher in the lower-dose group, according to results published in the Journal of the National Cancer Institute.
A Swedish study led by Hildur Helgadottir at Karolinska Institutet's Department of Oncology-Pathology has found that a modified immunotherapy regimen for advanced, inoperable malignant melanoma was linked with improved outcomes compared with the traditional dosing schedule.
According to Karolinska Institutet, the research, published in the Journal of the National Cancer Institute, evaluated a so-called "flipped" regimen using full-dose nivolumab in combination with a reduced dose of ipilimumab, and compared it with the established combination in which both nivolumab and ipilimumab are given at their approved doses.
Standard treatment for malignant melanoma typically relies on the approved doses of nivolumab and ipilimumab. However, because this full-dose combination often causes substantial toxicity, clinicians in Sweden have increasingly adopted a regimen that uses less ipilimumab. Ipilimumab is described by the investigators as both the most expensive component of this immunotherapy and the drug most strongly linked to severe side effects.
"In Sweden, we have greater freedom to choose doses for patients, while in many other countries, due to reimbursement policies, they are restricted by the doses approved by the drug authorities," Helgadottir says in material released by Karolinska Institutet.
The study included nearly 400 patients with advanced, inoperable malignant melanoma, the most serious form of skin cancer. Patients treated with the lower-ipilimumab regimen had a response rate of 49 percent, compared with 37 percent among those receiving the traditional dose combination, according to the Karolinska report and related summaries.
Progression-free survival – the length of time patients lived without their disease worsening – reached a median of nine months in the lower-dose ipilimumab group, versus three months in the traditional-dose group. Median overall survival was also longer with the modified regimen, at 42 months compared with 14 months for patients on the full-dose combination.
Serious side effects were less frequent in the lower-dose group. The study reports that 31 percent of patients receiving reduced-dose ipilimumab experienced serious adverse events, compared with 51 percent in the standard-dose group.
"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," Helgadottir says.
Because the analysis was a retrospective observational study based on real-world data, the authors caution that it cannot definitively establish a causal link between the lower dose of ipilimumab and the better outcomes. The advantage of the reduced-dose regimen remained after they adjusted for several factors, including age and tumor stage, but randomized clinical trials would be needed to prove causation.
The work was carried out in collaboration with the Sahlgrenska Comprehensive Cancer Center at Sahlgrenska University Hospital. According to Karolinska Institutet, the study received funding from the Cancer Foundation, Region Stockholm, and the Radiumhemmet Research Fund.
The findings highlight how reducing treatment-related toxicity may enhance the overall effectiveness of immune checkpoint blockade in melanoma and could inform discussions about dose flexibility in countries where reimbursement rules closely follow regulatory label doses.
