Modified dosing of melanoma immunotherapy shows better results, fewer side effects

A modified immunotherapy regimen for advanced melanoma achieved better tumor control and longer patient survival while causing significantly fewer dangerous side effects, according to a new study.

The research, published in the Journal of the National Cancer Institute, found that patients receiving a lower dose of Yervoy (ipilimumab) combined with Opdivo (nivolumab) had a 49% response rate, compared with 37% for those on the standard regimen. The modified approach also extended median overall survival to 42 months versus 14 months with traditional dosing.

The study, led by Hildur Helgadottir, M.D., Ph.D., of Karolinska Institutet in Sweden, followed nearly 400 patients with advanced unresectable melanoma. Among 209 patients who received the modified lower dose, serious side effects occurred in 31% of cases. In contrast, 51% of the 190 patients on the standard dose experienced severe immune-related adverse events.

"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," Helgadottir said in a news release.

The modified regimen flips the dosing of the two medicines: the standard treatment combination is 3 mg/kg of Yervoy with 1 mg/kg of Opdivo. The study compared patients on that with a group taking 1 mg/kg of Yervoy with 3 mg/kg of Opdivo.

This modified approach allowed more patients to complete treatment. More than half of those on the lower Yervoy dose finished all four combination therapy sessions, compared with 34% on standard dosing. Additionally, 46% of modified-dose patients received at least three doses of follow-up Opdivo maintenance therapy, versus 27% in the standard group.

Swedish clinicians adopted the modified approach after a 2019 trial showed it caused fewer side effects, although that study found no significant survival differences at 19 months of follow-up.

“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 said.

The combination of Opdivo and Yervoy works by blocking immune checkpoints that prevent the body from attacking cancer cells. While effective, the standard regimen's high toxicity often forces patients to pause or stop treatment. By reducing side effects, the study showed more patients were able to stay on therapy longer, potentially explaining the improved outcomes.

Median progression-free survival was nine months with the modified dose compared with three months with standard dosing. After researchers adjusted for factors including age, disease stage and baseline health status, the modified regimen remained associated with a 41% lower risk of death.

The study included patients typically excluded from clinical trials, such as those with brain metastases and poor performance status. Among patients with brain metastases, the modified dose still showed superior outcomes compared to standard treatment.

Treatment groups differed in baseline characteristics, particularly disease stage distribution. The standard-dose group had more patients with brain metastases, while the modified-dose group included more patients with earlier-stage disease.

Similar benefits with the modified dose have been seen in other cancers. The FDA and European Medicines Agency have approved the modified regimen for renal cell carcinoma and lung cancer, but not for melanoma.