Could lower-dose immunotherapy help patients with advanced melanoma live longer?

A study published in the Journal of the National Cancer Institute has found that patients with advanced melanoma who received a reduced dose of immunotherapy had higher survival rates than those who received a standard dose, raising questions about whether overtreatment can be a factor.In an earlier study, a third of patients receiving the standard combination of 1 mg/kg of nivolumab and 3 mg/kg of ipilimumab (NIVO1 + IPI3) were found to have stopped treatment because of severe side effects, most of them linked to ipilimumab.So researchers in Sweden, where medical teams have some flexibility in choosing cancer treatment doses administered to patients, posed themselves a question: would reversing the doses improve patient tolerance? They compared the effects of the two protocols in a retrospective observational study of nearly 400 patients. What they found was that administering a reversed dose—3 mg/kg of nivolumab, plus 1 mg/kg of ipilimumab (NIVO3 + IPI1)—not only reduced adverse effects, but also improved survival rates in patients with unresectable metastatic melanoma.After adjusting for covariates, including disease stage and number of metastatic sites, the NIVO3 + IPI1 combination remained associated with a lower risk of death than the standard dose (adjusted HR = 0.59; 95% CI; 0.44–0.78).The researchers believe the results are primarily due to improved treatment adherence, as many patients receiving the standard dose discontinued treatment. “In our opinion, longer exposure to the treatment is the most plausible explanation for the greater efficacy with the reversed dose,” the researchers noted.Half of the patients receiving the lower dose reported stage 3 to 5 adverse events, compared to 30.6% of patients receiving the reversed dose. A more recent administration of the reversed dose may also partly explain why a larger proportion of patients on the NIVO3+IPI1 regimen reported fewer side effects. “Increased clinical experience with immune checkpoint inhibitors among healthcare professionals, including better management of adverse events related to immunotherapy, may have led to better outcomes,” the authors suggested. Beyond a reduction in adverse events, the reversed dose showed greater improvement in overall survival and progression-free survival.The median overall survival rate with the reversed dose was 42.4 months (95% CI = 27.8 – NR), whereas it was only 14.5 months with the standard dose (95% CI = 8.5–19.8).Progression-free survival tripled with the NIVO3+IPI1 regimen: it was 8.9 months (95% CI = 5.8–14.8), compared to only 2.7 months (95% CI = 2.2–4.8) in the group receiving the NIVO1+IPI3 dose.“This raises concerns about potential overtreatment with the higher dose of ipilimumab in the traditional NIVO1+IPI3 regimen and provides evidence supporting the use of NIVO3+IPI1 as a first-line treatment with improved efficacy and tolerability,” the study authors concluded.ReferenceKarl Björkström, Cissi Liu, Anna Fager, Lisa L Liu, Lars Ny, Hildur Helgadottir, Evaluation of the flipped dose NIVO3+IPI1 in patients with advanced unresectable melanoma, JNCI: Journal of the National Cancer Institute, 2025This article was initially published on our sister site ProfessionSanté.ca and has been translated from its original French.

Could lower-dose immunotherapy help patients with advanced melanoma live longer?

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