For years, the fight against malignant melanoma has relied on powerful immunotherapies delivered at doses set by long-standing clinical practice. These drugs, nivolumab and ipilimumab, were approved at specific levels meant to unleash the immune system against one of the deadliest forms of skin cancer. Yet behind the scenes, clinicians in Sweden had begun to wonder whether those doses were truly necessary—or even ideal. Their suspicions were born not out of bold speculation but from the daily realities of treating patients who struggled with severe, sometimes life-threatening reactions.
A new study from researchers at Karolinska Institutet has now transformed that quiet curiosity into evidence. Published in the Journal of the National Cancer Institute, the findings suggest something few expected: lower doses of approved immunotherapy can actually deliver better outcomes for patients with malignant melanoma, while reducing the very side effects that once seemed an unavoidable trade-off.
“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,” says last author Hildur Helgadottir, who led the investigation at the Department of Oncology–Pathology at Karolinska Institutet.
When Clinicians Decided to Ask “What If?”
Sweden’s oncology community has, over time, taken a distinctive approach to nivolumab and ipilimumab. While the traditional dose remains the established global standard, Swedish clinicians have increasingly adopted a regimen that lowers the amount of ipilimumab—the more toxic and more expensive of the two drugs. This shift did not stem from a formal national directive but from clinical discretion.
“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,” says Hildur Helgadottir.
This freedom created a natural experiment across hospitals: two treatment regimens, one traditional and one with reduced ipilimumab, administered to real patients under real clinical conditions. If dose reduction truly offered no advantage, outcomes between groups would look similar. But the researchers suspected otherwise, and the data they later assembled confirmed their suspicions in dramatic fashion.
The Patients Behind the Numbers
Nearly 400 people with advanced, inoperable malignant melanoma formed the heart of the study. This was not an early-stage population nor a controlled trial with narrow inclusion criteria. These were individuals facing the most serious form of skin cancer, treated in routine practice, where every decision carries immense weight.
When researchers compared the two dosing strategies, the differences they discovered were striking. Patients who received the lower dose of ipilimumab responded to therapy at a rate of 49 percent, a notable improvement over the 37 percent response in the traditional-dose group. Response rates in melanoma immunotherapy have always been difficult to push higher; this jump suggested that dose reduction was not a compromise but a distinct advantage.
Even more compelling was the timeline of disease progression. With the lower dose, the median progression-free survival—how long patients lived before their cancer worsened—was nine months. Under the traditional dose, this figure fell to just three months.
The difference extended to overall survival as well. Patients treated with the low-dose approach lived a median of 42 months, compared to 14 months for those treated with the standard regimen. Such a widening of survival curves would be notable even in a randomized trial. In real-world data, it is remarkable.
The Weight of Side Effects and the Relief of Fewer
Immunotherapies can be astonishingly effective, but they are infamous for their toxicities. The same immune activation that destroys cancer can damage organs, disrupt hormones, and trigger chronic complications.
“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,” says Hildur Helgadottir.
This point proved essential in the study’s findings. Serious side effects occurred in 31 percent of patients receiving the low-dose regimen, compared to 51 percent in the traditional group. The difference was not subtle: nearly half of all severe reactions disappeared when clinicians shifted to the reduced dose.
For patients, this meant fewer emergency interventions, fewer cases of organ-damaging inflammation, and fewer situations where treatment had to be paused or abandoned altogether. The improved tolerability may help explain the better survival outcomes: when patients can continue a therapy for longer, they have more time to benefit from it.
Science With Caveats and an Open Future
No observational study, however sweeping, can determine causality with absolute certainty. The researchers are clear on this point. Some differences did exist between the treatment groups, and while the analyses adjusted for several factors—such as age and tumor stage—unmeasured variables may still play a role.
The study was retrospective, examining outcomes after treatment had already been given rather than assigning therapies prospectively. This limits the conclusions that can be drawn, even though the patterns in the data are strong and consistent.
Still, the fact that the advantage of low-dose ipilimumab persisted after adjustments lends weight to the findings. It suggests that Sweden’s unconventional approach may not be accidental luck but a meaningful shift in how immunotherapy can be optimized in practice.
Why This Research Matters
This work challenges a core assumption in cancer treatment: that more medication inevitably yields stronger results. Here, the opposite proved true. The study offers evidence that high-intensity immunotherapy may not always be the most effective strategy, and that thoughtful dose modification can enhance both efficacy and safety.
For patients with advanced malignant melanoma—a disease once thought nearly untreatable—the implications are profound. Better responses, longer periods without progression, improved overall survival, and fewer dangerous side effects create a combination that could transform standard care if confirmed in future studies.
Perhaps most importantly, the findings point toward a future in which precision does not mean increasing potency but calibrating it. If lower doses can achieve better outcomes, oncology may be entering a new chapter—one where treatment is not escalated but refined, and where the immune system’s power is harnessed with greater nuance.
In this sense, the study is more than a surprising discovery; it is an invitation for the global cancer community to reconsider long-held assumptions and explore whether gentler regimens might sometimes offer stronger hope.
More information: Evaluation of the flipped dose NIVO3+IPI1 in patients with advanced unresectable melanoma, JNCI Journal of the National Cancer Institute (2025). DOI: 10.1093/jnci/djaf327, doi.org/10.1093/jnci/djaf327
