Adding an individualized mRNA-based cancer vaccine to standard immunotherapy after surgery for high-risk cutaneous melanoma reduced the probability of relapse or death by 42%, according to data from the phase 3 clinical trial INTerpath-001 presented at the ESMO Congress of 2026.
This preparation, called autologous intismerán, was administered along with pembrolizumab and was compared to the use of pembrolizumab in monotherapy as adjuvant treatment.
Anti-PD-1 immunotherapy, such as pembrolizumab, has become a standard option after surgery for high-risk melanoma, although a relevant proportion of patients continue to experience recurrences.
Previous phase 3 trials that added a second immune checkpoint inhibitor did not manage to improve the results obtained with anti-PD-1 monotherapy.
Intismerán presents a different strategy: the tumor of each patient is sequenced to locate neoantigens, that is, abnormal proteins specific to their cancer. The treatment incorporates up to 34 of these neoantigens in mRNA molecules with the aim of training the immune system to identify and destroy residual tumor cells.
In the trial, 1,137 adults operated on for stage IIB-IV cutaneous melanoma were randomly assigned to receive pembrolizumab combined with intismerán (757 people) or pembrolizumab with placebo (380 people).
After a median follow-up of 24.6 months, the addition of intismerán reduced the risk of recurrence or death. At two years, 82.2% of patients treated with the combination were still alive and free of relapse, compared to 70.0% of those who received only pembrolizumab.
The combination also reduced the risk of distant metastasis or death by 38%, and at two years, 88.5% of patients remained without distant metastasis, compared to 80.2% of the control group. These benefits were comparable in both lower-risk and higher-risk cases.
In this interim analysis, the overall survival data were still immature and no statistically significant differences were detected between the study arms. The researchers note that longer follow-up will be necessary to clarify whether the lower recurrence rate translates into a survival advantage.
Adverse events of grade 3 or higher were recorded in 23.6% of patients who received the combination and in 20.3% of those treated with pembrolizumab alone.
Among the most common side effects with the combination were fever (52.2% versus 8.2%), pain at the injection site (51.0% versus 9.5%), and fatigue (38.5% versus 29.7%). Reactions associated with intismeran injections were generally mild and short-lived.
"This is the first phase 3 study that demonstrates that a treatment designed from the unique 'fingerprint' of each patient's own tumor can reduce the risk of recurrence or death from cancer," emphasized the lead author, Dr. Georgina Long, from the Melanoma Institute Australia and the University of Sydney (Australia).
"This fingerprint is identified through tumor sequencing, and from it, a 'wanted poster' of the cancer is created in the form of mRNA, which shows the immune system exactly what to look for and attack," she explains.
Long has stressed the clinical relevance of these findings for people with melanoma, although she insists that broader long-term follow-up data is needed.
"For a patient, having more time without melanoma is an important benefit in itself --she emphasizes--. Longer follow-up is needed to demonstrate whether there is an impact on melanoma-specific survival and overall survival, as well as to determine whether the initial benefit we are observing in different stages and subgroups is maintained and which patients benefit the most."
"The data from the INTerpath-001 study represent a significant advance in the adjuvant treatment of melanoma in stages II and III; the reduction in the risk of relapse is clinically significant and, regarding adverse effects, intismeran in combination with pembrolizumab presents a very favorable tolerability profile," highlighted Dr. James Larkin, scientific co-chair of the ESMO 2026 Congress, who did not participate in the study.
Looking ahead to the coming years, Larkin has emphasized the need to promote new trials to see if this strategy can also benefit patients with other tumors. Studies in lung, bladder, and kidney cancer are already being developed.
Larkin has also highlighted the difference between treating an already diagnosed cancer and preventing its onset: "This is very different from vaccinating people who do not have cancer with the aim of reducing the risk of them developing cancer later on."