In the large phase III INTerpath-001 study evaluating individuals with resected stage IIB–IV melanoma, recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) improved when the mRNA-based individualized neoantigen therapy intismeran autogene was added to pembrolizumab compared with pembrolizumab alone.
INTerpath-001 met both the primary (RFS) and key secondary (DMFS) endpoints after a median follow-up of 24.6 months, noted lead investigator Dr Georgina Long from the University of Sydney, Australia, at ESMO 2026.
Compared with placebo + pembrolizumab, the intismeran + pembrolizumab combination significantly reduced the risk of recurrence or death by 42 percent (hazard ratio [HR], 0.58; p<0.001) and the risk of distant metastasis or death by 38 percent (HR, 0.62; p=0.002) in the intent-to-treat (ITT) population.
The 24-month RFS rate was higher in the experimental vs the placebo group (82.2 percent vs 70 percent), as was the DMFS rate (88.5 percent vs 80.2 percent).
Sensitivity analyses demonstrated sustained improvements in the ITT population at 6 months (RFS: HR, 0.42; DMFS: HR, 0.50) and the modified ITT population at 24 months (HRs, 0.51 and 0.55, respectively).
According to Long, these benefits were observed across most prespecified subgroups, including risk-based disease stages. [ESMO 2026, abstract LBA1]
Of note, overall survival was immature at the time of the analysis and did not meet the prespecified significance boundary (HR, 0.77), but follow-up is ongoing to ascertain if the reduction in recurrence would translate into a survival benefit.
Safety profile
Compared with the placebo group, the experimental group had a similar rate of grade ≥3 treatment-related adverse events (TRAEs; 14.2 percent vs 13.4 percent) but a higher rate of TRAEs that led to the discontinuation of any drug (14 percent vs 8.7 percent).
Of the five deaths that occurred before the first intismeran dose, two were attributed to pembrolizumab. After the first intismeran dose, none of the three deaths reported were attributed to treatment.
The most common AEs in the experimental group were pyrexia, injection site pain, and fatigue (52.2, 51, and 38.5 percent, respectively). In the placebo group, the most common were fatigue, diarrhoea, and pruritus (29.7, 23.7, and 23.4 percent, respectively). These AEs were mostly low-grade, transient, and were managed per standard practice.
The most common AEs of interest for pembrolizumab were thyroid disorders in both investigational (hypothyroidism: 15.9 percent; hyperthyroidism: 9.9 percent) and placebo groups (16.1 percent and 8.2 percent, respectively). Long noted that intismeran did not potentiate pembrolizumab-associated AEs.
High recurrence
According to Long, many patients with resected high-risk melanoma experience recurrence despite adjuvant therapy. “Dual checkpoint blockade in the adjuvant setting has failed to improve efficacy while increasing toxicity in phase III trials … Enhancing immune activation may improve efficacy.”
“Intismeran is designed to strengthen existing and create new T cell responses. Pembrolizumab blocks PD-1 to enhance T-cell activity, complementing intismeran’s mechanism of action,” Long explained.
In INTerpath-001, 1,137 patients (median age 61 years, 60 percent men) were randomized 2:1 to receive IV pembrolizumab 400 mg Q6W (nine cycles) + IM intismeran 1 mg Q3W or placebo (nine doses). Approximately one-third of the participants had stage IIIC disease.
Ninety-one percent of the randomized patients had the maximum 34 neoantigens identified for intismeran design, and over 99 percent of those in the experimental group had their intismeran successfully manufactured. The median time to first intismeran dose was 64 days, and the median number of intismeran doses were nine.
Several firsts
“This is the first phase III study to show that a treatment built from the unique ‘fingerprint’ of a patient’s own tumour can reduce the risk of recurrence or death from cancer,” noted Long in the ESMO press release. “That fingerprint is read by sequencing the tumour, then a ‘wanted poster’ of the cancer is made as mRNA, showing the immune system exactly what to look for and attack.”
“This is the first personalized agent designed for each patient using a computer algorithm to move through the regulatory process, and it will be very interesting to monitor its progress,” noted study discussant Prof Inge Marie Svane from Copenhagen University Hospital, Herlev, Denmark, in another ESMO news release.
“These findings set a new benchmark for adjuvant therapy in melanoma and establishes intismeran as a landmark advance in personalized cancer medicine,” Long said.
Svane added that the results mark a crucial moment in the field of cancer vaccines. “The reported HRs are convincing and show that intismeran offers additional benefit to pembrolizumab in the adjuvant setting.”
Studies evaluating intismeran for bladder cancer, melanoma, non-small cell lung cancer, and renal cell carcinoma in the neoadjuvant, adjuvant, or metastatic settings are underway.