INTerpath-001 Data Detail Survival, Subgroup, and Safety Findings in Melanoma

At the 2026 European Society for Medical Oncology (ESMO) Congress, Georgina V. Long, of Melanoma Institute Australia, presented full results from the phase 3 INTerpath-001 trial (NCT05933577) of intismeran autogene (intismeran), an investigational mRNA-based individualized neoantigen therapy, plus pembrolizumab (Keytruda) in patients with completely resected stage IIB to IV cutaneous melanoma. Presented as a late-breaking abstract (LBA1) during Presidential Symposium I, the data included overall survival (OS), subgroup, manufacturing, and detailed safety findings.¹

The presentation built on the primary recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) results from the trial.² At a median follow-up of 24.6 months (data cutoff, June 30, 2026), intismeran plus pembrolizumab reduced the risk of recurrence or death by 42% vs placebo plus pembrolizumab (HR, 0.58; 95% CI, 0.45-0.75; two-sided P <.001), with RFS events in 136 patients (18.0%) vs 111 patients (29.2%). The combination also reduced the risk of distant metastasis or death by 38% (HR, 0.62; 95% CI, 0.45-0.85; two-sided P = .002), with DMFS events in 89 patients (11.8%) vs 71 patients (18.7%). The 2-year RFS rates were 82.2% vs 70.0%, and the 2-year DMFS rates were 88.5% vs 80.2%.

OS data were immature and did not meet the prespecified significance boundary (HR, 0.77; 95% CI, 0.45-1.31; two-sided P = .33). End points were tested hierarchically in the order of RFS, DMFS, and OS, with alpha passed to DMFS and OS only if the preceding end point was significant. Follow-up for OS is ongoing.

RFS and DMFS benefits were observed in most prespecified subgroups, including both risk-based disease stage groups. For RFS, the HR was 0.60 (95% CI, 0.41-0.88) among patients with stage IIB/IIC/IIIA/IIIB disease and 0.57 (95% CI, 0.41-0.79) among those with stage IIIC/IIID/IV disease; the corresponding DMFS HRs were 0.65 (95% CI, 0.41-1.02) and 0.59 (95% CI, 0.39-0.91). RFS HRs were 0.65 (95% CI, 0.47-0.91) for patients younger than 65 years and 0.53 (95% CI, 0.36-0.77) for those 65 years and older. Confidence intervals crossed 1 in several smaller subgroups, including the US subgroup for DMFS (HR, 1.77; 95% CI, 0.38-8.35), which was based on 10 events.

Benefit with the combination emerged after the first 6 months. In a prespecified piecewise analysis, the RFS HR was 0.99 (95% CI, 0.66-1.49) from 0 to 6 months and 0.42 (95% CI, 0.30-0.58) beyond 6 months; the respective DMFS HRs were 1.01 (95% CI, 0.58-1.79) and 0.50 (95% CI, 0.34-0.73). In the modified intention-to-treat population, which included patients who received intismeran or placebo as planned, the RFS HR was 0.51 (95% CI, 0.39-0.67) and the DMFS HR was 0.55 (95% CI, 0.40-0.77), with 2-year RFS rates of 84.2% vs 70.4% and 2-year DMFS rates of 90.1% vs 80.7%.

Of 1749 patients screened, 302 (17.3%) were excluded because of an inadequate tumor sample. Intismeran was successfully manufactured for more than 99% of the 757 patients in the combination arm, and 91% of the 1137 randomized patients had the maximum 34 neoantigens identified for intismeran design. The median time to the first intismeran dose was 64 days, and patients received a median of 9 doses. Treatment was completed by 69.8% of patients in the combination arm and 69.1% in the pembrolizumab arm; discontinuation due to recurrence occurred in 10.8% and 17.9%, respectively.

Treatment-related adverse events (TRAEs) occurred in 95.8% of patients in the combination arm vs 90.0% in the pembrolizumab arm, including grade 3 to 5 TRAEs in 14.2% vs 13.4% and serious TRAEs in 9.8% vs 11.1%. TRAEs led to discontinuation of any study drug in 14.0% vs 8.7% of patients. All-cause grade 3 to 5 AEs occurred in 23.6% vs 20.3%. Two treatment-related deaths (0.3%) occurred in the combination arm, both attributed to pembrolizumab; no deaths were related to intismeran. The most common all-cause AEs with the combination were pyrexia (52.2% vs 8.2%), injection site pain (51.0% vs 9.5%), fatigue (38.5% vs 29.7%), and influenza-like illness (25.4% vs 9.2%), which investigators described as low grade and transient. Immune-mediated AEs of interest for pembrolizumab occurred in 36.0% vs 34.7% of patients, and intismeran did not potentiate pembrolizumab-associated AEs.

In the trial, 1137 patients were randomly assigned 2:1 to intismeran at 1 mg intramuscularly every 3 weeks for up to 9 doses plus pembrolizumab at 400 mg intravenously every 6 weeks for up to 9 cycles (n = 757) or placebo plus pembrolizumab (n = 380). Eligible patients had resected AJCC 8th edition stage IIB/IIC, III, or IV cutaneous melanoma, no prior systemic therapy, an ECOG performance status of 0 or 1, and a tumor sample suitable for next-generation sequencing. Randomization was stratified by risk-based stage and age. The median age was 61 years, and approximately 60% of patients were male.

The results have been accepted for publication in The New England Journal of Medicine, and the companies developing intismeran are engaging with regulatory authorities.

References

1. Long GV. INTerpath-001: phase 3 study of the mRNA-based individualized neoantigen therapy (INT) intismeran autogene (intismeran) plus pembrolizumab (pembro) vs pembro alone for adjuvant treatment of resected stage IIB-IV melanoma (MEL). Presented at: 2026 European Society for Medical Oncology Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA1.
2. Merck and Moderna announce phase 3 INTerpath-001 trial of intismeran autogene plus Keytruda met endpoints of recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in patients with completely resected stage IIB-IV melanoma. News release. Merck. August 19, 2026. Accessed October 24, 2026. https://tinyurl.com/77htwprv