Adjuvant Intismeran Autogene Plus Pembrolizumab Improves RFS and DMFS in Melanoma

The addition of intismeran autogene (V940; mRNA-4157) to pembrolizumab (Keytruda) improved recurrence-free survival (RFS) and distant metastasis–free survival (DMFS) vs placebo plus pembrolizumab in patients with resected stage IIB to IV melanoma, according to findings from the phase 3 INTerpath-001 trial (NCT05933577) presented at the 2026 ESMO Congress.¹

At a median follow-up of 24.6 months, the combination reduced the risk of recurrence or death by 42% in the intention-to-treat (ITT) population (HR, 0.58; 95% CI, 0.45-0.75; 2-sided P < .001). The 24-month RFS rates were 82.2% (95% CI, 79.3%-84.8%) among patients who received intismeran plus pembrolizumab (n = 757) vs 70.0% (95% CI, 65.0%-74.5%) among those who received placebo plus pembrolizumab (n = 380).

The combination also reduced the risk of distant metastasis or death by 38% (HR, 0.62; 95% CI, 0.45-0.85; 2-sided P = .002), with 24-month DMFS rates of 88.5% (95% CI, 86.0%-90.6%) vs 80.2% (95% CI, 75.6%-84.0%). Overall survival (OS) data were immature and did not cross the prespecified significance boundary (HR, 0.77; 95% CI, 0.45-1.31; P = .33).

"INTerpath-001 sets a new benchmark for adjuvant treatment in melanoma. But critically, it establishes [intismeran autogene] as a landmark advance in personalized cancer medicine," said lead study author Georgina V. Long, MD, PhD, of Melanoma Institute Australia, in a presentation of the data during the Presidential Symposium.

How was the phase 3 INTerpath-001 trial of intismeran autogene in resected melanoma designed?

Intismeran autogene is an individualized messenger RNA–based therapy encoding up to 34 neoantigens specific to each patient's tumor. Five-year data from the phase 2b KEYNOTE-942 trial (NCT03897881) showed durable RFS and DMFS benefit with intismeran plus pembrolizumab in resected stage IIIB to IV melanoma.² In that trial, the hazard ratios were 0.510 for RFS and 0.411 for DMFS, Long noted.¹

The randomized, double-blind INTerpath-001 trial enrolled adults with resected stage IIB to IV cutaneous melanoma, an ECOG performance status of 0 or 1, no prior systemic therapy, and a tumor sample suitable for intismeran generation. Of 1749 patients screened, 1137 were randomly assigned 2:1 to receive intismeran at 1 mg intramuscularly every 3 weeks for 9 doses or placebo, each with pembrolizumab at 400 mg intravenously every 6 weeks for 9 cycles. Randomization was stratified by risk-based stage (IIB/IIC/IIIA/IIIB vs IIIC/IIID/IV) and age (younger than 65 years vs 65 years or older). Pembrolizumab began at randomization, and intismeran began upon availability, between cycle 1, day 22, and cycle 4, day 1.

RFS per investigator assessment was the primary end point, with DMFS and OS tested hierarchically. The median time to the first intismeran dose was 64 days, and more than 99% of patients in the combination arm had their intismeran successfully manufactured.

Did intismeran plus pembrolizumab benefit patients with resected melanoma across sensitivity analyses and subgroups?

In a piecewise analysis, the RFS HR was 0.99 (95% CI, 0.66-1.49) during months 0 to 6 and 0.42 (95% CI, 0.30-0.58) after month 6, representing a 58% reduction in the risk of recurrence or death beyond 6 months. Long attributed the early overlap of the curves to the delay before the first intismeran dose and the time intismeran needs to elicit T-cell responses. The corresponding DMFS HRs were 1.01 (95% CI, 0.58-1.79) and 0.50 (95% CI, 0.34-0.73).

In the modified ITT population, which included only patients who received intismeran (n = 726) or placebo (n = 365) as planned, the RFS HR was 0.51 (95% CI, 0.39-0.67), with 24-month RFS rates of 84.2% (95% CI, 81.3%-86.7%) vs 70.4% (95% CI, 65.3%-74.9%).

RFS benefit was observed across most prespecified subgroups, including risk-based disease stage IIB/IIC/IIIA/IIIB (intismeran, n = 440; placebo, n = 230; HR, 0.60; 95% CI, 0.41-0.88) and IIIC/IIID/IV (intismeran, n = 316; placebo, n = 150; HR, 0.57; 95% CI, 0.41-0.79).

What was the safety profile of intismeran autogene plus pembrolizumab in INTerpath-001?

In the as-treated population (intismeran, n = 755; placebo, n = 380), grade 3 or higher adverse effects (AEs) occurred in 23.6% vs 20.3% of patients, respectively, and serious AEs occurred in 17.6% vs 15.8%, respectively. Grade 3 or higher treatment-related AEs occurred in 14.2% vs 13.4% of patients, respectively. AEs led to discontinuation of any study drug in 16.6% vs 9.5% of patients.

AEs proved fatal in 1.1% of patients (n = 8) in the combination arm vs none in the control arm; none were determined to be related to intismeran autogene. Two deaths were attributed to pembrolizumab, and both occurred before the first dose of intismeran autogene.

AEs more common with the combination were largely low grade, transient, and related to injection, including pyrexia (52.2% vs 8.2%), injection site pain (51.0% vs 9.5%), and influenza-like illness (25.4% vs 9.2%). AEs of interest for pembrolizumab occurred in 36.0% vs 34.7% of patients, suggesting that intismeran did not potentiate pembrolizumab-associated toxicity.

What are the next steps for intismeran autogene in melanoma and other cancers?

Merck and Moderna previously announced that INTerpath-001 met its primary and key secondary end points at this prespecified interim analysis.³ OS follow-up is ongoing, and the full results are slated for publication in The New England Journal of Medicine on November 11, 2026.¹ Phase 2 and 3 trials are evaluating intismeran in bladder cancer, melanoma, non–small cell lung cancer, and renal cell carcinoma across the neoadjuvant, adjuvant, and metastatic settings.

Disclosures: Long reported serving as a consultant or advisor for BioNTech, Boehringer Ingelheim, Bristol Myers Squibb, Byondis B.V., Evaxion, Fortiva Biologics, GI Innovation, Immunocore, Innovent Biologics USA, Iovance Biotherapeutics, Jazz Pharmaceuticals, MSD, Replimune, Regeneron, Scancell, and Strand Therapeutics; and serving as a principal investigator for more than 60 clinical trials.

References

1. Long GV, Khattak MA, Gogas HJ, et al. INTerpath-001: phase 3 study of the mRNA-based individualized neoantigen therapy (INT) intismeran autogene plus pembrolizumab vs pembrolizumab alone for adjuvant treatment of resected stage IIB-IV melanoma. Presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA1.
2. Carlino MS. Dr Carlino on 5-year data with intismeran plus pembrolizumab in resected melanoma. OncLive. Published August 13, 2026. Accessed October 24, 2026. https://www.onclive.com/view/dr-carlino-on-5-year-data-with-intismeran-plus-pembrolizumab-in-resected-melanoma
3. Intismeran autogene plus pembrolizumab meets RFS and DMFS end points in resected stage IIB-IV melanoma. OncLive. Published August 19, 2026. Accessed October 24, 2026. https://www.onclive.com/view/intismeran-autogene-plus-pembrolizumab-meets-rfs-dmfs-end-points-in-resected-melanoma