Merck and Moderna present Phase 3 INTerpath‑001: intismeran + KEYTRUDA reduces recurrence in resected stage IIB–IV melanoma
- INTerpath‑001 randomized 1,137 patients (2:1) with completely resected stage IIB–IV melanoma in a double‑blind, placebo‑ and active‑comparator‑controlled Phase 3 trial.
- Primary analysis (median follow‑up 24.6 months): recurrence‑free survival HR=0.58 (95% CI 0.45–0.75; p<0.001); two‑year RFS 82.2% vs 70.0%.
- Distant metastasis‑free survival improved: HR=0.62 (95% CI 0.45–0.85; p=0.002); two‑year DMFS 88.5% vs 80.2%.
- Safety: treatment‑related adverse events in 95.8% vs 90.0%; grade 3–5 TRAEs 14.2% vs 13.4%; most common AEs were pyrexia (52.2%), injection‑site pain (51.0%) and fatigue (38.5%).
Trial design
INTerpath‑001 (NCT05933577) is a randomized, double‑blind, placebo‑ and active‑comparator‑controlled global Phase 3 trial that enrolled 1,137 patients with completely resected stage IIB–IV cutaneous melanoma. Patients were randomized 2:1 to receive individualized mRNA neoantigen therapy intismeran (1 mg every three weeks for up to nine doses) plus pembrolizumab (400 mg every six weeks up to nine cycles) or placebo plus pembrolizumab for approximately one year. The primary endpoint was recurrence‑free survival (RFS); key secondaries included distant metastasis‑free survival (DMFS) and overall survival (OS).
Key efficacy results
At the pre‑specified primary analysis (median follow‑up 24.6 months), intismeran plus pembrolizumab reduced the risk of recurrence or death by 42% versus pembrolizumab alone (HR=0.58; 95% CI 0.45–0.75; two‑sided p<0.001). DMFS was also improved (HR=0.62; 95% CI 0.45–0.85; two‑sided p=0.002). Two‑year RFS rates were 82.2% with the combination versus 70.0% with pembrolizumab alone; two‑year DMFS rates were 88.5% versus 80.2%. Overall survival data remain immature but show a favorable trend.
Timing and sensitivity analyses
Efficacy during the first six months was comparable between arms (RFS HR=0.99; DMFS HR=1.01). In a pre‑specified sensitivity analysis after completion of the intismeran immunization regimen at six months, the combination reduced risk of recurrence or death by 58% (HR=0.42; 95% CI 0.30–0.58) and reduced risk of distant metastasis or death by 50% (HR=0.50; 95% CI 0.34–0.73). A modified‑ITT sensitivity analysis excluding patients who did not receive at least one dose showed RFS HR=0.51 and DMFS HR=0.55.
Safety and next steps
Treatment‑related adverse events occurred in 95.8% of patients receiving intismeran plus pembrolizumab versus 90.0% with pembrolizumab alone; grade 3–5 TRAEs were 14.2% versus 13.4%. No new safety signals were observed. The results will be presented at ESMO 2026 Presidential Symposium I and have been accepted for publication in The New England Journal of Medicine; the sponsors are engaging with regulatory authorities.
Source: Merck