Dr Long on INTerpath-001 Data for Intismeran Autogene Plus Pembrolizumab in Resected Melanoma

"It's very exciting to have, for the first time, proof of concept [for] a change in the way we can activate the immune system against the cancer."

Georgina V. Long, AO, BSc, PhD, MBBS, medical director of Melanoma Institute Australia (MIA), and chair of Melanoma Medical Oncology and Translational Research at MIA and Royal North Shore Hospital, The University of Sydney, discussed findings from the phase 3 INTerpath-001 trial (NCT05933577) evaluating the individualized neoantigen therapy intismeran autogene (mRNA-4157; V940) plus pembrolizumab (Keytruda) as adjuvant treatment in patients with resected stage IIB to IV melanoma, and why the benefit emerged after the first 6 months.

The trial randomly assigned 1,137 patients 2:1 to intismeran plus pembrolizumab (n = 757) or placebo plus pembrolizumab (n = 380), with results presented at the 2026 ESMO Congress. At a median follow-up of 24.6 months, the combination reduced the risk of recurrence or death by 42% (HR, 0.58; 95% CI, 0.45-0.75; P < .001), Long said. The 24-month recurrence-free survival (RFS) rates were 82.2% (95% CI, 79.3%-84.8%) and 70.0% (95% CI, 65.0%-74.5%), respectively.

Because intismeran must prime an immune response, and because it was started a median of 64 days after pembrolizumab, investigators planned sensitivity analyses to account for a delayed onset, Long explained. In a piecewise analysis, the RFS curves overlapped through 6 months (HR, 0.99; 95% CI, 0.66-1.49) before separating thereafter (HR, 0.42; 95% CI, 0.30-0.58). In the modified intention-to-treat population, which included the 96% of patients per arm who received study treatment, the RFS HR was 0.51 (95% CI, 0.39-0.67).

The combination also reduced the risk of distant metastasis or death by 38% (HR, 0.62; 95% CI, 0.45-0.85; P = .002), with a piecewise HR beyond 6 months of 0.50 (95% CI, 0.34-0.73) and a modified intention-to-treat HR of 0.55 (95% CI, 0.40-0.77).

Long described how each therapy is built: next-generation sequencing identifies mutations in the patient's tumor that are absent from normal cells, candidate neoantigens are computationally ranked by clonality, expression, and MHC class I and II profile, and up to 34 are encoded in mRNA packaged in a lipid nanoparticle.

Intismeran did not potentiate pembrolizumab's immune-related adverse effects, Long noted. Its toxicities were transient grade 1 or 2 injection-site and vaccination-related effects, including chills, fever, redness, pain, and swelling.

Ongoing trials are evaluating intismeran in advanced melanoma and other cancers, with readouts expected in the coming years, Long concluded.