Intismeran Plus Pembrolizumab Outperforms Pembrolizumab Alone in Resected Stage IIB-IV Melanoma

Topline Results from the INTerpath-001 Trial

Clinical Summary:  

• Design/Population: INTerpath-001 was a phase 3, randomized, double-blind trial evaluating adjuvant intismeran autogene plus pembrolizumab vs pembrolizumab alone in patients with completely resected stage IIB-IV cutaneous melanoma who had not received prior systemic therapy. 

• Key Outcomes: At a prespecified interim analysis, intismeran plus pembrolizumab met the primary end point of recurrence-free survival and the key secondary end point of distant metastasis-free survival, with statistically significant and clinically meaningful improvements compared with pembrolizumab alone. Detailed efficacy results have not yet been reported. 

• Clinical Relevance: The positive phase 3 findings support individualized neoantigen therapy as a potentially practice-changing addition to adjuvant PD-1 blockade in resected high-risk melanoma, although the magnitude of benefit, detailed safety findings, and overall survival results remain pending. 

Topline results from the phase 3 INTerpath-001 trial showed that adding the individualized neoantigen therapy intismeran autogene to pembrolizumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival compared with pembrolizumab alone as adjuvant treatment for patients with completely resected stage IIB-IV melanoma. 

In this double-blind, placebo- and active-comparator controlled trial, 1137 patients with completely resected stage IIB, IIC, III, or IV cutaneous melanoma who had not received prior systemic therapy were randomized 2:1 to receive either 1 mg of intismeran every 3 weeks for up to 9 doses plus 400 mg of pembrolizumab every 6 weeks for up to 9 cycles or pembrolizumab alone. Treatment continued for approximately 1 year, until disease recurrence or unacceptable toxicity, or for a maximum duration of approximately 56 weeks. 

The primary end point was RFS, defined as the time from randomization to local, locoregional, regional, or distant recurrence or death from any cause. Key secondary end points included distant metastasis-free survival, overall survival (OS), safety, tolerability, and quality of life. 

At the prespecified interim analysis, intismeran plus pembrolizumab produced statistically significant and clinically meaningful improvements in both RFS and distant metastasis-free survival compared with pembrolizumab alone. The companies did not disclose hazard ratios, survival rates, or median follow-up in the topline announcement. The trial will continue to assess OS and other secondary end points. 

The safety profiles of intismeran and pembrolizumab were consistent with findings previously reported for the combination, with no new safety signals identified. Detailed adverse event data were not included in the topline release. 

Intismeran is an investigational mRNA-based individualized neoantigen therapy designed using mutations identified within an individual patient’s tumor. Each treatment can encode up to 34 neoantigens and is intended to stimulate tumor-specific T-cell responses against cancer cells carrying those mutations. 

The phase 3 findings build on previously reported phase 2b results from KEYNOTE-942/mRNA-4157-P201, in which intismeran plus pembrolizumab reduced the risk of recurrence or death by 49% and the risk of distant metastasis or death by 59% compared with pembrolizumab alone at 5-year follow-up. 

“Today’s results represent a landmark moment for adjuvant melanoma treatment,” stated Georgina Long, MD, PhD, principal investigator of the study and medical director of Melanoma Institute Australia. “Intismeran in combination with pembrolizumab has the potential to establish a new treatment paradigm in the adjuvant melanoma setting, helping patients remain cancer-free for longer.” 

The companies plan to present the phase 3 results at an upcoming international medical meeting and discuss the findings with regulatory authorities. 

Source:  

Businesswire. 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. https://www.businesswire.com/news/home/20260819675697/en/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