Moderna and Merck report five-year follow-up data from KEYNOTE-942 showing sustained recurrence-free survival with personalized mRNA therapy intismeran autogene plus KEYTRUDA in high-risk melanoma
Written By: Pharmacally Medical News Desk
Moderna and Merck (MSD outside the United States and Canada) have reported median five-year follow-up results from the Phase 2b KEYNOTE-942/mRNA-4157-P201 study, strengthening the long-term clinical evidence for a personalized mRNA-based cancer vaccine approach in melanoma.
The study evaluated intismeran autogene (mRNA-4157 or V940), an investigational individualized neoantigen therapy, in combination with KEYTRUDA (pembrolizumab) as adjuvant treatment in patients with completely resected, high-risk stage III or IV melanoma.
Commenting on the five-year data, Kyle Holen, Senior Vice President and Head of Development, Oncology and Therapeutics at Moderna, said the results highlight the potential for prolonged benefit with the intismeran autogene and KEYTRUDA combination in patients with resected high-risk melanoma. He noted that outcomes such as these continue to support Moderna’s investment in oncology and illustrate the broader potential of mRNA-based approaches in cancer care. Holen added that upcoming milestones include results from the ongoing Phase 3 adjuvant melanoma study and continued progress across multiple Phase 2 and Phase 3 programs in other tumor types.
Sustained Reduction in Recurrence Risk at Five Years
In this pre-planned analysis, the combination continued to demonstrate a sustained and clinically meaningful improvement in recurrence-free survival (RFS). Patients treated with intismeran autogene plus KEYTRUDA experienced a 49% reduction in the risk of recurrence or death compared with KEYTRUDA alone (HR 0.51).
These findings build on previously reported two-year and three-year analyses and suggest that the benefit of adding a personalized mRNA vaccine to PD-1 inhibition can persist long after completion of adjuvant therapy.
For the secondary endpoint of distant metastasis-free survival (DMFS), results favoured the intismeran autogene plus KEYTRUDA combination over KEYTRUDA alone, showing a consistent trend toward reduced risk of distant metastatic recurrence. Detailed DMFS analyses are planned for presentation at an upcoming medical meeting.
How Intismeran Autogene Works
Intismeran autogene is designed individually for each patient based on the unique mutational profile of their tumor. The therapy consists of synthetic mRNA encoding up to 34 tumor-specific neoantigens identified through tumor DNA sequencing.
Once administered, the mRNA is translated within the body, and the encoded neoantigens are processed and presented to the immune system. This approach aims to generate a targeted, tumor-specific T-cell response, which may complement immune checkpoint blockade with KEYTRUDA to improve long-term disease control after surgery.
Clinical Trial
KEYNOTE-942 (NCT03897881) is an ongoing, randomized, open-label Phase 2b trial that enrolled 157 patients with high-risk stage III or IV melanoma following complete surgical resection. Patients were randomized 2:1 to receive intismeran autogene plus KEYTRUDA or KEYTRUDA alone.
Treatment included intismeran autogene administered every three weeks for nine doses, alongside KEYTRUDA given every three weeks for up to one year. The primary endpoint was recurrence-free survival, with secondary endpoints including distant metastasis-free survival and safety.
Safety and Tolerability
With extended follow-up, the safety profile of intismeran autogene in combination with KEYTRUDA remained consistent with earlier analyses, and no new or unexpected safety signals were identified.
Adverse events observed with the combination were generally in line with the known safety profile of KEYTRUDA-based immunotherapy. These included immune-mediated adverse reactions affecting organs such as the skin, gastrointestinal tract, endocrine glands, liver, and lungs. Most immune-mediated events were manageable with established treatment guidelines, including treatment interruption and corticosteroid therapy when appropriate.
Overall, the five-year results support a favourable benefit–risk profile for the combination in the adjuvant treatment of high-risk melanoma.
Marjorie Green, Senior Vice President and Head of Oncology, Global Clinical Development at Merck Research Laboratories, emphasized that many patients with stage III or IV melanoma remain at substantial risk of recurrence following surgery. She described the five-year follow-up results as a meaningful milestone, demonstrating the longer-term potential of combining a personalized mRNA vaccine with PD-1 inhibition, and noted that the data support continued advancement of the INTerpath development program across cancers with significant unmet need.
Ongoing and Future Development
In collaboration with Merck, the Phase 3 adjuvant melanoma trial (INTerpath-001, NCT05933577) is fully enrolled. Additional late-stage and mid-stage studies are ongoing or enrolling across several tumor types, including non-small cell lung cancer, renal cell carcinoma, bladder cancer, and metastatic melanoma.
References
Moderna & Merck Announce 5-Year Data for Intismeran Autogene in Combination With KEYTRUDA(R) (pembrolizumab) Demonstrated Sustained Improvement in the Primary Endpoint of Recurrence-Free Survival in Patients With High-Risk Stage III/IV Melanoma Following Complete Resection, 20 January 2026, News Release
Moderna & Merck Announce 5-Year Data for Intismeran Autogene in Combination With KEYTRUDA® (pembrolizumab) Demonstrated Sustained Improvement in the Primary Endpoint of Recurrence-Free Survival in Patients With High-Risk Stage III/IV Melanoma Following Complete Resection, 20 January 2026, https://www.merck.com/news/moderna-merck-announce-5-year-data-for-intismeran-autogene-in-combination-with-keytruda-pembrolizumab-demonstrated-sustained-improvement-in-the-primary-endpoint-of-recurrence-free-survival-i/
An Efficacy Study of Adjuvant Treatment with the Personalized Cancer Vaccine mRNA-4157 and Pembrolizumab in Participants with High-Risk Melanoma (KEYNOTE-942), ClinicalTrials.gov ID NCT03897881, https://clinicaltrials.gov/study/NCT03897881
Weber JS et al, Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study. Lancet. 2024 Feb 17;403(10427):632-644. Epub 2024 Jan 18. PMID: 38246194. https://doi.org/10.1016/s0140-6736(23)02268-7