Intismeran autogene

Intismeran autogene (previously known by its investigational drug name mRNA-4157/V940) is an mRNA based cancer vaccine encapsulated in solid lipid nanoparticles. The 34 mRNA sequences in mRNA-4157/V940 vaccine were generated by an automated algorithm integrated with workflow based on massive parallel sequencing of tissue generated from cancer patients.[1] As adjuvant therapy, mRNA-4157 monotherapy and in combination with pembrolizumab have been investigated in patients with resected solid tumors (melanoma, bladder carcinoma, HPV negative HNSCC, NSCLC, SCLC, MSI-high, or TMB-high cancers). It was also investigated in patients with HNSCC and MSS-CRC.[2][3]

Clinical development history

Clinical development of intismeran autogene: the twelve trials registered on ClinicalTrials.gov as of August 2026. Bars run from each trial's start date to its primary completion date, shaded by phase.

mRNA-4157/V940 was initially developed by Moderna starting in 2017. In May 2018, Moderna and MSD (Merck in US) announced collaboration on further development of the investigational agent. In 2019 Moderna and Merck jointly put mRNA-4157/V940 into clinical trials in combination with Merck's cancer immunotherapy drug pembrolizumab in resected stage IIIB-IV melanoma.[4][5][6][7] In December 2022, Moderna and MSD announced that the study met its endpoint and demonstrated superiority.[8] In February 2023, the Food and Drug Administration granted mRNA-4157/V940 breakthrough status.[9] In April 2023, mRNA-4157 in combination with pembrolizumab received Prime Scheme Designation from the European Medicines Agency.[10]

In the 2023 AACR meeting, Jeffrey S. Weber, the deputy director of the Perlmutter Cancer Center, presented the primary analysis outcome from the open-label, 2:1 randomization phase 2b study. At the pre-specified analysis point when 42 recurrence-free survival (RFS) events occurred among 157 participants with resected stage IIIC–IV melanoma, 22.4% (24/107) in the mRNA-4157 plus pembrolizumab arm had recurrent disease, and 40% (20/50) in the pembrolizumab arm had recurrent disease, concluding that mRNA-4157 in combination with pembrolizumab reduced risk by 44% in surgical resected melanoma.

In July 2023, MSD and Moderna initiated the phase III study (study V940-001) evaluating mRNA-4157 in combination with pembrolizumab for adjuvant treatment of patients with resected high-risk stage IIB-stage IV melanoma.[11]

In the meantime, a phase III study of V940 plus Pembrolizumab versus placebo plus pembrolizumab as adjuvant therapy in non-small cell lung cancer patient with resected stage II, IIIA, IIIB (N2) is registered and expected to start at November 2023. Of note, patients who received prior neoadjuvant therapy for their current NSCLC diagnosis, or have been treated with any agent directed to stimulatory or coinhibitory T-cell receptors (e.g. PD-1, PD-L1, CTLA-4, et al.) are not allowed to enroll in the study.[12]

On 19 August 2026, Merck and Moderna announced that the phase 3 INTerpath-001 trial (NCT05933577) had met both of its efficacy endpoints. In patients with completely resected stage IIB–IV cutaneous melanoma, intismeran autogene combined with pembrolizumab produced statistically significant improvements in recurrence-free survival and in distant metastasis-free survival compared with pembrolizumab alone. The trial randomized 1,137 patients 2:1 to intismeran autogene plus pembrolizumab or to placebo plus pembrolizumab. The companies reported no new safety signals. Detailed efficacy results, including overall survival, were not released at the time of the announcement.[13][14]

Registered clinical trials

Twelve trials of the agent are registered on ClinicalTrials.gov. Nine are designated phase 2 or phase 3; the remainder are the 2017 first-in-human study, a phase 1/2 study in urothelial carcinoma, and a phase 2/3 study in cutaneous squamous-cell carcinoma that was terminated in 2026, the registry giving the reason as "business reasons".[15]

Registered clinical trials of intismeran autogene, as of August 2026
TrialPhasePopulationStatusEnrollmentStarted
KEYNOTE-603
NCT03313778		1Advanced solid tumorsActive, not recruiting1612017-08
KEYNOTE-942
NCT03897881		2Resected melanomaActive, not recruiting2672019-07
INTerpath-001
NCT05933577		3Resected stage IIB–IV melanomaActive, not recruiting1,089
(est.)		2023-07
INTerpath-002
NCT06077760		3Resected NSCLCRecruiting868
(est.)		2023-12
INTerpath-005
NCT06305767		1/2Muscle-invasive urothelial carcinomaActive, not recruiting230
(est.)		2024-03
INTerpath-004
NCT06307431		2Resected renal cell carcinomaActive, not recruiting272
(est.)		2024-04
INTerpath-007
NCT06295809		2/3Cutaneous squamous-cell carcinomaTerminated462024-04
NCT066234223Resectable stage II–IIIB (N2) NSCLCRecruiting680
(est.)		2024-10
NCT068330732High-risk non-muscle-invasive bladder cancerRecruiting308
(est.)		2025-03
NCT069610062MelanomaRecruiting160
(est.)		2025-05
INTerpath-13
NCT07221474		2First-line metastatic squamous NSCLCRecruiting180
(est.)		2025-12
INTerpath-014
NCT07513376		3Resected NSCLC (subcutaneous pembrolizumab)Recruiting876
(est.)		2026-05

Individualized neoantigen cancer vaccines have largely remained in early-phase testing. Of the interventional trials of such vaccines registered on ClinicalTrials.gov, only ten have reached phase 3 or phase 2/3, and five of those are trials of intismeran autogene.[15]

mRNA-4157 is experienced in a clinical trial (INTerpath-004) phase 2 (NCT06307431). In this trial, mRNA-4157 is combined with adjuvant pembrolizumab. It aimed to prevent relapse for patients with RCC who have already undergone nephrectomy. [16][17][18][19]

Mechanism of action

mRNA-4157/V940 is an mRNA based cancer vaccine. When administered, it will produce one of several dozen possible abnormal proteins commonly found in cancerous tissues. The production of those proteins is intended to invoke an immune response. mRNA-4157/V940 is given to patients after their tumors have been sequenced and abnormal proteins identified. The drug is then customized to match a patient's tumor, which makes it an example of personalized medicine.

References

  1. ↑ "Medical areas of focus & Modalities". Moderna. Retrieved 2023-11-16.
  2. ↑ Bauman, Julie; Burris, Howard; Clarke, Jeffrey; Patel, Manish; Cho, Daniel; Gutierrez, Martin; Julian, Ricklie; Scott, Aaron; Cohen, Pamela; Frederick, Joshua; Robert-Tissot, Celine; Zhou, Honghong; Mody, Kinjal; Keating, Karen; Meehan, Robert (2020-11-01). "798 Safety, tolerability, and immunogenicity of mRNA-4157 in combination with pembrolizumab in subjects with unresectable solid tumors (KEYNOTE-603): an update". Journal for ImmunoTherapy of Cancer. 8 (Suppl 3): A477.1–A477. doi:10.1136/jitc-2020-SITC2020.0798. ISSN 2051-1426. S2CID 228944158.
  3. ↑ "CTG Labs - NCBI". beta.clinicaltrials.gov. Retrieved 2023-11-16.
  4. ↑ Markman, Jon (10 May 2023). "Moderna's Revolutionary Cancer Vaccine Sets Investors Abuzz". Forbes. Retrieved 6 July 2023.
  5. ↑ Steenhuysen, Julie (16 April 2023). "Moderna/Merck cancer vaccine plus Keytruda delays skin cancer return". Reuters. Retrieved 6 July 2023.
  6. ↑ "Moderna and Merck Announce mRNA-4157/V940, an Investigational Personalized mRNA Cancer Vaccine, in Combination With KEYTRUDA® (pembrolizumab), Met Primary Efficacy Endpoint in Phase 2b KEYNOTE-942 Trial" (Press release). Merck. Retrieved 2023-07-06.
  7. ↑ "An Efficacy Study of Adjuvant Treatment With the Personalized Cancer Vaccine mRNA-4157 and Pembrolizumab in Participants With High-Risk Melanoma (KEYNOTE-942) - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2023-11-15.
  8. ↑ "Moderna and Merck Announce mRNA-4157/V940, an Investigational Personalized mRNA Cancer Vaccine, in Combination With KEYTRUDA® (pembrolizumab), Met Primary Efficacy Endpoint in Phase 2b KEYNOTE-942 Trial". Merck.com. Retrieved 2023-11-15.
  9. ↑ "Moderna and Merck Announce mRNA-4157/V940, an Investigational Personalized mRNA Cancer Vaccine, in Combination With KEYTRUDA® (pembrolizumab), was Granted Breakthrough Therapy Designation by the FDA for Adjuvant Treatment of Patients With High-Risk Melanoma Following Complete Resection". Merck.com. Retrieved 2023-11-15.
  10. ↑ "mRNA-4157/V940, an Investigational Personalized mRNA Cancer Vaccine, in Combination with KEYTRUDA® (pembrolizumab), Receives PRIME Scheme Designation from the European Medicines Agency for Adjuvant Treatment of Patients with High-Risk Stage III/IV Melanoma Following Complete Resection". Merck.com. Retrieved 2023-11-15.
  11. ↑ Carvalho, Thiago (2023-08-16). "Personalized anti-cancer vaccine combining mRNA and immunotherapy tested in melanoma trial". Nature Medicine. 29 (10): 2379–2380. doi:10.1038/d41591-023-00072-0. PMID 37773210. S2CID 263264691.
  12. ↑ Merck Sharp & Dohme LLC (2024-04-17). A Phase 3, Randomized, Double-blind, Placebo- and Active-Comparator-Controlled Clinical Study of Adjuvant V940 (mRNA-4157) Plus Pembrolizumab Versus Adjuvant Placebo Plus Pembrolizumab in Participants With Resected Stage II, IIIA, IIIB (N2) Non-small Cell Lung Cancer (Report). clinicaltrials.gov.
  13. ↑ "Merck and Moderna Announce Phase 3 INTerpath-001 Trial of Intismeran Autogene Plus KEYTRUDA (pembrolizumab) Met Endpoints of Recurrence-Free Survival (RFS) and Distant Metastasis-Free Survival (DMFS) in Patients With Completely Resected Stage IIB-IV Melanoma" (Press release). Merck & Co. 19 August 2026. Retrieved 19 August 2026.
  14. ↑ "Moderna and Merck say mRNA cancer vaccine succeeded in late-stage melanoma trial". STAT. 19 August 2026. Retrieved 19 August 2026.
  15. 1 2 "Intismeran autogene (mRNA-4157/V940): all 12 trials and where it is enrolling". Hipa.ai. 19 August 2026. Retrieved 19 August 2026.
  16. ↑ "INTerpath-004: A phase 2, randomized, double-blind study of adjuvant pembrolizumab (pembro) with V940 (mRNA-4157) or placebo for renal cell carcinoma (RCC). | Journal of Clinical Oncology". Archived from the original on 2025-07-04. Retrieved 2025-12-01.
  17. ↑ "45 INTerpath-004: A phase 2, randomized, double-blind study of pembrolizumab with V940 (mRNA-4157) or placebo in the adjuvant treatment of renal cell carcinoma - PMC". Archived from the original on 2025-02-02. Retrieved 2025-12-01.
  18. ↑ "H.E.C.T.O.R. - INTerpath-004 / V940-004". hector-essais-cliniques.fr. Retrieved 2025-12-01.
  19. ↑ "mRNA Therapies in Oncology: Key Pipeline Developments and Clinical Trial Insights" (PDF). Archived from the original (PDF) on 2024-12-04.
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