1515MO Clinical outcomes and PD-L1 expression analyses from a trial of mRNA-4359 plus pembrolizumab in checkpoint inhibitor-resistant/refractory (CPI-R/R) melanoma

D.J. Pinato; R.J. Sullivan; A. Khattak; D. Sarker; T. Medina; I. Karydis; G. Middleton; P. Spiliopoulou; A. Rohatgi; M. Gutierrez; A.I. Daud; V. Boni; M.R. Middleton; R. Sweis; J.E. Bauman; X. Mao; H. Daghestani; M. Abadier; F. Barlaskar; G.V. Long

doi:10.1016/j.annonc.2025.08.2146

Abstract

Background
mRNA-4359 is an mRNA-based therapy encoding PD-L1 and IDO1 antigens, designed to elicit T-cell responses against tumor and immunosuppressive cells. It is being evaluated in an ongoing phase 1/2 trial as monotherapy or in combination with pembrolizumab. We previously reported mRNA-4359 was well tolerated across all monotherapy dose levels. Here we present clinical, safety and translational data from the fully enrolled CPI-R/R melanoma cohort treated with mRNA-4359 plus pembrolizumab.

Methods
As of 28 Feb 2025, 29 patients (pts) received pembrolizumab plus mRNA-4359 at 400 μg (n=14) or 1000 μg (n=15), given IM every 3 weeks for up to 9 doses. Primary endpoint was safety/tolerability. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), and duration of response (DOR) per RECIST v1.1. Translational analyses included antigen-specific T-cell responses, T cell receptor (TCR) clonality, and baseline PD-L1 immunohistochemistry (IHC).

Results
All pts were CPI-R/R and received ≥1 prior CPI (median prior lines: 3; range: 1-8). No dose-limiting toxicities or treatment-related deaths occurred. mRNA-4359 adverse events (AEs) were mostly Grade 1/2 injection site reactions and self-limited systemic AEs. Pembrolizumab AEs were consistent with its known safety profile. Among 25 evaluable pts, ORR was 24% (n=6), DCR 60% (n=15); median DOR not reached (median follow-up time: 70.9 weeks). Of 22 pts with evaluable pre-treatment PD-L1 IHC, 41% (n=9) had a tumor proportion score (TPS) ≥1%; all responders (6/9, 67%) were in this group (Table). Treatment induced peripheral antigen-specific T-cell responses and emergence of novel TCR clones.

Conclusions

mRNA-4359 plus pembrolizumab demonstrated a favorable safety profile, T-cell responses and durable clinical activity in CPI-R/R melanoma pts with PD-L1 TPS ≥1%, supporting PD-L1 as a potential predictive biomarker in this high unmet need population.

Clinical trial identification

NCT05533697.

Original language	English
Pages (from-to)	S908-S909
Number of pages	2
Journal	Annals of Oncology
Volume	36
Issue number	Supplement 2
DOIs	https://doi.org/10.1016/j.annonc.2025.08.2146
Publication status	Published - 5 Nov 2025
Event	European Society for Medical Oncology Congress 2025 - Berlin, Germany Duration: 17 Oct 2025 → 21 Oct 2025 https://www.esmo.org/meeting-calendar/esmo-congress-2025

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Pinato, D. J., Sullivan, R. J., Khattak, A., Sarker, D., Medina, T., Karydis, I., Middleton, G., Spiliopoulou, P., Rohatgi, A., Gutierrez, M., Daud, A. I., Boni, V., Middleton, M. R., Sweis, R., Bauman, J. E., Mao, X., Daghestani, H., Abadier, M., Barlaskar, F., & Long, G. V. (2025). 1515MO Clinical outcomes and PD-L1 expression analyses from a trial of mRNA-4359 plus pembrolizumab in checkpoint inhibitor-resistant/refractory (CPI-R/R) melanoma. Annals of Oncology, 36(Supplement 2), S908-S909. https://doi.org/10.1016/j.annonc.2025.08.2146

@article{876f566d74bc49c6bff7b5642a299294,

title = "1515MO Clinical outcomes and PD-L1 expression analyses from a trial of mRNA-4359 plus pembrolizumab in checkpoint inhibitor-resistant/refractory (CPI-R/R) melanoma",

abstract = "Background mRNA-4359 is an mRNA-based therapy encoding PD-L1 and IDO1 antigens, designed to elicit T-cell responses against tumor and immunosuppressive cells. It is being evaluated in an ongoing phase 1/2 trial as monotherapy or in combination with pembrolizumab. We previously reported mRNA-4359 was well tolerated across all monotherapy dose levels. Here we present clinical, safety and translational data from the fully enrolled CPI-R/R melanoma cohort treated with mRNA-4359 plus pembrolizumab. Methods As of 28 Feb 2025, 29 patients (pts) received pembrolizumab plus mRNA-4359 at 400 μg (n=14) or 1000 μg (n=15), given IM every 3 weeks for up to 9 doses. Primary endpoint was safety/tolerability. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), and duration of response (DOR) per RECIST v1.1. Translational analyses included antigen-specific T-cell responses, T cell receptor (TCR) clonality, and baseline PD-L1 immunohistochemistry (IHC). Results All pts were CPI-R/R and received ≥1 prior CPI (median prior lines: 3; range: 1-8). No dose-limiting toxicities or treatment-related deaths occurred. mRNA-4359 adverse events (AEs) were mostly Grade 1/2 injection site reactions and self-limited systemic AEs. Pembrolizumab AEs were consistent with its known safety profile. Among 25 evaluable pts, ORR was 24\% (n=6), DCR 60\% (n=15); median DOR not reached (median follow-up time: 70.9 weeks). Of 22 pts with evaluable pre-treatment PD-L1 IHC, 41\% (n=9) had a tumor proportion score (TPS) ≥1\%; all responders (6/9, 67\%) were in this group (Table). Treatment induced peripheral antigen-specific T-cell responses and emergence of novel TCR clones. ConclusionsmRNA-4359 plus pembrolizumab demonstrated a favorable safety profile, T-cell responses and durable clinical activity in CPI-R/R melanoma pts with PD-L1 TPS ≥1\%, supporting PD-L1 as a potential predictive biomarker in this high unmet need population. Clinical trial identificationNCT05533697.",

author = "D.J. Pinato and R.J. Sullivan and A. Khattak and D. Sarker and T. Medina and I. Karydis and G. Middleton and P. Spiliopoulou and A. Rohatgi and M. Gutierrez and A.I. Daud and V. Boni and M.R. Middleton and R. Sweis and J.E. Bauman and X. Mao and H. Daghestani and M. Abadier and F. Barlaskar and G.V. Long",

year = "2025",

month = nov,

day = "5",

doi = "10.1016/j.annonc.2025.08.2146",

language = "English",

volume = "36",

pages = "S908--S909",

journal = "Annals of Oncology",

issn = "0923-7534",

publisher = "Oxford University Press",

number = "Supplement 2",

note = "European Society for Medical Oncology Congress 2025, ESMO 2025 ; Conference date: 17-10-2025 Through 21-10-2025",

url = "https://www.esmo.org/meeting-calendar/esmo-congress-2025",

}

Pinato, DJ, Sullivan, RJ, Khattak, A, Sarker, D, Medina, T, Karydis, I, Middleton, G, Spiliopoulou, P, Rohatgi, A, Gutierrez, M, Daud, AI, Boni, V, Middleton, MR, Sweis, R, Bauman, JE, Mao, X, Daghestani, H, Abadier, M, Barlaskar, F & Long, GV 2025, '1515MO Clinical outcomes and PD-L1 expression analyses from a trial of mRNA-4359 plus pembrolizumab in checkpoint inhibitor-resistant/refractory (CPI-R/R) melanoma', Annals of Oncology, vol. 36, no. Supplement 2, pp. S908-S909. https://doi.org/10.1016/j.annonc.2025.08.2146

TY - JOUR

T1 - 1515MO Clinical outcomes and PD-L1 expression analyses from a trial of mRNA-4359 plus pembrolizumab in checkpoint inhibitor-resistant/refractory (CPI-R/R) melanoma

AU - Pinato, D.J.

AU - Sullivan, R.J.

AU - Khattak, A.

AU - Sarker, D.

AU - Medina, T.

AU - Karydis, I.

AU - Middleton, G.

AU - Spiliopoulou, P.

AU - Rohatgi, A.

AU - Gutierrez, M.

AU - Daud, A.I.

AU - Boni, V.

AU - Middleton, M.R.

AU - Sweis, R.

AU - Bauman, J.E.

AU - Mao, X.

AU - Daghestani, H.

AU - Abadier, M.

AU - Barlaskar, F.

AU - Long, G.V.

PY - 2025/11/5

Y1 - 2025/11/5

N2 - Background mRNA-4359 is an mRNA-based therapy encoding PD-L1 and IDO1 antigens, designed to elicit T-cell responses against tumor and immunosuppressive cells. It is being evaluated in an ongoing phase 1/2 trial as monotherapy or in combination with pembrolizumab. We previously reported mRNA-4359 was well tolerated across all monotherapy dose levels. Here we present clinical, safety and translational data from the fully enrolled CPI-R/R melanoma cohort treated with mRNA-4359 plus pembrolizumab. Methods As of 28 Feb 2025, 29 patients (pts) received pembrolizumab plus mRNA-4359 at 400 μg (n=14) or 1000 μg (n=15), given IM every 3 weeks for up to 9 doses. Primary endpoint was safety/tolerability. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), and duration of response (DOR) per RECIST v1.1. Translational analyses included antigen-specific T-cell responses, T cell receptor (TCR) clonality, and baseline PD-L1 immunohistochemistry (IHC). Results All pts were CPI-R/R and received ≥1 prior CPI (median prior lines: 3; range: 1-8). No dose-limiting toxicities or treatment-related deaths occurred. mRNA-4359 adverse events (AEs) were mostly Grade 1/2 injection site reactions and self-limited systemic AEs. Pembrolizumab AEs were consistent with its known safety profile. Among 25 evaluable pts, ORR was 24% (n=6), DCR 60% (n=15); median DOR not reached (median follow-up time: 70.9 weeks). Of 22 pts with evaluable pre-treatment PD-L1 IHC, 41% (n=9) had a tumor proportion score (TPS) ≥1%; all responders (6/9, 67%) were in this group (Table). Treatment induced peripheral antigen-specific T-cell responses and emergence of novel TCR clones. ConclusionsmRNA-4359 plus pembrolizumab demonstrated a favorable safety profile, T-cell responses and durable clinical activity in CPI-R/R melanoma pts with PD-L1 TPS ≥1%, supporting PD-L1 as a potential predictive biomarker in this high unmet need population. Clinical trial identificationNCT05533697.

AB - Background mRNA-4359 is an mRNA-based therapy encoding PD-L1 and IDO1 antigens, designed to elicit T-cell responses against tumor and immunosuppressive cells. It is being evaluated in an ongoing phase 1/2 trial as monotherapy or in combination with pembrolizumab. We previously reported mRNA-4359 was well tolerated across all monotherapy dose levels. Here we present clinical, safety and translational data from the fully enrolled CPI-R/R melanoma cohort treated with mRNA-4359 plus pembrolizumab. Methods As of 28 Feb 2025, 29 patients (pts) received pembrolizumab plus mRNA-4359 at 400 μg (n=14) or 1000 μg (n=15), given IM every 3 weeks for up to 9 doses. Primary endpoint was safety/tolerability. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), and duration of response (DOR) per RECIST v1.1. Translational analyses included antigen-specific T-cell responses, T cell receptor (TCR) clonality, and baseline PD-L1 immunohistochemistry (IHC). Results All pts were CPI-R/R and received ≥1 prior CPI (median prior lines: 3; range: 1-8). No dose-limiting toxicities or treatment-related deaths occurred. mRNA-4359 adverse events (AEs) were mostly Grade 1/2 injection site reactions and self-limited systemic AEs. Pembrolizumab AEs were consistent with its known safety profile. Among 25 evaluable pts, ORR was 24% (n=6), DCR 60% (n=15); median DOR not reached (median follow-up time: 70.9 weeks). Of 22 pts with evaluable pre-treatment PD-L1 IHC, 41% (n=9) had a tumor proportion score (TPS) ≥1%; all responders (6/9, 67%) were in this group (Table). Treatment induced peripheral antigen-specific T-cell responses and emergence of novel TCR clones. ConclusionsmRNA-4359 plus pembrolizumab demonstrated a favorable safety profile, T-cell responses and durable clinical activity in CPI-R/R melanoma pts with PD-L1 TPS ≥1%, supporting PD-L1 as a potential predictive biomarker in this high unmet need population. Clinical trial identificationNCT05533697.

U2 - 10.1016/j.annonc.2025.08.2146

DO - 10.1016/j.annonc.2025.08.2146

M3 - Abstract

SN - 0923-7534

VL - 36

SP - S908-S909

JO - Annals of Oncology

JF - Annals of Oncology

IS - Supplement 2

T2 - European Society for Medical Oncology Congress 2025

Y2 - 17 October 2025 through 21 October 2025

ER -

1515MO Clinical outcomes and PD-L1 expression analyses from a trial of mRNA-4359 plus pembrolizumab in checkpoint inhibitor-resistant/refractory (CPI-R/R) melanoma

Abstract

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