intismeran autogene (mRNA-4157)

P2, N=308, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting

P2, N=272, Active, not recruiting, Merck Sharp & Dohme LLC | Recruiting --> Active, not recruiting

P2, N=308, Not yet recruiting, Merck Sharp & Dohme LLC

P2/3, N=1012, Active, not recruiting, Merck Sharp & Dohme LLC | Recruiting --> Active, not recruiting | Trial completion date: May 2033 --> Mar 2026 | Trial primary completion date: Apr 2029 --> Mar 2026

P1/2, N=230, Recruiting, Merck Sharp & Dohme LLC | Trial completion date: Apr 2031 --> Oct 2031 | Trial primary completion date: Oct 2026 --> Apr 2027

P3, N=680, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting

P3, N=1089, Active, not recruiting, Merck Sharp & Dohme LLC | Recruiting --> Active, not recruiting

P1/2, N=230, Recruiting, Merck Sharp & Dohme LLC | Phase classification: P2 --> P1/2

P3, N=680, Not yet recruiting, Merck Sharp & Dohme LLC

Following combination therapy, sustained mRNA-4157-induced neoantigen-specific T cell responses and expansion of cytotoxic CD8 and CD4 T cells were observed. These findings show the potential of a novel mRNA INT approach in oncology.

P2/3, N=1012, Recruiting, Merck Sharp & Dohme LLC | Trial completion date: Apr 2029 --> May 2033

P2/3, N=1012, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting

P2, N=272, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting

P2, N=200, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting

P2, N=200, Not yet recruiting, Merck Sharp & Dohme LLC

P2, N=272, Not yet recruiting, Merck Sharp & Dohme LLC

P2/3, N=1012, Not yet recruiting, Merck Sharp & Dohme LLC

P1, N=242, Recruiting, ModernaTX, Inc. | Active, not recruiting --> Recruiting | N=108 --> 242

P3, N=868, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting

P3, N=868, Not yet recruiting, Merck Sharp & Dohme LLC

There was a trend for enhanced efficacy of mRNA-4157 + pembro across BRAF V600E/K WT (n=96) (HR [95% CI]: 0.808 [0.366–1.784]) and MUT (n=61) subpopulations (0.332 [0.130–0.850]); however, considering ctDNA status by focusing on ctDNA-negative subpopulation increased similarity of efficacy across BRAF WT (n=68) and MUT (n=42) subgroups (0.334 [0.121–0.923] vs 0.069 [0.009–0.563]). Table: LBA49 ctDNA subgroup Patient criteria Molecular responders Patients with MRD at baseline that resolved during treatment (ctDNA positive at treatment initiation became ctDNA negative) OR Patients with no MRD at baseline that became ctDNA positive on treatment (MRec), and then ctDNA negative again Molecular non-responders Patients with MRD at baseline that did not resolve during treatment (ctDNA positive at treatment initiation and stayed positive) OR Patients with no MRD at baseline who showed molecular progression (MRec, ctDNA negative at treatment initiation became ctDNA positive and stayed positive) Conclusions These results suggest a potential relationship between ctDNA dynamics and treatment outcomes in pts with high-risk resectable melanoma and support further exploration in upcoming planned studies.

P3, N=1089, Not yet recruiting, Merck Sharp & Dohme LLC

Findings from the phase IIb KEYNOTE-942 trial indicate that the investigational vaccine mRNA-4157/V940 plus pembrolizumab is a potential adjuvant therapy for high-risk melanoma. Following surgery, patients who received the combination experienced a significant reduction in disease recurrence risk, compared with those given just PD-1 inhibitor.

P2, N=257, Recruiting, ModernaTX, Inc. | Active, not recruiting --> Recruiting | N=157 --> 257 | Trial completion date: Sep 2024 --> Sep 2029 | Trial primary completion date: Sep 2024 --> Sep 2029

MRD detection by plasma ctDNA assay at the start of adjuvant melanoma treatment is uncommon in mRNA4157-p201 but is associated with shorter RFS. Treatment with the combination of mRNA-4157/V940 and pembrolizumab was associated with prolonged RFS compared to pembrolizumab monotherapy in patients with high-risk resectable melanoma, irrespective of MRD status Additional analyses including assessment of longitudinal ctDNA patterns are ongoing. The association between MRD and mRNA-4157/V940 treatment effect will be further explored in upcoming planned studies.

Our results indicate that mRNA-4157 demonstrates improvements in RFS irrespective of TMB status when administered in combination with pembrolizumab compared to pembrolizumab monotherapy in patients with resected high-risk cutaneous melanoma. The novel mechanism of action of mRNA-4157 may both deepen the activity of pembrolizumab and broaden the population of patients that can benefit from immune therapy. The association between TMB and mRNA-4157 treatment effect will be further explored in upcoming planned studies.

P1, N=108, Active, not recruiting, ModernaTX, Inc. | Recruiting --> Active, not recruiting

P1, N=143, Recruiting, ModernaTX, Inc. | Trial completion date: Jun 2022 --> Jun 2025 | Trial primary completion date: Jun 2022 --> Jun 2025

P1, N=142, Recruiting, ModernaTX, Inc. | N=90 --> 142 | Trial primary completion date: Dec 2020 --> Jun 2022

The bioinformatics algorithm for mRNA-4157 is able to predict and select neoantigens with pre-existing TIL reactivities based on human ex vivo assays for vaccine designs with high accuracy.