Moderna : AACR INT Head & Neck Poster

CT141	mRNA-4157 (V940) Individualized Neoantigen Therapy + Pembrolizumab in Advanced
	Unresectable HPV-negative Head and Neck Carcinoma: Clinical and Translational Analysis
	Julie E. Bauman,1 Ricklie A. Julian,2 Jessica L. Geiger,3 Janice M. Mehnert,4 Jeffrey M. Clarke,5 Manish R. Patel,6,7 Martin Gutierrez,8 Justin F. Gainor,9 Shyam Srivats,10 Zhaojie Zhang,10
	Anjali Rao,10 Vasudha Sehgal,10 Peijie Hou,10 Manju Morrissey,10 Igor Feldman,10 Lakshmi Srinivasan,10 Praveen Aanur,10 Michelle Brown,10 Robert S. Meehan10

1George Washington University, Washington, DC, USA; 2University of Arizona Cancer Center, Tucson, AZ, USA; 3The Cleveland Clinic Foundation, Cleveland, OH, USA; 4Perlmutter Cancer Center at NYU Langone Health, New York, NY, USA; 5Duke University Medical Center, Durham, NC, USA;

6Florida Cancer Specialists, Sarasota, FL, USA; 7Sarah Cannon Research Institute, Nashville, TN, USA; 8Hackensack University Medical Center, Hackensack, NJ, USA; 9Massachusetts General Hospital, Boston, MA, USA; 10Moderna Inc., Cambridge, MA, USA

Background

•	Patients with human papillomavirus negative
	(HPV-) head and neck squamous cell carcinoma
	(HNSCC) have poor prognosis with a 5-year
	survival rate <50%1; limited durable clinical
	responses to PD1/PD-L1 blockade may be due
	to diminished effector cytolytic activity and
•	clonal diversity2-5
mRNA-4157 (V940) is a novel mRNA-based
	individualized neoantigen therapy that encodes up
	to 34 neoantigens inducing specifi c antitumor T cell
	activation; durable clinical responses with
•	pembrolizumab have been shown in melanoma6
mRNA-4157-P101/KEYNOTE-603 (NCT03313778)

Results

• Of 28 enrolled patients, 22 received mRNA-4157
  + pembrolizumab (Table 1); six discontinued prior to receiving mRNA-4157 due to death or disease progression/deterioration and were not included in this analysis. All patients are off treatment as of the clinical cutoff date (May 4, 2023)

Table 1. Baseline characteristics

	mRNA-4157 +
Baseline characteristics	pembrolizumab
	N = 22
Sex, n (%)
Male	14 (63.6)

Safety

• Most mRNA-4157-related TEAEs were grade 1-2; the most common being infl uenza-like illness, injection-site pain, and pyrexia (Table 2)
• The safety profi le was consistent with mRNA-4157 monotherapy and the well-characterized safety profi le of pembrolizumab, with AEs being managed with established management guidelines

Clinical Response

• The objective response rate was 27.3% (6/22, 95% CI 10.7-50.2) and disease control rate was 63.6% (14/22, 95% CI 40.7-82.8), with best overall responses of 2 (9.1%) complete and 4 (18.2%) partial responses, and 8 (36.4%) stable disease at data cutoff (Figure 2)

Biomarkers

• Sustained de novo T cell induction to targeted neoantigens was seen in 5/5 available patient samples (Figure 3); IFN-γ responses were higher post mRNA- 4157 + pembrolizumab compared with baseline
• Decrease in ctDNA levels post-baseline were observed in 3/4 patients with disease control and in 0/3 patients with progressive disease (Figure 4)

Figure 3. Neoantigen-reactive T cell response to neoantigen peptide pools

1250

• Differential gene expression from pre-treatment tumor samples suggests increased baseline infl amed T cell- associated gene expression in patients with disease control (Figure 5A)
• Hallmark IL-2/STAT5 signaling and hallmark
  infl ammatory response at baseline were found to be signifi cantly enriched in patients with disease control by de novo Gene Set Enrichment Analysis (Benjamini- Hochberg-adjusted descriptive P< 0.05; Figure 5B)

Figure 5. (A) Heatmap of transcript expression by disease control status and (B) gene set enrichment analyses from baseline tumor samples

Conclusions

•	mRNA-4157 + pembrolizumab was associated with
	preliminary positive clinical responses and disease
	control in patients with HPV- HNSCC, including two
•	complete responses
mRNA-4157 + pembrolizumab was well tolerated,
	with an mRNA-4157 safety profi le consistent with
•	mRNA-4157 monotherapy
mRNA-4157 + pembrolizumab showed evidence of
	activation of immune responses
	• Patients within the disease control subgroup
	demonstrated baseline infl amed T cell gene
	expression with decreased ctDNA levels post
	baseline

is an ongoing phase 1 study evaluating mRNA-4157

alone or in combination with pembrolizumab in

solid tumors

Objective

• To assess safety, tolerability, preliminary clinical activity, and translational biomarkers for mRNA-4157
  + pembrolizumab in patients with HPV- HNSCC (Part C)

Methods

•	Part C of this study enrolled patients 18 years old
	with checkpoint inhibitor (CPI)-naive, recurrent/
•	metastatic HPV- HNSCC
Eligible patients received 200 mg pembrolizumab
	Q3W IV during a 6-weeklead-in (during mRNA-
	4157 manufacture), then combined with 1 mg
	mRNA-4157 for up to 9 doses Q3W IM, followed
	by pembrolizumab, until disease progression,
	unacceptable toxicity, or 35 total cycles of
•	pembrolizumab (Figure 1)
Safety, tolerability, and preliminary clinical response
	were assessed per RECIST v1.1 criteria

Female	8 (36.4)
Age, median (range), years	62.5 (29-81)
65 years, n (%)	9 (40.9)
ECOG PS score, n (%)
0	9 (40.9)
1	13 (59.1)
Prior immuno-oncology therapy, n	0
Number of prior systemic therapies, n (%)
0	3 (13.6)
1	15 (68.2)
2	4 (18.2)
PD-L1, n
Not evaluable	7
CPS 1	15

CPS, combined positive score; ECOG PS, Eastern Cooperative Oncology Group performance status; PD-L1, programmed death ligand-1.

• After the clinical cutoff date, the median (range) follow-up was 38.4 (11.7-194.9) weeks
• 8 (36.4%) patients completed 9 doses of mRNA-
  4157 (median 5.5 doses, range 1-9). Median (range) treatment duration of mRNA-4157 was 13.8 (0.1-26.1) weeks, and 20.1 (6.1-68.0) weeks for pembrolizumab. Most patients (n = 19/22, 86.4%) received 2 cycles of lead-in pembrolizumab (range, 2-4 cycles)

Figure 2. Percent change of target lesion from baseline over time

(%)
from baseline	300
200
diameter
100
target lesion
0
Change in
-100
	0	6	12	18	24	30	36	42	48	54	60	66	72	78	84	90 120 150

Time on study (weeks)

Tumor type = HPV- HNSCC

CR

PR

SD

PD

First new lesion

The vertical reference line marks the scheduled start of mRNA-4157 + pembrolizumab dosing Q3W that followed the pembrolizumab Q3W lead-in dose. The horizontal reference lines are plotted at y = 20 for PD (20% increase in the sum of diameters of target lesions) and y = -30 for PR (30% decrease in the sum of diameters of target lesions).

CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.

• Kaplan-Meierestimated median (95% CI) progression- free survival and overall survival were 15.0 (11.6-38.6) weeks and 107.1 (42.7-NE) weeks, respectively

(SFU/1x10cells)6

1000

750

pools

neoantigen

500

Combined

250

0

Pre-treatment

Post-pembrolizumab,

Post-pembrolizumab,

pre-mRNA-4157

post-mRNA-4157

Patient		Patient 1 (DC)		Patient 2 (NDC)		Patient 3 (DC)		Patient 4 (DC)		Patient 5 (DC)

Immunogenicity was evaluable in 5/22 (22.7%) patients with all 3 timepoints; 7 patients had insuffi cient sample quantity or quality. Data are plotted as sum of responses to mRNA-4157- specifi c neoantigen peptide pools (mix of individualized neoantigen peptides) at indicated timepoints during treatment. Patients with CR, PR, or SD were classifi ed as 'disease control' and patients with PD were classifi ed as 'no disease control'.

DC, disease control; NDC, no disease control; SFU, spot forming unit.

Figure 4. ctDNA dynamics

Disease control

A

Status

TMB

ALDH1A1

SOX2

SOX21

EZH2

ZNF812

KRT13

KRT4

MUC4

ADH7

CEACAM5

S100A1

GRAP2

CD28

PTPN7

CD27

CXCR6

SH2D1A

ITK

CD48

SELL

TNFSF8

SELP

CCL5

CMKLR1

TBX21

PRF1

GZMB

HLA−E

TIGIT

EOMES

FASLG

CD8A

NKG7

CXCL9

IDO1

PSMB10

LAG3

CD8B

HLA−DQA1

KLRC2

KLRD1

KLRC4

CD274

PDCD1LG2

STAT1

ROS1

TGFBI

COL27A1

CD276

SOX9

AGRN

RAET1G

RAET1E

RAET1L

ULBP3

ULBP2

TGFA

LAMA3

EGFR

B

HALLMARK_ALLOGRAFT_REJECTION

HALLMARK_ADIPOGENESIS

HALLMARK_OXIDATIVE_PHOSPHORYLATION

HALLMARK_MYOGENESIS

HALLMARK_IL2_STAT5_SIGNALING

HALLMARK_P53_PATHWAY

HALLMARK_INFLAMMATORY_RESPONSE

Status

Disease control

No disease control

TMB

400

400

200

0

RNA expression 3 2 1 0 -1-2-3

Hallmark pathways NES from GSEA

•	Randomized assessment of the mRNA-4157 +
	pembrolizumab treatment effect in the advanced
	disease setting may be warranted

References

1. Schiff BA. 2022. Oropharyngeal Squamous Cell Carcinoma. https://www.msdmanuals.com/ en-gb/professional/ear,-nose,-and-throat-disorders/tumors-of-the-head-and-neck/oropharyngeal-squamous-cell-carcinoma. Accessed March 7, 2024.
2. Lechner A, et al. Oncotarget 2017;8:44418-44433.
3. Wang J, et al. Sci Rep 2019;9:13404.
4. Tosi A, et al. J Exp Clin Cancer Res 2022;41:279.
5. Xu K, et al Br J Cancer 2020;123:932-941.
6. Weber JS, et al. Lancet 2024;403:632-644.

Acknowledgments

The study (NCT03313778) was sponsored by Moderna, Inc., in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Editorial assistance was provided by Caudex, a division of IPG Health Medical Communications, New York, NY, USA, funded by Moderna Inc. and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and under the direction of the authors. Thank you to patients and their families, site staff, vendors, collaborators, scientists, regulatory, operations, and manufacturing teams who discovered, improved, and enabled mRNA-4157 (V940).

Disclosures

JEB has received scientifi c consulting fees from Exelixis and Bluedot Bio, and has research grants from Celldex, CUE, and Moderna. RAJ has received consulting fees from Bristol Myers Squibb, BioAtla, Jazz Pharmaceuticals, and Merck; has received honoraria from Jazz Pharmaceuticals; has received meeting or travel support from ASCO and APPOS; and has held a leadership or fi duciary role for NCI. JLG has received consulting fees from Astellas, EMD Serono, and Merck; and has received honoraria from Astellas and Aveo Oncology. JMM has received consulting fees from

•	Longitudinal assessments of immunogenicity via
	IFN-γ ELISpot and ctDNA detection were performed
•	using collected peripheral blood
Next-generation sequencing was performed on
	baseline tumor biopsies

Figure 1. mRNA-4157-P101/KEYNOTE 603 Part C study design for patients with

HPV- HNSCC

HNSCC

HPV-

CPI-naive

advanced/metastic,

unresectable

N = 28

200 mg pembrolizumab Q3W: up to 35 cycles

Ecacy

follow-up

1 mg mRNA-4157 Q3W: up to 9 cycles

n = 22

Baseline	EoT
tumor

EoT, end of treatment.

Table 2. Summary of TEAEs in 2 patients

			mRNA-4157 + pembrolizumab
TEAEa			N = 22
	Any grade		Grade 3
All TEAEs, n (%)	22	(100.0)		14	(63.6)
mRNA-4157-related TEAE	15 (68.2)		3b (13.6)
Infl uenza-like illness	9	(40.9)			0
Injection-site pain	8	(36.4)			0
Pyrexia	8	(36.4)		1	(4.5)
Fatigue	6	(27.3)			0
Vaccination-site pain	6	(27.3)			0
Chills	3	(13.6)			0
Nausea	3	(13.6)			0
Headache	2 (9.1)			0
Injection-site erythema	2 (9.1)			0
Lipase increased	2 (9.1)		1	(4.5)
Lymphocyte count decreased	2 (9.1)		1	(4.5)
Pain in extremity	2 (9.1)			0

aDefi ned as any event not present before exposure to mRNA-4157 or pembrolizumab, or any present event that worsens in intensity or frequency after exposure to study drug; bGrade 3 AEs were related to both mRNA-4157 and pembrolizumab; there were no grade 4 or 5 AEs related to mRNA-4157.

TEAE, treatment-emergent adverse event.

	-2
10	-3
log
ctDNA	-4
	-5
	-6
	0	100	200	300	400

No disease control

-2

10	-3
log
ctDNA	-4

-5-6

0	100	200		300	400
	Days from first dose of mRNA-4157 + pembrolizumab
	Cancer detected	Detected	Not detected

There were 8 (36.4%) patients with evaluable samples; 14 patients had insufficient sample quantity or quality.

	HALLMARK_REACTIVE_OXYGEN_SPECIES_PATHWAY
	HALLMARK_PEROXISOME
	HALLMARK_UV_RESPONSE_UP
	HALLMARK_APOPTOSIS
	HALLMARK_PANCREAS_BETA_CELLS
	HALLMARK_XENOBIOTIC_METABOLISM
	HALLMARK_FATTY_ACID_METABOLISM
	HALLMARK_COMPLEMENT
	HALLMARK_ESTROGEN_RESPONSE_EARLY
	HALLMARK_TNFA_SIGNALING_VIA_NFKB
	HALLMARK_BILE_ACID_METABOLISM
	HALLMARK_KRAS_SIGNALING_DN
	HALLMARK_KRAS_SIGNALING_UP
	HALLMARK_HEME_METABOLISM
	HALLMARK_INTERFERON_GAMMA_RESPONSE
	HALLMARK_APICAL_SURFACE
	HALLMARK_HYPOXIA
	HALLMARK_DNA_REPAIR
	HALLMARK_UV_RESPONSE_DN
	HALLMARK_IL6_JAK_STAT3_SIGNALING
	HALLMARK_PI3K_AKT_MTOR_SIGNALING
	HALLMARK_SPERMATOGENESIS
Pathway	HALLMARK_COAGULATION
HALLMARK_ESTROGEN_RESPONSE_LATE
HALLMARK_APICAL_JUNCTION
HALLMARK_MTORC1_SIGNALING
HALLMARK_GLYCOLYSIS

HALLMARK_ANGIOGENESIS

HALLMARK_UNFOLDED_PROTEIN_RESPONSE

HALLMARK_INTERFERON_ALPHA_RESPONSE

HALLMARK_HEDGEHOG_SIGNALING

HALLMARK_G2M_CHECKPOINT

HALLMARK_CHOLESTEROL_HOMEOSTASIS

HALLMARK_E2F_TARGETS

HALLMARK_NOTCH_SIGNALING

HALLMARK_ANDROGEN_RESPONSE

HALLMARK_EPITHELIAL_MESENCHYMAL_TRANSITION

HALLMARK_PROTEIN_SECRETION

HALLMARK_MITOTIC_SPINDLE

HALLMARK_MYC_TARGETS_V1

HALLMARK_WNT_BETA_CATENIN_SIGNALING

HALLMARK_TGF_BETA_SIGNALING

HALLMARK_MYC_TARGETS_V2

-1	0	1	2
	Normalized enrichment score
	Adjusted descriptive P< 0.05	True	False

1. Box indicates upregulated genes associated with infl amed T cell expression. (B) Gene set enrichment analysis categorized as hallmark pathways; blue indicates statistical significance and red indicates no statistical signifi cance with multiplicity adjusted by Benjamini-Hochberg procedure.
   TMB, tumor mutational burden.

Bristol Myers Squibb, Merck, Novartis, Regeneron, and Seagen; and has participated in data safety monitoring or advisory boards for Moderna. JMC has received grants from AbbVie, Adaptimmune, Array Biopharma, AstraZeneca, Bristol Myers Squibb, CBMG, G1 Therapeutics, Genentech, GlaxoSmithKline, Grid Therapeutics, Moderna, Pfi zer, and Spectrum; has received consulting fees from Amgen, AstraZeneca, Corbus Pharmaceuticals, Genentech, Merck, Novartis, Omega Pharma, Pfi zer, Sanofi , Spectrum, Turning Point Therapeutics, and Vivacitas; has participated in data safety monitoring or advisory boards for G1 Therapeutics and STCube; and has served on the board

of the Lung Cancer Initiative of North Carolina. MRP has received consulting fees from Accutar Biotech, Daiichi Sankyo, EMD Serono, Janssen, Kura Oncology, Nurix, Olema Pharmaceuticals, and Pfi zer; has received honoraria from Janssen; and has received research funding (to institution) from Acerta Pharma, Accutar Biotech, Adagene, ADC Therapeutics, Agenus, Allorion Therapeutics, Artios Pharma, Astellas, AstraZeneca, BioNTech, BioTheryX, Blueprint Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb/Celgene, Compugen, Conjupro Biotherapeutics, Cullinan Oncology, Cyteir Therapeutics, Daiichi Sankyo, Erasca, Genentech/Roche, Georgiamune, Gilead Sciences, GlaxoSmithKline, H3 Biomedicine, Hengrui Therapeutics, Hotspot Therapeutics, Hutchison Medipharma, Immune-Onc Therapeutics, Immunitas, Incyte, Janssen, Kineta, Klus Pharma,

Kura Oncology, Kymab, Lilly, Loxo Oncology, LSK Biopartners, Mabspace, Macrogenics, Merck, Millenium Pharma, Moderna, Novartis, Nurix, Olema, ORIC Pharmaceuticals, Pfi zer, Pionyr, Prelude Therapeutics, PureTech, Ribon Therapeutics, Seven and Eight Biopharmaceuticals, Step Pharma, Syndax, Taiho Pharmaceutical, TeneoBio, Tesaro, Treadwell Therapeutics, Vividion Therapeutics, and Zymeworks. MG has received consulting fees from Cellularity, Guardant, and Merck; and has participated in data safety monitoring or advisory boards for Sanofi. JFG has received consulting fees from AI Proteins, Amgen, AstraZeneca, Blueprint Medicines, Bristol Myers Squibb, Genentech, Gilead Sciences, ITeos Therapeutics, Jounce Therapeutics, Karyopharm, Lilly/Loxo, Mariana Therapeutics, Merck, Merus Pharmaceuticals, Mirati Therapeutics, Moderna, Novartis, Novocure, Nuvalent, Pfi zer, Sanofi , Silverback Therapeutics, and Takeda; has received honoraria from Merck, Novartis, Pfi zer, and Takeda; has received research funding (to institution) from Adaptimmune, Alexo Therapeutics, AstraZeneca, Blueprint Medicines, Bristol Myers Squibb, Genentech, Jounce Therapeutics, Merck, Moderna, Novartis, NextPoint Therapeutics, and Palleon Pharmaceuticals; has received research funding from Genentech, Novartis, and Takeda; has equity in AI

Proteins; and has an immediate family member who has equity in and is employed by Ironwood Pharmaceuticals. SS, ZZ, AR, PH, MM, IF, LS, PA, and RSM hold stock in and are employees of Moderna. VS holds stock in AbbVie and Moderna and is an employee of Moderna. MB holds stock in Bristol Myers Squibb, Moderna, and Novartis; and is an employee of Moderna.

Presented at the American Association for Cancer Research Annual Meeting; San Diego, CA, USA; April 5-10, 2024