Moderna : 2020 SITC (poster)

A Phase 1, Open-Label, Multicenter Study to Assess the Safety, Tolerability, and Immunogenicity of mRNA-4157 Alone in Subjects With Resected Solid Tumors and in Combination

With Pembrolizumab in Subjects With Unresectable Solid Tumors (Keynote-603)

Julie E. Bauman1, Howard A. Burris III2 ,Jeffrey M. Clarke3, Manish R. Patel4 , Daniel C. Cho5 , Martin Gutierrez6, Ricklie A. Julian1, Aaron J. Scott1, Pamela S. Cohen7, Joshua Frederick7,

Celine Robert-Tissot7, Jing Sun7, Scott Kallgren7, Honghong Zhou7, Kinjal Mody7, Karen Keating7, Robert S. Meehan7 , Justin F. Gainor8

1 University of Arizona, Tuscon, AZ, 2 Sarah Cannon Research Institute, Tennessee Oncology, Nashville, TN, 3 Duke University Medical Center, Durham, NC, 4 Florida Cancer Specialists, Sarah Cannon Research Institute, Sarasota, FL 5 New York University School of Medicine, New York, NY 6 Hackensack University Medical Center, Hackensack, NJ 7 Moderna ,Inc., Cambridge, MA 8 Massachusetts General Hospital, Boston, MA

Background		Personalized cancer vaccine process

Clinical Data

Biomarker Data

T-cell targeting of mutation-derived epitopes (neoantigens) has been demonstrated to drive anti-tumor responses. Immunizing patients against such neoantigens in combination with a checkpoint inhibitor (CPI) may elicit greater anti-tumor responses than CPI alone. Mutations are rarely shared between patients, thus requiring a personalized approach to vaccine design. mRNA-4157 is a personalized neoantigen cancer vaccine with the following properties:

• mRNA encoding up to 34 neoantigens selected by a proprietary algorithm based on whole exome and RNA sequencing of tumor and blood samples
• Encapsulated in a novel lipid nanoparticle and delivered intramuscularly
• Individually designed and manufactured for each patient

This report includes updates from the mRNA-4157 Phase 1 study, as of 01-Oct-2020, with a focus on the Part C checkpoint naïve HPV-negativeHPV(-) HNSCC and MSS-CRC cohorts. Data from dose escalation was presented at ASCO 2019 [1].

		Study design
Dose escalation		Dose expansion (1 mg)
Part A (Adjuvant patients):	4 dose levels	Part B (Metastatic patients): mRNA-4157 + pembrolizumab
monotherapy mRNA-4157	(0.04-1 mg)
		Part C (CPI naïve MSS CRC): mRNA-4157 + pembrolizumab
		Part C (CPI naïve HPV-negativeHPV(-) HNSCC): mRNA-4157 + pembrolizumab
Part B (Metastatic patients):	4 dose levels
combination mRNA-4157 +
(0.04-1 mg)	Part D (Adjuvant melanoma): mRNA-4157 + pembrolizumab
pembrolizumab

Histologies in Parts A and B:		•	MSI high malignancies		Objectives:
•	NSCLC	•	HPV(-) HNSCC		•	Safety and tolerability
•	SCLC	•	Urothelial carcinoma	•	TMB high malignancies		• Biomarkers, including antigen-specificT-cell responses
•	Cutaneous Melanoma						•	Anti-tumor activity

Screening	pembrolizumab monotherapy	mRNA-4157+pembrolizumab	pembrolizumab	Safety follow-up	Efficacy follow-up
run-in*	monotherapy	(100-day post	(Observe until
period	(Dosing every 21 days for up to 9 cycles)
(Dosing every 21 days for 2 cycles)	(Dosing up to 35 cycles)	treatment)	progression)

*Part A patients are adjuvant patients receiving mRNA-4157 monotherapy. Pembrolizumab run-in and pembrolizumab monotherapy period does not apply.

Clinical Data

Table 1-4 Best overall response in CPI naïve HPV(-) HNSCC and MSS CRC patients receiving mRNA- 4157 + pembrolizumab

	HPV(-) HNSCC (n=10*)	MSS CRC (n=17)
Best overall response
Complete Response (CR)	2	0
Partial Response (PR)	3	0
Stable Disease (SD)	4	1
Progressive Disease (PD)	1	16
Overall response rate (ORR)	50%	0%
Disease control rate (DCR)	90%	6%
Median progression-free survival (mPFS)	9.8 months	2.7 months
Median duration of response (mDOR)	Not reached	N/A

*4 additional patients started pembrolizumab dosing but progressed and came off study prior to the start of vaccine dosing.

Figure 1-1: CPI naïve HPV(-) HNSCC patients receiving mRNA-4157+pembrolizumab Spider plot of tumor burden (% change from baseline)

(%)

)

6 weeks

12 weeks

21 weeks

30 weeks

39 weeks

48 weeks

Figure 1-1: Four out of five responding patients achieved PR after 2 doses of pembrolizumab prior to the start of vaccine administration. Two PRs converted to CR after the addition of vaccine. Patient 109's tumor burden was decreasing but then started to progress until 2 doses of vaccine were given, and then subsequently achieved a PR. Patient 067 also had started to progress until after the 5th dose of vaccine, then ultimately had a discordant CR in the neck while progressing in the lung (vaccine was manufactured from the genetic sequencing of the dermal neck disease). Patient 117 progressed on monotherapy pembrolizumab until vaccine was started and tumor burden continues to decrease.

Figure 1-2: CPI naïve HPV(-) HNSCC patients receiving mRNA-4157+pembrolizumab Spider plot of tumor burden (absolute mm)

Figure 1-3: CPI naïve HPV(-) HNSCC and MSS CRC patients receiving mRNA-4157 + pembrolizumab swimmer plot

Figure 1-3: Ten out of seventeen MSS-CRC patients progressed rapidly within 6 weeks of mRNA-4157 vaccine administration. Only one patient completed all doses of vaccine and remains on study. Six HPV(-) HNSCC patients currently remain on study.

Figure 2-1 Radiological scans from HPV(-)HNSCC patient 125

Baseline

After 2 doses of pembrolizumab

After 2 combination doses

After 5 combination doses

Figure 2-1: Patient 125 had a symptomatic 3.1 cm right glossopharyngeal sulcus tumor at baseline. After 2 doses of pembrolizumab they had a reduction of tumor size to 1.7cm which was a partial response. The response then plateaued until 5 doses of vaccine were given, after which the response deepened to a complete response. They had a hotspot mutation for TP53 with a p.G266R protein change and 0.55 allele fraction. This patient remains on study.

Figure 3-2: Potentially predictive biomarker levels in tumors of HPV(-) HNSCC and MSS CRC patients

Figure 3-2: The distribution of TMB in individual tumors and a heatmap of RNA biomarker measurements relative to pan-cancer TCGA quartiles, including GEP and CYT scores and transcript PD-L1 expression, are shown for HPV(-) HNSCC and MSS CRC patients treated with mRNA-4157 and pembrolizumab combination. The indicated TMB levels represent numbers of non- synonymous mutations with an allele frequency ≥5%. The GEP score reflects RNA expression of 18 inflammatory genes related to antigen presentation, chemokine expression, cytolytic activity and adaptive immune resistance, including PD-L1, and indicates the level of T cell inflammation in the TME (4). The CYT score is based on transcript levels of two key cytolytic effectors, granzyme A and perforin (5). The expression of these biomarkers measured in the indicated patients corresponds to expected ranges based on histology-matched TCGA data (not shown). A comprehensive analysis of TCGA MSS CRC tumors had previously revealed generally low GEP scores and TMB values for this histology, associated with a reduced likelihood of response to pembrolizumab therapy (6). Accordingly, a majority of tumors of the treatment unresponsive MSS CRC patient cohort exhibit low GEP and CYT scores indicating TMEs detrimental to T cell responses. In contrast, favorable clinical outcome in HPV(-) HNSCC is associated with higher GEP and CYT scores, suggesting the requirement of a TME permissible to inflamed T cells for response to treatment. Mean TMB is comparable in both MSS CRC and HPV(-) HNSCC tumors* and across HPV(-) HNSCC responders and non-responders*, suggesting that clinical response in HPV(-) HNSCC patients can occur in lesions with relatively low mutation numbers less likely to respond to pembrolizumab therapy alone. Although PD-L1 transcript levels are higher in HPV(-) HNSCC tumors, expression was comparable in responding and non-responding tumors.

CYT=Cytolytic Activity score, GEP=Gene Expression Profile score, N-s=non-synonymous,PD-L1=Programmed Death Ligand-1, TCGA= The Cancer Genome Atlas, TMB=Tumor mutational burden, TME=Tumor microenvironment, *as measured by a Mann Whitney test

Conclusions

• mRNA-4157 is well tolerated at all dose levels. The majority of AEs are low grade and reversible.

• Of the ten CPI-naïveHPV(-) HNSCC patients in Part C to date, the overall response rate (ORR) to mRNA-4157 and

pembrolizumab by RECIST 1.1 is 50% (2CR, 3PR), DCR is 90% (2CR, 3PR, 4SD), and mPFS is 9.8 months, which

compares favorably to the published pembrolizumab ORR and mPFS of 14.6% and 2.0 months respectively [2,3].

mDOR is not yet reached.

• A general trend towards favorable clinical response in HPV(-) HNSCC patients with more inflamed tumors as

indicated by a higher GEP and CYT scores was observed, while TMB was similar in responding and non-responding

HPV(-) HNSCC tumors.

• No clinical responses were noted in the 17 patients with MSS CRC. Most of these tumors were immunologically

'cold', with microenvironments that may be impermissible to inflamed T cells, as indicated by low GEP (including low

PD-L1 transcript expression) and CYT score.

• TMB levels were similar across HPV(-) HNSCC and MSS CRC tumors regardless of clinical outcome.

• We hypothesize that (a) 'warmer' tumors such as HPV(-) HNSCC harbor more amenable microenvironments for T cell

responses to mRNA-4157 + pembrolizumab, and that (b) addition of mRNA-4157 neoantigens may lower the

minimal TMB required for response to pembrolizumab.

Table 1-1 Patient demographics	Table 1-2 Prior therapies		Table 1-3 Safety data
All patients		Part C HPV(-) HNSCC and MSS CRC		All patients
			Number of	HPV(-)
		n= 94	MSS CRC	Related adverse event	All grades	G3/4
			prior	HNSCC
			Part A: mRNA-4157 monotherapy (n=16)
	Age(y)		n=17
		therapies	n=10 to date
	Injection site pain		5		0
Range:		36-88
	0	1	0	Pyrexia		5		0
Median:		66	Influenza-like illness		4		0
				Myalgia		4		0
	Sex		1	7	0	Fatigue		3		0
			Related to study treatment in at least 3 patients
Male:		59				There were no mRNA-4157-related grade 3/4/5 events reported
				Part B, C and D: pembrolizumab & mRNA-4157 (n=78)
Female:		35	2	1	2	Injection site pain		23		0
Race	Pyrexia		19		0
					Fatigue		18		2
Caucasian	89	3	0	4	Influenza-like illness		9		0
			Lipase increase		9		2
Black		3				Nausea		9		0
Asian		2	3+	1	11	Chills		8		0
				Related to either study treatment in >10% of patients
						There were no mRNA-4157-related grade 4/5 events reported

)

Figure 1-2: Tumor responses were noted in patients regardless of tumor burden. Patient 109 had the largest total tumor burden at baseline, and the greatest reduction in size after vaccine administration.

Hotspot mutations

Figure 3-1 HNSCC hotspot mutations included in mRNA-4157 for individual patients

Subject ID	Gene	Protein change	Allele fraction
	PIK3CA	p.E542K	0.25
049	EP300	p.D1399N	0.38
093	TP53	p.C238Y	0.18
096	TP53	p.P151S	0.56
109	HIST1H3B	p.E106D	0.35
120	STAT3	p.D661Y	0.13
125	TP53	p.G266R	0.55

Figure 3-1: Hotspot mutations considered drivers in HNSCC (7) were expressed in tumors of the indicated six HPV(-) HNSCC patients, for whom mRNA encoding for these mutations was included in the manufactured mRNA-4157. Despite the presence of these strong mutational drivers of disease at intermediate to high allele frequencies, combination therapy of mRNA-4157 with pembrolizumab lead to clinical responses in four out of six of these patients.

• The HPV(-) HNSCC cohort of patients continues to recruit. Although 4 of the 5 clinical responses started prior to

vaccine administration, the current 50% response rate, prolonged mPFS, and the overall trend of further tumor

burden decrease over time is encouraging and warrants further expansion of the HPV(-) HNSCC cohort.

References:

1. Burris, H. et al; A phase I multicenter study to assess the safety, tolerability, and immunogenicity of mRNA-4157 alone in patients with resected solid tumors and in combination with pembrolizumab in patients with unresectable solid tumors. Journal of Clinical Oncology 2019; 37: 2523-2523
2. Burtness, B. et al; Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomized, open-label, phase 3 study. Lancet 2019; 394: 1915-28.
3. Cohen, E. et al; Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomized, open-label, phase 3 study. Lancet 2019; 393: 156-167.
4. Ayers, M. et al; IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. The Journal of Clinical Investigation 2017;
5. 1. 2930-2940.
6. Rooney, M. et al; Molecular and Genetic Properties of Tumors Associated with Local Immune Cytolytic Activity. Cell 2015; 160: 48-61.
7. Cristescu, R. et al; Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science 2018; 362.
8. Chang, M. et al; Accelerating Discovery of Functional Mutant Alleles in Cancer. Cancer Discovery 2018; 8: 174-183.

Acknowledgements:

Merck & Company, Inc: Scott Pruitt MD, PhD; Sybil Williams PhD	NCT 03739931
Moderna: Baoyu Ding PhD