Study of mRNA-4359 Administered Alone and in Combination With Immune Checkpoint Blockade in Participants With Advanced Solid Tumors

Key Inclusion Criteria:

• Dose Escalation (Arm 1a): Participant has histologically confirmed locally advancedor metastatic cancer (cutaneous melanoma, non-small-cell lung carcinoma (NSCLC),non-muscle invasive bladder cancer, head and neck squamous cell carcinoma,Microsatellite stable colorectal cancer (MSS CRC), basal cell carcinoma, or triplenegative breast cancer) with measurable disease as determined by RECIST v1.1. Arm 1aparticipants must have received, and then progressed, relapsed, or been intolerantto, or ineligible for, at least 1 standard treatment regimen in the advanced ormetastatic setting. Participants with a known driver mutation must have alsoreceived or been offered a mutation-directed therapy, where indicated. Participantsmust have a tumor lesion amenable to biopsy and must have another lesion that can befollowed for response.

• Dose Confirmation (Arm 1b): Participant has histologically confirmed locallyadvanced or metastatic, and checkpoint inhibitor refractory melanoma or locallyadvanced or metastatic, and checkpoint inhibitor refractory NSCLC with measurabledisease as determined by RECIST v1.1 who have disease progression after, at least 1line of standard therapy (no limit to prior lines of therapy), and have been treatedwith or refused standard of care treatment. Must have primary refractory or acquiredsecondary resistance to prior immune checkpoint treatments. Primary refractory isdefined as prior exposure to anti-programmed death-1 (PD-1)/programmed deathligand-1 (PD-L1) antibody for at least 6 weeks but no more than 6 months withdemonstration of progression on 2 separate scans at least 4 weeks apart but no morethan 12 weeks apart and progression occurring within 6 months after first dose ofanti-PD-1 antibody. Acquired secondary resistance must have confirmed objectiveresponse or prolonged stable disease (SD) (>6 months), followed by diseaseprogression in the setting of ongoing treatment and confirmed progression on scansat least 4 weeks apart. Participants must have a tumor lesion amenable to biopsy andmust have another lesion that can be followed for response. a. For NSCLC participants with known epidermal growth factor receptor (EGFR),anaplastic lymphoma kinase (ALK), proto-oncogene tyrosine-protein kinase reactiveoxygen species (ROS1), or other actionable mutations for which there are approvedtargeted therapies, must have received prior approved targeted therapy or have beenoffered and declined approved targeted therapy.

• Dose Expansion Arm (Arm 2) only: Participant has histologically confirmed locallyadvanced, metastatic melanoma, or locally advanced or metastatic NSCLC with a PD-L1TPS of ≥50% and with no EGFR or ALK positive tumor mutations, with measurabledisease as determined by RECIST v1.1 and have not had any prior therapy for thiscancer in this setting (that is, first line therapy). Participants must have a tumorlesion amenable to biopsy and must provide tumor biopsy sample at baseline (archivalformalin-fixed, paraffin-embedded [FFPE]. If the participant is undergoing a newbiopsy, they must have another lesion that can be followed for response.

• Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤1.

• Participant has adequate hematological and biological function

Key Exclusion Criteria:

• Participant has active central nervous system tumors or metastases.

• Participant has received treatment with prohibited medications (that is, concurrentanticancer therapy including other chemotherapy, radiation [local radiation forpalliative care is permitted with approval from the Sponsor], hormonal anticancertreatment, biologic therapy, or immunotherapy) or investigational agents within 5half-lives or 14 days prior to the first day of study intervention, whichever isshorter.

• Participant has required the use of additional immunosuppression other thancorticosteroids for the management of an AE, has experienced recurrence of an AE ifrechallenged, and currently requires maintenance doses of >10 milligrams (mg)prednisone or equivalent per day.

• Participant has any plan to receive a live attenuated vaccine during studyintervention or has received a live vaccine within 30 days before the first dose ofstudy intervention. Examples of live vaccines include, but are not limited tomeasles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies,Bacillus Calmette-Guérin, and typhoid vaccine. Seasonal influenza vaccines andnon-live coronavirus disease 2019 (COVID-19) for injection are generally allowed.

• Participant has reversible toxicities from prior cancer therapy that have notrecovered to Grade 1 or baseline. Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria for AEs (CTCAE) Grade ≥2 from previous anticancertherapy with the exception of alopecia, vitiligo, and prespecified laboratoryvalues.

• Participant who is pregnant, breastfeeding, or is of childbearing potential, definedas those who are capable of becoming pregnant who are not willing to employ a highlyeffective method of contraception during dosing and for 90 days after the last doseof mRNA-4359 or 120 days after the last dose of pembrolizumab, whichever is longer.

• Sexually active participants who refuse to use a condom during intercourse orparticipants who will not refrain from sperm donation while taking studyintervention and for 90 days after the last dose of mRNA-4359 or 120 days after thelast dose of pembrolizumab, whichever is longer.

• Participant has any unstable or clinically significant concurrent medical condition (for example, substance abuse, uncontrolled intercurrent illness including activeinfection, arterial thrombosis, and symptomatic pulmonary embolism) that would, inthe opinion of the Investigator, jeopardize the safety of a participant, impacttheir expected survival through the end of the study participation, and/or impacttheir ability to comply with the protocol. Also including but not limited to,ongoing or active infection, interstitial lung disease, serious chronicgastrointestinal conditions associated with diarrhea, active gastrointestinalbleeding or hemoptysis or history of bleeding disorder, or psychiatricillness/social situations that would limit compliance with study requirement,substantially increase risk of incurring AEs, or compromise the ability of theparticipant to give written informed consent.

• Participant has concurrent enrollment in another clinical study (unless it is anobservational noninterventional clinical study) or during the follow-up period of aninterventional study.