A Study of (Neo)Adjuvant Intismeran Autogene (V940) and Pembrolizumab in Cutaneous Squamous Cell Carcinoma (V940-007)

Inclusion Criteria:

• Has a histologically confirmed diagnosis of resectable cSCC as the primary site ofmalignancy (metastatic skin involvement from another primary cancer or from anunknown primary cancer is not permitted).

• Has LA Stage II-IV (M0) cSCC without distant metastases.

• cSCC must be amenable to surgery (resectable) with curative intent.

• Has a formalin-fixed, paraffin-embedded (FFPE) tumor sample available or is able toprovide one that is suitable for the Next-generation Sequencing (NGS) required forthis study.

• For males, agrees to be abstinent from penile-vaginal intercourse OR agrees to use ahighly effective contraceptive method while receiving adjuvant radiation therapy (RT), and for ≥3 months after the last dose of study intervention

• Is female and not pregnant/breastfeeding and at least one of the following appliesduring the study : is not a woman of childbearing potential (WOCBP), is a WOCBP anduses highly effective contraception (low user dependency method OR a user dependenthormonal method in combination with a barrier method) at least during use ofintismeran autogene: 15 days, Pembrolizumab: 120 days, Adjuvant RT, if performed: 90days after last exposure or is a WOCBP who is abstinent from heterosexualintercourse.

• Has measurable disease per RECIST 1.1 as assessed by the local siteinvestigator/radiology.

• Has a life expectancy of >3 months per investigator assessment.

• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1assessed within 14 days before randomization.

• Has adequate organ function.

• If hepatitis B surface antigen (HBsAg) positive, must have received hepatitis Bvirus (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV viralload prior to randomization

• If there is a history of hepatitis C virus (HCV) infection, HCV viral load must beundetectable at screening

• If human immunodeficiency virus (HIV)-infected, must have well controlled HIV onantiretroviral therapy (ART)

Exclusion Criteria:

• Has any other histologic type of skin cancer other than invasive cSCC as well asmixed histology, eg, basal cell carcinoma that has not been definitively treatedwith surgery or radiation, Bowen's disease, Merkel cell carcinoma (MCC), or melanoma

• Has distant metastatic disease (M1), visceral and/or distant nodal

• Has received prior therapy with an anti-programmed cell death receptor 1 (anti-PD-1), anti-programmed cell death receptor ligand 1 (anti-PD-L1), oranti-programmed cell death receptor ligand 2 (anti-PD-L2) agent, or with an agentdirected to another stimulatory or coinhibitory T-cell receptor (e.g., cytotoxicT-lymphocyte associated protein 4 (CTLA-4), OX-40, CD137)

• Has received prior systemic anticancer therapy including investigational agents forcSCC before randomization

• Has received prior radiotherapy within 2 weeks of start of study intervention, orhas radiation-related toxicities, requiring corticosteroids

• Has received a live or live-attenuated vaccine within 30 days before the first doseof study intervention

• Has received transfusion of blood products (including platelets or red blood cells)or administration of colony stimulating factors (including granulocytecolony-stimulating factor, granulocyte macrophage colony-stimulating factor, orrecombinant erythropoietin) within 2 weeks of the screening blood sample (includingthe NGS blood sample)

• Has received prior treatment with another cancer vaccine

• Has received prior radiotherapy to the index lesion (in-field lesion). Must haverecovered from all radiation-related toxicities prior to randomization and not havehad radiation pneumonitis

• Has received an investigational agent or has used an investigational device within 4weeks prior to study intervention administration

• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form ofimmunosuppressive therapy within 7 days prior the first dose of study medication

• Has a known additional malignancy that is progressing or has required activetreatment within the past 2 years

• History of chronic lymphocytic leukemia (CLL)

• History of central nervous system (CNS) metastases and/or carcinomatous meningitis

• Has severe hypersensitivity (≥Grade 3) to either intismeran autogene orpembrolizumab and/or any of its excipients

• Has an active autoimmune disease that has required systemic treatment in the past 2years. Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid)is allowed

• History of (noninfectious) pneumonitis/interstitial lung disease that requiredsteroids or has current pneumonitis/interstitial lung disease

• Has an active infection requiring systemic therapy

• Has HIV with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease

• Has concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBVDNA) and Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA)infection

• Has had a myocardial infarction within 6 months of randomization

• History of allogeneic tissue/solid organ transplant

• Has not adequately recovered from major surgery or have ongoing surgicalcomplications