Pembrolizumab Plus Lenvatinib in Unresectable Cutaneous Angiosarcoma Patients

Inclusion Criteria: 1. Histologically diagnosed with cutaneous angiosarcoma. 2. Unresectable primary or metastatic disease. 3. No spinal metastases that require radiotherapy or surgical intervention. 4. No pericardial effusion, pleural effusion, or ascites that require treatment. 5. Age at enrollment: 18 years or older and 85 years or younger. 6. The most recent performance status score (ECOG) within 14 days prior to enrollment is 0 or 1. 7. A contrast-enhanced CT/MRI (head, neck, chest, abdomen, pelvis: slice thickness 5 mm or less) performed within 14 days prior to enrollment or have at least one measurable lesion that can be confirmed to be present on the surface of the body by visual inspection (for patients with contrast allergy or renal function deterioration, plain CT is allowed). 8. Cohort A (untreated patients): Cutaneous angiosarcoma without prior therapy. Cohort B (previously treated patients): Cutaneous angiosarcoma with prior therapy. 9. Have adequately controlled BP with or without antihypertensive medications (of 2 or less counted by components), defined as BP \<=150/90 mmHg with no change in antihypertensive medications within 7 days prior to enrollment. 10. Wounds (e.g., those after a surgical procedure or trauma) have healed at enrollment. 11. Did not have major surgery within 21 days prior to the first dose of study interventions. Note: Adequate wound healing after major surgery must be assessed clinically, independent of time elapsed for eligibility. 12. Laboratory tests performed within 14 days before the enrollment date meet the following criteria: (1) to (10). However, patients should not receive granulocyte colony-stimulating factor (G-CSF) or blood transfusions within 14 days before the day of blood collection. (1) Neutrophil count \>=1,500/mm3 (2) Platelet count \>=10×104/mm3 (3) Hemoglobin \>=9.0 g/dL (4) AST \<=100 U/L (5) ALT\<=100 U/L (6) Total bilirubin \<=1.5 mg/dL (7) Serum creatinine \<=1.5 mg/dL (8) Creatinine/clearance \>=30 mL/min (Cockcroft-Gault). (Even if the calculated value is less than 30 mL/min, it can be registered if the value is more than 30 mL/min by the 24-hour urine collection method). (9) Urine protein \<1 g/24 hours. Note: Participants with proteinuria \>=2+ on urine dipstick testing (urinalysis) will undergo 24-hour urine collection for quantitative assessment of proteinuria. (10) PT-INR \<=1.5 13) Male patients agree to use highly effective contraception and not donate sperm during treatment and for at least 120 days after the last dose of the investigational drugs. Female patients agree to use contraception methods, are not pregnant or breastfeeding, and at least one of the following conditions applies: * Is not a woman of childbearing potential (WOCBP). * Is a WOCBP tested negative by pregnancy test within 14 days prior to enrollment, and using a contraceptive method that is highly effective, with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle during the intervention period and for at least 120 days post pembrolizumab or 30 days post lenvatinib, whichever occurs last. A WOCBP must have a negative result of a highly sensitive pregnancy test within 24 hours before the first dose of study intervention. 14\) Twenty-eight days have passed since the last day of prior chemotherapy if applicable, and the patient has recovered from all toxicities except alopecia and blood toxicity (below Grade 1 or to baseline). 15\) Written informed consent for study participation has been obtained from the patient. Exclusion Criteria: 1. Persons previously treated with anti-PD-1, anti-PD-L1, anti-PD-L2 agents, or agents targeting other co-inhibitory T-cell receptors (e.g., CTLA-4, OX-40, CD137). 2. Individuals previously treated with lenvatinib or another angiogenesis inhibitor, including treatment for other cancer types. 3. Patients who are likely to be cured with chemoradiotherapy, at the discretion of the treating physician. 4. Patients who received radiation therapy within 14 days prior to enrollment or patients with radiation therapy-related toxicities at enrollment. 5. Patients positive for either HIV antibody, HBs antigen, or HCV antibody. 6. Patients of HBs antigen-negative, HBs antibody, or HBc antibody-positive, and HBV-DNA assay-positive. 7. Patients receiving live or live attenuated vaccines within 30 days of enrollment. 8. Patients who received other investigational products or used investigational medical devices within 28 days prior to enrollment. 9. Patients diagnosed as being in an immunocompromised state or patients treated with long-term systemic steroidal therapy or other immunosuppressive therapies in the 14 days prior to enrollment. 10. Patients with other malignancies requiring progressive or aggressive treatment within the past 3 years. 11. Patients with active CNS metastases or carcinomatous meningitis. 12. Patients with severe (\>= Grade 3) hypersensitivity to pembrolizumab or lenvatinib additives. 13. Patients with active autoimmune disease requiring systemic treatment, excluding replacement therapy within the past 2 years. 14. Patients with a history of interstitial lung disease/pneumonitis complicated by interstitial lung disease/pneumonitis or interstitial lung disease/pneumonitis requiring steroid administration (non-infectious). 15. Patients with active infections requiring systemic treatment at enrollment. 16. Patients with preexisting \>=Grade 3 gastrointestinal or non-gastrointestinal fistula at enrollment. 17. Patients with gastrointestinal malabsorption or any other condition that might affect the absorption of lenvatinib. 18. Patients with a history of acute coronary syndrome, coronary angioplasty, or stenting within 6 months prior to enrollment. 19. Patients with clinically significant cardiovascular diseases within the 12 months prior to enrollment. 20. Patients having left ventricular ejection fraction (LVEF) below 50% within 14 days before the date of enrollment. 21. Patients with complications requiring hospitalization. 22. Patients with radiographic evidence of encasement or invasion of a major blood vessel, or of intratumoral cavitation. 23. Patients with QTcF spacing prolongation beyond 480 msec within 14 days prior to enrollment. 24. Patients with active hemoptysis in the 21 days prior to enrollment. 25. Patients who have comorbid psychotic or psychiatric symptoms or substance use disorders that interfere with daily life. 26. Patients with a history of allogeneic transplantation.