This is a pilot study determining the feasibility of combination treatments, pembrolizumab and stereotactic ablative radiotherapy (SBRT) in subjects with soft-tissue sarcoma. These are subjects who have metastatic disease initially, or recurrent or progressive disease that is not eligible for curative surgery.

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed soft-tissue sarcoma, or a soft-tissue sarcoma with tumor mutational burden ≥10 mut/Mb.

• Patient must either have started a checkpoint inhibitor immunotherapy regimen within 60 days, or have a soft-tissue sarcoma histology amenable to pembrolizumab therapy (inclusive of undifferentiated pleomorphic sarcoma [formerly known as malignant fibrous histiocytoma], myxofibrosarcoma, dedifferentiated liposarcoma or undifferentiated sarcoma [unclassified histology]).

• Patients with soft-tissue sarcoma must have advanced disease (stage IV) or previously treated disease that has become progressive, recurrent, or metastatic, and either previously received first-line systemic therapy or been deemed ineligible to receive first-line systemic therapy. Staging is by AJCC 8th Edition.

• Must not have disease amenable to curative intent surgery.

• Must have at least 2 measurable lesions per RECIST v1.1 assessed by CT scan. A measurable lesion is defined to mean at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >20 mm with conventional techniques or as >10 mm with spiral CT scan.

• Must have at least 1 site of non-central nervous system (CNS) disease amenable to treatment with radiation therapy. This lesion may have been previously treated with radiation if the cumulative spinal cord dose will remain below a Biologically Effective Dose (BED)α/β 2Gy of 112 Gy (single fraction equivalent 14 Gy) and the radiation will be delivered at least 180 days after completion of the prior radiation course to the same site. BED will be calculated using the linear-quadratic formula: d * f * (1 + [d / (α/β)]), where d is the dose per fraction, f is the total number of fractions, and α/β is the property of irradiated tissue measured in Gray.

• Must be age ≥ 18 years. Because initial and subsequent therapies for pediatric sarcomas (<18 years of age) are different than those ≥18, children are excluded from this study. In addition, because no adverse event data are currently available on the use of SBRT combined with pembrolizumab in patients <18 years of age, children are excluded from this study but will be eligible for future pediatric trials, if applicable.

  1. Both men and women and members of all races and ethnic groups are eligible for this trial. Non-English speaking, deaf, hard of hearing and illiterate individuals are eligible for this trial

• Performance status: ECOG performance status ≤2 (Karnofsky ≥50%).

• Life expectancy of ≥3 months.

• Adequate organ and marrow function as defined below. Labs should be performed within 14 days of treatment.

  1. Leukocytes ≥2,000/mcL
  2. Absolute neutrophil count ≥1,000/mcL
  3. Platelets ≥75,000/mcL
  4. AST(SGOT)/ALT(SPGT) ≤3 times institutional upper limit of normal (ULN), or ≤5 times ULN for patients with liver metastases
  5. Total bilirubin ≤2.5 times institutional ULN
  6. Serum creatinine ≤2.5 times institutional ULN, or calculated creatinine clearance ≥30 mL/min (if serum creatinine >2.5 times institutional ULN)
  7. Thyroid stimulating hormone within institutional limits, or T4 is within institutional limits if TSH is outside of institutional limits

• Female patients of childbearing potential must have a negative urine or serum pregnancy within 72 hours before receiving the first dose of pembrolizumab. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

• The effects of pembrolizumab and ionizing radiation on the developing human fetus are known to have the potential for congenital abnormalities and fetal harm. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 120 days following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

  1. A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

  1. Has not undergone a hysterectomy or bilateral oophorectomy; or
  2. Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).

• Patients who are HIV-positive with undetectable HIV viral load are eligible provided they meet all other protocol criteria for participation.

• Patients with HBV or HCV infection are eligible provided viral loads are undetectable. Patients on suppressive therapy are eligible.

• Patients must not be on active immunosuppression within 7 days prior to the first dose of treatment.

• Patients must not have a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.

• Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 2 weeks prior to initiation of study therapy.

• Patients who have not recovered from adverse events due to prior anti-cancer therapy administered.

• Patients must not be receiving any other investigational agents.

• Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to pembrolizumab.

• Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

• Patients must not be pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.

  1. Pembrolizumab can cause fetal harm when administered to a pregnant woman based on the biological mechanism that PD-1/PD-L1 signaling is an important pathway in the maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue.1 Human IgG4 is known to cross the placenta. Animal models have found that blocking PD-L1 signaling increases the risk of fetal loss, and immune-mediated disorders occurred in PD-1 knockout mice.
  2. Although there are not data on the presence of pembrolizumab in either animal or human milk or its effects on breastfed children or on milk production, there is a potential for serious adverse reactions in breastfed children. Thus, women are advised not to breastfeed during treatment with pembrolizumab and for 120 days after the final dose.

• Patients with disease amenable to curative intent surgery.

• Patient has had a prior monoclonal antibody for treatment of sarcoma, unless the current regimen is checkpoint inhibitor immunotherapy.

• Patient has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin.

• Patient has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Patients with resolved childhood asthma, hypothyroidism stable on hormone replacement, Sjogren's syndrome, or with vitiligo would not be excluded. Patients requiring intermittent bronchodilators, inhaled steroids, or local steroid injections would not be excluded. Patients requiring physiologic doses of corticosteroids may be approved after consultation with the protocol principal investigator.