Pembrolizumab and Radiation Therapy in Treating Patients With Intermediate or High-Grade Soft Tissue Sarcoma

This phase I/II trial studies pembrolizumab and radiation therapy in treating patients with intermediate or high-grade soft tissue sarcoma. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving pembrolizumab and radiation therapy may work better in treating patients with soft tissue sarcoma.

OUTLINE:

Patients receive pembrolizumab intravenously (IV) per institutional standard at the Seattle Cancer Care Alliance as an outpatient therapy. Cycles repeat every 3 weeks, up to a maximum of three doses, for 3 months in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy daily for 5-6 weeks beginning on Day 1 of Week 2.

After completion of study treatment, patients are followed up at 30 days after last dose, 90 days after last dose, 30 days after post-operative visit (wound care follow-up), and then every 12 weeks for up to 1 year, then every 6 months up to 5 years.

Eligibility Criteria:
Inclusion Criteria:

* Be willing and able to provide written informed consent for the trial
* Be ≥18 years of age on day of signing informed consent documents
* Have measurable disease based on RECIST 1.1
* Have newly diagnosed disease or localized recurrent or oligometastatic lesions that are candidates for radiation

  * NOTE: Subjects may not have any prior systemic therapy or radiation for this sarcoma. They may have received systemic therapy and/or radiation for a different cancer
  * NOTE: Oligometastatic disease will be defined as 3 or fewer detectable lesions with plans to radiate all detectable disease with conventionally fractionated radiation prior to resection
* Have an intermediate- or high-grade soft tissue sarcoma at the discretion of the reviewing Sarcoma pathologist
* The tumor must be at least 3 cm in maximum dimension for intermediate-grade tumors, or 1.5 cm in maximum dimension for high-grade tumors
* Have plans to undergo neo-adjuvant radiation and surgery with curative intent. A minimum of 45 Gy is necessary, planned to be administered over a minimum of 25 fractions
* Be willing to provide tissue from a newly obtained core incisional or excisional biopsy of a tumor lesion. Archival tissue from a recent clinical or research biopsy (within 90 days prior to Week 1 treatment) may be used in place of a fresh tissue biopsy
* Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale or \> 70% on the Karnofsky scale. Evaluation of performance status is to be performed within 7 days prior to the date of enrollment
* Absolute neutrophil count (ANC) \>= 1,500/mcL (performed within 28 days of enrollment)
* Platelets \>= 100,000/mcL (performed within 28 days of enrollment)
* Hemoglobin \>= 9 g/dL or \>= 5.6 mmol/L (performed within 28 days of enrollment)

  \* Criteria must be met without erythropoeiten dependency and without packed red blood cell (pRBC) transfusion within last two weeks
* Serum creatinine =\< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate \[GFR\] can also be used in place of creatinine or creatinine clearance \[CrCl\]) \>= 60 mL/min for subject with creatinine levels \> 1.5 X institutional ULN (performed within 28 days of enrollment)

  \* Creatinine clearance should be calculated per institutional standard
* Serum total bilirubin =\< 1.5 X ULN OR direct bilirubin =\< ULN for subjects with total bilirubin levels \> 1.5 ULN (performed within 28 days of enrollment)
* Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 X ULN (performed within 28 days of enrollment)
* Albumin \>= 2.5 mg/dL (performed within 28 days of enrollment)
* International normalized ratio (INR) or prothrombin time (PT) =\< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (performed within 28 days of enrollment)
* Activated partial thromboplastin time (aPTT) =\< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (performed within 28 days of enrollment)
* Female subjects of childbearing potential should have a negative serum pregnancy within 72 hours prior to receiving the first dose of study medication
* All individuals of child-bearing potential must be willing to use an adequate method of contraception, from the first dose of the study medication through 120 days after the last dose of study medication

Exclusion Criteria:

* Has had prior radiation to affected area
* Has one of the following sarcoma subtypes where neoadjuvant chemotherapy is established as practice at our institution: extra-skeletal Ewing's sarcoma, embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma

  \* NOTE: Pleomorphic rhabdomyosarcoma is allowed. Bone sarcomas including osteosarcoma, Ewing's sarcoma and chondrosarcoma are not allowed. Extra-skeletal Osteosarcoma is considered a soft tissue sarcoma and is allowed.
* Has a diagnosis of immunodeficiency or has an active autoimmune disease that has required systemic treatment in the past 2 years except replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid)
* Is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
* Has a known history of active TB (Bacillus tuberculosis)
* Hypersensitivity (\>= grade 3) to pembrolizumab and/or any of its excipients
* Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years

  \* NOTE: The time requirement does not apply to participants who underwent successful definitive resection of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, in situ cervical cancer, or other in-situ cancers
* Has current or a history of any distant metastatic disease (including brain)

  \*NOTE: An isolated or oligo-metastatic regional recurrence may be allowed if all other criteria are met, curative attempt is being pursued
* Has known history of (non-infectious) pneumonitis that required steroids, or has current evidence of pneumonitis
* Has an active infection requiring systemic therapy
* Has known psychiatric or substance abuse disorders that would interfere with adherence to the requirements of the trial
* Is pregnant (positive urine pregnancy test within 72 hours prior to enrollment) or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment. If a urine pregnancy test is positive or cannot be confirmed negative, a serum pregnancy test will be required
* Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-CTLA4 or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory 1-cell receptor (eg, CTLA-4, OX 40, CD137)
* Has a known history of human immunodeficiency virus (HIV) infection
* Has a known history of Hepatitis B (e.g., hepatitis B surface antigen \[HBsAg\] reactive) or Hepatitis C (e.g., hepatitis C virus \[HCV\] ribonucleic acid \[RNA\] \[qualitative\] is detected) infection
* Has received a live vaccine or live-attenuated vaccine within 30 days of planned start of study therapy. Administration of killed vaccines is allowed. Note: Any licensed coronavirus (COVID-19) vaccine (including for emergency use) is allowed in the study as long as they are messenger ribonucleic acid (mRNA) vaccines, adenoviral vaccines, or inactivated vaccines. These vaccines will be treated just as any other concomitant therapy. Investigational vaccines (i.e., those not licensed or approved for emergency use) are not allowed.
* Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration
* Has a history or current evidence of any condition, therapy, or laboratory abnormality or other circumstance that might confound the results of the study, interfere with the subject's participation for the full duration of the study, such that it is not in the best interest of the subject to participate, in the opinion of the treating investigator or has not adequately recovered from any major surgery or has ongoing surgical complications
* Has had an allogenic tissue/solid organ transplant