Patient case: 86-year-old female with melanoma; genetic feature: high tumor mutational burden

Clinical trial: Pembrolizumab and Stereotactic Radiosurgery for Melanoma or Non-Small Cell Lung Cancer Brain Metastases

Summary: This pilot trial studies the side effects of giving pembrolizumab together with stereotactic radiosurgery to treat patients with melanoma or non-small cell lung cancer that has spread to the brain. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Stereotactic radiosurgery is a specialized radiation therapy that delivers a single, high dose of radiation directly to the tumor and may cause less damage to normal tissue. Giving pembrolizumab together with stereotactic radiosurgery may be a better treatment for patients with melanoma or non-small cell lung cancer that has spread to the brain.

Detailed description: PRIMARY OBJECTIVES:
  I. To determine the safety of three different stereotactic radiosurgery (SRS) radiation arms in combination with pembrolizumab for melanoma and non-small cell lung cancer (NSCLC) brain metastasis (BM) patients.
  SECONDARY OBJECTIVES:
  I. To evaluate intracranial outcomes - control of the treated lesion in the brain with SRS+ pembrolizumab (i.e. local control), development of additional sites of disease in the brain that were not initially treated with SRS (i.e. anywhere intra-cranial failure), intra-cranial progression free survival (local control of the area that received SRS and anywhere intra-cranial failure), extra-cranial disease response (overall progression free survival), rate of leptomeningeal dissemination, and overall survival.
  II. To determine the overall response rate and overall survival of combination SRS and pembrolizumab compared to SRS alone (historical control).
  III. To determine the overall response rate and overall survival of combination SRS and pembrolizumab compared to pembrolizumab alone (historical control).
  IV. To evaluate treatment response at un-irradiated and extra-cranial sites (i.e. the abscopal effect) with all three arms.
  V. To compare differences in potential immune biomarkers, pretreatment, during treatment, and post treatment.
  OUTLINE: Patients are assigned to 1 of 3 arms.
  ARM A (SRS 6 Gy): Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Courses repeat every 3 weeks (Q3W) for at least 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo 5 SRS fractions between days 2-15 of course 1.
  ARM B (SRS 9 Gy): Patients receive pembrolizumab IV as in Arm A. Patients undergo 3 SRS fractions between days 2-15 of course 1.
  ARM C (SRS 18-21 Gy): Patients receive pembrolizumab IV as in Arm A. Patients undergo 1 SRS fraction between days 2-3 of course 1.
  After completion of study treatment, patients are followed up every 12 weeks or at physician's discretion by radiologic imaging to monitor disease.

Eligibility: Inclusion Criteria:
  -  Be willing and able to provide written informed consent/assent for the trial
  -  Eastern Cooperative Oncology Group (ECOG) performance scale (PS) of 0-1; Karnofsky performance status ≥ 70%
  -  Patients must have histological diagnosis of melanoma or non-small cell lung cancer (biopsy will be done per standard of care, if needed to prove metastatic melanoma and/or NSCLC as well as for clinically relevant mutation analysis); additional biopsy will be per standard of care
  -  Patients can be treated either in first line or in the refractory setting; PD-L1 positivity is not required for enrollment
  -  All melanoma patients should be tested for proto-oncogene B-Raf (BRAF) as part of routine standard of care; All NSCLC patients should be tested for with epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) as part of standard of care
  -  Patients with ocular, mucosal and unknown primary melanoma will also be eligible
  -  Patients with 1-10 untreated brain metastases at time of initial brain metastases diagnosis (surgery to one of the brain lesions and/or biopsy of a lesion for diagnostic purposes and/or for standard of care purposes is acceptable)
  -  Largest brain metastases volume measures less than 14.15 cc³
  -  Prior radiation to the primary and/or regional radiotherapy for melanoma and/or NSCLC is acceptable
  -  Baseline labs as within standard of care (complete blood count [CBC], basic metabolic panel [BMP], lactate dehydrogenase [LDH], erythrocyte sedimentation rate [ESR], etc) are required within 14 days of enrollment
  -  Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
  -  Patients must have at least 14 days to recover from all prior treatment, including surgery, chemotherapy, immunotherapies, prior to enrollment on this protocol
  -  Demonstrate adequate organ function, all screening labs should be performed within 14 days of treatment initiation
  -  Absolute neutrophil count (ANC) ≥ 1,500/mcL
  -  Platelets ≥ 100,000/microliters (mcL)
  -  Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment)
  -  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 (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
  -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases
  -  Albumin ≥ 2.5 mg/dL
  -  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
  -  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
  -  Female subject of childbearing potential should have a negative urine or serum pregnancy within 2 weeks prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
  -  Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
  -  Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy
  -  Abstinence is acceptable, if this is the usual life style and preferred contraception for the patient
  Exclusion Criteria:
  -  Has received prior therapy with an anti-programmed cell death (PD)-1, anti- programmed cell death ligand (PD-L)1, or anti-PD-L2 agent
  -  Has received prior whole brain radiation therapy and or SRS for brain metastases
  -  Patient is symptomatic and as a result is requiring steroids at time of the start of therapy
  -  Patients must be off of steroids for at least two weeks prior to cycle 1, day 1 (i.e, start of SRS and PD-1)
  -  They can get steroids anytime after completion of cycle 1, if clinically indicated, especially for the management of their side effects
  -  Symptomatic patients requiring other medications (i.e. anti-seizure medications) are still eligible
  -  If they have brain metastases located in the brain stem (including midbrain, pons, or medulla)
  -  Inability to undergo magnetic resonance imaging (MRI) evaluation for treatment planning and follow-up
  -  Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
  -  Has a diagnosis of immunodeficiency or 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 to pembrolizumab or any of its recipients
  -  Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., ≤ grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
  -  Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., ≤ grade 1 or at baseline) from adverse events due to a previously administered agent.
  -  Note: Subjects with ≤ grade 2 neuropathy are an exception to this criterion and may qualify for the study
  -  Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
  -  Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
  -  Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
  -  Has known history of (non-infectious) pneumonitis that required steroids or current pneumonitis
  -  Has an active infection requiring systemic therapy
  -  Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
  -  Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
  -  Is pregnant 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
  -  Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
  -  Has known active hepatitis B (e.g., hepatitis B specific antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
  -  Has received a live vaccine within 30 days of planned start of study therapy
  -  Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed

Relevance to patient case: not relevant