Pembrolizumab Plus Bevacizumab for Treatment of Brain Metastases in Metastatic Melanoma or Non-small Cell Lung Cancer

Major Inclusion Criteria:

1. Biopsy proven metastatic melanoma or non-squamous NSCLC with at least one untreatedbrain metastasis that is at least 5 mm AND twice the MRI slice thickness, but lessthan 20 mm, which is asymptomatic and not requiring immediate local therapy orsteroids.

2. Patients who have had prior resection or biopsy of a CNS metastasis will be requiredto provide a paraffin embedded specimen from tumor taken at the time of surgery, ifavailable.

3. Patients will be required to undergo biopsy or submit archival tumor tissue from asystemic site of disease for correlative studies. When not feasible, thisrequirement can be waived after discussion with the principal investigators.

4. PD-L1 expression in tumor tissue from any site determined by the Dako 22C3 assay isrequired for patients with NSCLC.

5. Adequate organ function.

6. ECOG performance status < 2.

7. Any number of previous treatments with the exception of previous inhibitors of PD-1or PD-L1.

8. Life expectancy of at least 3 months.

9. Understanding and willingness to consent.

10. A history of radiotherapy for brain metastases is allowed, but any lesion present atthe time of WBRT or included in the stereotactic radiotherapy field will NOT beconsidered evaluable unless documented to have progressed since treatment.

Overall Inclusion Criteria:

1. Biopsy proven metastatic melanoma or non-squamous NSCLC with at least one untreatedcerebral metastasis that is at least 5 mm AND twice the MRI slice thickness, butless than 20 mm, that is asymptomatic and does not require local therapy at the timeof enrollment ("clinically evaluable lesion(s)"). An untreated brain metastasis isdefined as a lesion not present at the time of whole brain radiation therapy orincluded in a stereotactic radiotherapy field (or within 2mm of a treated lesion),or any lesion that is new or unequivocally progressing since prior radiationtherapy.

2. ECOG performance status < 2

3. Any number of previous treatments with the exception of previous inhibitors of PD-1,PD-L1, or PD-L2. Other prior systemic therapies must have been administered at least 2 weeks before administration of pembrolizumab; the exception to this is ipilimumabwhich must have been administered at least 4 weeks prior to the start ofpembrolizumab. Patients are not required to have had prior systemic therapy.

4. Life expectancy of at least 3 months

5. A history of previously treated brain metastases is allowed, provided that at least 7 days have lapsed between radiation and initiation of pembrolizumab. Any brainmetastasis ≥ 20mm or causing symptoms must be treated with local therapy (i.e.radiation or surgical resection, as clinically appropriate) prior to studyenrollment. Any lesion present at the time of WBRT or included in the stereotacticradiotherapy field (or within 2mm of the treated lesion) will NOT be consideredevaluable unless it is new or documented to have progressed since treatment.

6. PD-L1 expression >1% in tumor tissue from any site is required for patients withNSCLC. Tumor tissue can be archival if no intercurrent systemic therapy wasadministered, however if no archival tissue is available or if intercurrent systemictherapy was administered, then a biopsy must be obtained for PD-L1 testing. PD-L1expression must be obtained using the Dako 22C3 assay in a CLIA-certifiedlaboratory. PD-L1 expression is not required for patients with melanoma.

7. All patients are required to submit a tumor specimen for analysis (brain orextra-cerebral). A formalin-fixed paraffin-embedded (FFPE) tissue block, or a 4mmpunch from an FFPE block must be submitted. If it is not possible to safely obtain abiopsy due to anatomic location of tumors, and no prior tissue is available, thisrequirement may be waived upon discussion with the study PI or co-PI.

8. Patients must have normal organ and marrow function (as defined in the protocol) atthe time of screening.

9. Female subject of childbearing potential should have a negative urine or serumpregnancy within 72 hours prior to receiving the first dose of study medication. Ifthe urine test is positive or cannot be confirmed as negative, a serum pregnancytest will be required.

10. Female subjects of childbearing potential should be willing to use 2 methods ofbirth control or be surgically sterile, or abstain from heterosexual activity forthe 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 sterilizedor have not been free from menses for > 1 year.

11. Male subjects should agree to use an adequate method of contraception starting withthe first dose of study therapy through 120 days after the last dose of studytherapy.

Major Exclusion Criteria:

1. Symptomatic brain metastases at the time of initiation of systemic therapy.

2. Other systemic therapy within 14 days of initiation of study drug.

3. Use of corticosteroids to control CNS symptoms. Low-dose steroid use (≤10 mg ofprednisone or equivalent) is allowed.

4. Presence of leptomeningeal disease.

5. Presence of active autoimmune disease. Autoimmune thyroid disease will be allowed ifthyroid function is within normal range.

Overall Exclusion Criteria:

1. Symptomatic brain metastases. Any neurologic symptoms present must have resolvedwith local therapy by the time of administration of study drug.

2. Patients with brain metastases for whom complete surgical resection is clinicallyappropriate.

3. Patients with lung cancer with squamous histology.

4. Has had prior chemotherapy or targeted small molecule therapy within 2 weeks priorto start of treatment or who has not recovered (i.e., ≤ Grade 1 or at baseline) fromadverse events due to a previously administered agent. Previous radiation toextracranial sites may be completed at any time prior to initiation ofpembrolizumab.

5. Note: If subject received major surgery, they must have recovered adequatelyfrom the toxicity and/or complications from the intervention prior to startingtherapy.

6. Note: Toxicity that has not recovered to ≤ Grade 1 is allowed if it meets theinclusion requirements for laboratory parameters.

7. Has had prior treatment with any other anti-PD-1 or PD-L1 or PD-L2 agent.

8. The use of corticosteroids to control cerebral edema or treat neurologic symptomswill not be allowed, and patients who previously required corticosteroids forsymptom control must be off steroids for at least 1 week prior to treatment on day 1of cycle 1. Low-dose steroid use (≤10 mg of prednisone or equivalent) ascorticosteroid replacement therapy is allowed

9. Has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agentsadministered more than 4 weeks earlier.

10. Presence of leptomeningeal disease

11. Has active autoimmune disease that has required systemic treatment in the past 2years (i.e. with use of disease modifying agents, corticosteroids orimmunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency, etc.) is not considered a form of systemic treatment.

12. Pregnancy or breast feeding. Should a woman become pregnant or suspect she ispregnant while participating in this study, she should inform her treating physicianimmediately. Because there is an unknown but potential risk for adverse events innursing infants secondary to treatment of the mother with pembrolizumab,breastfeeding must be discontinued if the mother is treated with pembrolizumab.

13. Patients may not be receiving any other investigational agents and may not haveparticipated in a study of an investigational agent or using an investigationaldevice within 4 weeks of the first dose of treatment.

14. Either a concurrent condition (including medical illness, such as active infectionrequiring treatment with intravenous antibiotics or the presence of laboratoryabnormalities) or history of a prior condition that places the patient atunacceptable risk if he/she were treated with the study drug or a medical conditionthat confounds the ability to interpret data from the study.

15. Concurrent, active malignancies in addition to those being studied (other thancutaneous squamous cell carcinoma or basal cell carcinoma)

16. Patients with active hemoptysis.

17. Any contraindication to MRI (i.e. patients with pacemakers or other metal implantedmedical devices). An MRI safety questionnaire is required prior to MR imaging.

18. Has a history of (non-infectious) pneumonitis that required steroids or currentpneumonitis.

19. Has a known Human Immunodeficiency Virus (HIV), Hepatitis B (HBV), or Hepatitis C (HCV) infection.

20. Has received a live vaccine within 30 days prior to the first dose of trialtreatment.

21. Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHgand/or diastolic blood pressure > 100 mmHg). Anti-hypertensive therapy to achievethese parameters is allowable.

22. History of myocardial infarction or unstable angina within 3 months prior to Cycle 1, Day 1

23. History of stroke or transient ischemic attack within 3 months prior to Cycle 1, Day 1

24. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair orrecent peripheral arterial thrombosis) within 6 months prior to Cycle 1, Day 1

25. Evidence of bleeding diathesis or clinically significant coagulopathy (in theabsence of therapeutic anticoagulation). Any history of significant bleeding orthrombosis should be discussed the study PIs.

26. Current or recent (within 10 calendar days prior to Cycle 1, Day 1) use ofdipyramidole, ticlopidine, clopidogrel, or cilostazol

27. Warfarin is not permitted. Prophylactic or therapeutic use of low molecular-weightheparin (e.g., enoxaparin) or direct thrombin inhibitors are permitted.

28. History of abdominal or tracheoesophageal fistula or gastrointestinal perforationwithin 6 months prior to Cycle 1, Day 1

29. Serious, non-healing or dehiscing wound

30. Proteinuria > 2.0 g of protein in a 24-hour urine collection. All patients with 2protein on dipstick urinalysis at baseline must undergo a 24-hour urine collectionfor protein.

31. Has a history of (non-infectious) pneumonitis that required steroids, currentpneumonitis or evidence of interstitial lung disease.