MK-3475 in Melanoma and NSCLC Patients With Brain Metastases

1. Biopsy proven metastatic melanoma or NSCLC as follows:

   1. Patients with metastatic melanoma must have untreated brain metastases including:

      • At least one cerebral metastasis that requires local intervention and is amenable to craniotomy or LITT therapy either due to symptoms, lesion size, location, edema or hemorrhage ("surgical lesion"). Alternatively, a patient may be eligible if a cerebral metastasis was resected or biopsied any time prior to enrollment and there is tumor tissue available for analysis.
      • At least one cerebral metastasis that is at least 5 mm AND twice the MRI slice thickness, but less than 20 mm, that is asymptomatic and does not require local therapy at the time of enrollment ("clinically evaluable lesion(s)"). OR
   2. Patients with stage IV NSCLC with at least one cerebral metastasis that is at least 5 mm AND twice the MRI slice thickness, but less than 20 mm, that is asymptomatic and does not require local therapy at the time of enrollment ("clinically evaluable lesion(s)").
2. Age ≥18
3. ECOG performance status \< 2
4. 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 MK-3475 with the exception of bevacizumab which must have been administered at least 4 weeks prior to MK-3475. Patients are not required to have had prior systemic therapy. The exception to this is patients with NSCLC who test negative for PD-L1 expression or are unevaluable for PD-L1 expression must have received prior platinum-based chemotherapy for entry into Cohort 2. Note: Ipilimumab treatment should have been administered at least 4 weeks prior to the start of MK-3475.
5. Life expectancy of at least 3 months
6. A history of previously treated brain metastases is allowed, provided that at least 14 days have lapsed between radiation and initiation of MK-3475. Any lesion present at the time of WBRT or included in the stereotactic radiotherapy field (or within 2mm of the treated lesion) will NOT be considered evaluable unless it is new or documented to have progressed since treatment.
7. PD-L1 expression in tumor tissue from any site is required for patients with NSCLC for entry into Cohort 1. Tumor tissue must be obtained after the last systemic therapy. PD-L1 expression will be analyzed by a Merck assay. For NSCLC Cohort 2, patients may test PD-L1 negative or may be unevaluable for PD-L1 expression (i.e. insufficient tumor tissue). PD-L1 expression is not required for patients with melanoma, but melanoma patients are required to submit an extra-cerebral specimen for analysis, unless it is not feasible to obtain one.
8. Patients must have normal organ and marrow function as defined per protocol.
9. For women of childbearing potential, agreement to the use of two acceptable methods of contraception, including one barrier method, during the study and for 6 months after discontinuation of MK-3475.
10. For men with female partners of childbearing potential, agreement to use a latex condom, and to advise their female partner to use an additional method of contraception during the study and for 6 months after discontinuation of MK-3475.
11. Negative serum or urine pregnancy test within 72 hours of commencement of treatment in premenopausal women.
12. Patients must have the ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. Symptomatic brain metastases. Symptoms may be present from the surgical lesion prior to resection or LITT but must have resolved by the time of administration of study drug.
2. Patients with brain metastases for whom complete surgical resection is clinically appropriate.

3. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy to the lung or brain 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. Previous radiation to other sites may be completed at any time prior to initiation of MK-3475.

   1. Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
   2. Note: Toxicity that has not recovered to ≤ Grade 1 is allowed if it meets the inclusion requirements for laboratory parameters.
4. Has had prior treatment with any other anti-PD-1 or PD-L1 or PD-L2 agent or an antibody targeting other immune-regulatory receptors or mechanisms. Examples of such antibodies include (but are not limited to) antibodies against IDO, PD-L1, IL-2R, GITR. Prior ipilimumab, IL2, bevacizumab and adoptive cell therapy is allowed.
5. The use of corticosteroids to control cerebral edema or treat neurologic symptoms will not be allowed, and patients who previously required corticosteroids for symptom control must be off steroids for at least 2 weeks. Low-dose steroid use (≤10 mg of prednisone or equivalent) as corticosteroid replacement therapy is allowed
6. Has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
7. Presence of leptomeningeal disease
8. Has an active automimmune 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. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of inhaled steroids or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study.

9. Pregnancy or breast feeding. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

   Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with MK-3475, breastfeeding must be discontinued if the mother is treated with MK-3475.

10. Patients may not be receiving any other investigational agents and may not have participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment.
11. Either a concurrent condition (including medical illness, such as active infection requiring treatment with intravenous antibiotics or the presence of laboratory abnormalities) or history of a prior condition that places the patient at unacceptable risk if he/she were treated with the study drug or a medical condition that confounds the ability to interpret data from the study.
12. Concurrent, active malignancies in addition to those being studied (other than cutaneous squamous cell carcinoma or basal cell carcinoma)
13. Any contraindication to MRI (i.e. patients with pacemakers or other metal implanted medical devices). An MRI safety questionnaire is required prior to MR imaging.
14. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
15. Has a known Human Immunodeficiency Virus (HIV), Hepatitis B (HBV), or Hepatitis C (HCV) infection.
16. Has received a live vaccine within 30 days prior to the first dose of trial treatment.
17. Evidence of interstitial lung disease