MK-3475 in Melanoma and NSCLC Patients With Brain Metastases

While recent advances in the treatment of metastatic melanoma and NSCLC (non-small cell lung
cancer) with agents targeting PD-1 are striking, there remains a significant need to develop
therapies for patients with untreated brain metastases who were excluded from prior trials
with MK-3475 and the majority of other studies in these diseases. The brain is a common site
of disease spread in many solid tumors, most notably metastatic melanoma and NSCLC. 10-40% of
patients with metastatic melanoma develop brain metastases during their lifetime and >75%
have brain metastases at autopsy. Overall, historical melanoma patient cohorts have reported
a median survival of patients with brain metastases in the order of 2.5 - 4 months despite
use of whole brain radiation therapy (WBRT) and surgery. One older patient series showed a
median survival of < 4 months in melanoma patients with brain metastases and a neurological
death rate of >30% despite the treatment of intracranial metastases with whole brain
radiation therapy (WBRT). Among those with NSCLC, 10% have brain metastases at presentation
and another 30% develop them over the course of their disease. Survival after the development
of brain metastases is as dismal in those with NSCLC as it is for melanoma. Multifocal
disease is common in both of these diseases, with about half of patients with CNS disease
presenting with more than one brain lesion.

Patients with untreated brain metastases have been excluded from most clinical trials of
systemic therapy for two reasons: (1) historically their prognosis has been poor (overall
survival ≤ 4 months) and (2) experimental drugs are presumed to not penetrate the blood brain
barrier (BBB) or BBB penetration is not well studied. In melanoma, for example, one phase III
study evaluating ipilimumab excluded patients with untreated brain metastases and another
study evaluating ipilimumab and dacarbazine excluded all patients with a history of brain
metastases, regardless of prior treatment. A subsequent trial with ipilimumab for patients
with untreated brain metastases indeed showed that the drug had some activity in treating CNS
disease. In the initial vemurafenib studies, patients with progressing or unstable CNS
metastases were excluded. The pivotal BRIM-3 trial excluded patients with brain metastases
unless metastases had been definitively treated more than three months prior to trial
enrollment. Both temodar and sorafenib cross the BBB. Initial studies with sorafenib alone
and in combination with chemotherapy excluded patients with active brain metastases. A
combination study of temodar and sorafenib in patients with or without brain metastases
showed modest activity in patients without a history of prior temodar, and was thought to be
favorable in part due to local therapies. Although a number of studies have been conducted
for melanoma patients with untreated brain metastases using established therapies, most
initial clinical trials with novel agents exclude these patients. A recent trial with
dabrafenib, an inhibitor of mutated B-raf, is an exception to the long-standing paradigm. A
phase I/II study of this agent included a subset of patients with untreated brain metastases.
At the 2010 meeting of the European Society for Medical Oncology, Long et al reported that
nine of the ten patients with untreated cerebral metastases enrolled in this trial had
shrinkage of their brain lesions. This was the basis for a recent phase II trial of
dabrafenib specific for patients with untreated brain metastases61. In NSCLC, a small number
of trials have shown that combination chemotherapy regimens can induce a response in the CNS
with untreated brain metastases with a median PFS up to 4 months. These studies demonstrate
that asymptomatic brain metastases, similar to asymptomatic metastases in other sites, can be
treated systemically on clinical trials, and that drug activity in the CNS is not necessarily
different than in other metastatic locations.

Current standard of care for brain metastases that require immediate local intervention
(based on symptoms, location, size, or other concerning features) is craniotomy with
resection or radiation therapy. As an adjunct to standard craniotomy, LITT is emerging as a
new, minimally invasive local therapy to treat previously surgically inaccessible brain
metastases. Not only is cell death instantaneous, thus decreasing the risk of delayed
intra-tumoral hemorrhage, but another theoretical advantage of using LITT as part of
management of brain metastases is that the hyperthermia breaks down the blood brain barrier
at the edge of the coagulation region thereby possibly increasing access of chemotherapeutic
agents into the lesion. In patients in whom either craniotomy or LITT are performed, biopsies
of tumor and surrounding normal brain can also be obtained at the time of local therapy.

The purpose of this trial is to study the activity of MK-3475 in untreated brain metastases
from melanoma or NSCLC. Given the promising initial results of MK-3475 in these diseases but
the lack of data in patients with untreated brain metastases thus far, this trial will study
treatment in this patient population. Additionally, for patients with melanoma this trial
requires local therapy with craniotomy or LITT to at least 1 brain lesion prior to systemic
therapy, thereby allowing the acquisition of brain tumor tissue for correlative studies on
biomarkers that may be predictive of clinical response in the CNS and systemically. We will
also require a biopsy of an extra-cerebral metastasis when feasible, particularly when tissue
from the brain lesion is not obtained in patients with NSCLC.

Inclusion Criteria:

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