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. There will also be a biopsy of an extra-cerebral metastasis when feasible, particularly when tissue from the brain lesion is not obtained in patients with NSCLC.

Upon results entry, the primary outcome measure was aligned as originally presented in the study protocol (attached with results).