Background Immunotherapy targeting the PD-1 axis has activity in several tumor types. We aimed to determine the efficacy and safety of pembrolizumab in patients with untreated brain metastases. Here we present results from a Phase II trial of the PD-1 inhibitor pembrolizumab in patients with new or progressive brain metastases from melanoma or non-small cell lung cancer (NSCLC). Methods Thirty-six patients were enrolled, 18 with melanoma and 18 with NSCLC. Patients had at least one untreated or progressive brain metastasis between 5 and 20 mm in longest diameter without associated neurologic symptoms or the need for corticosteroids. NSCLC patients had tumor tissue demonstrating PD-L1 expression. Patients were treated with pembrolizumab 10 mg/kg every two weeks until progression, and brain metastasis response was assessed every eight weeks by modified RECIST. The primary endpoint was brain metastasis response rate and the analysis was performed on an intent-to-treat basis. The trial is ongoing and here we present an early analysis. The study is registered with clinicaltrials.gov, number NCT02085070. Findings Brain metastasis response rate was 22% and 33% among patients with melanoma and NSCLC, respectively. Responses were durable, with all but one patient who responded demonstrating an ongoing response at the time of data analysis. Treatment-related serious and grade 3–4 adverse events were rare and included transaminitis, colitis, pneumonitis, fatigue, endocrine abnormalities, and acute kidney injury (1 patient each). Serious neurological adverse events included cognitive dysfunction and seizures (1 and 3 patients, respectively), due to pembrolizumab, metastases or both. Interpretation Pembrolizumab demonstrates activity in brain metastases in patients with melanoma or NSCLC with an acceptable safety profile, indicating that there may be a role for systemic immunotherapy in patients with untreated or progressive brain metastases. Funding Merck and the Yale Cancer Center.

The magnetic susceptibility of tissue can be determined in gradient echo MRI by deconvolving the local magnetic field with the magnetic field generated by a unit dipole. This Quantitative Susceptibility Mapping (QSM) problem is unfortunately ill-posed. By transforming the problem to the Fourier domain, the susceptibility appears to be undersampled only at points where the dipole kernel is zero, suggesting that a modest amount of additional information may be sufficient for uniquely resolving susceptibility. A Morphology Enabled Dipole Inversion (MEDI) approach is developed that exploits the structural consistency between the susceptibility map and the magnitude image reconstructed from the same gradient echo MRI. Specifically, voxels that are part of edges in the susceptibility map but not in the edges of the magnitude image are considered to be sparse. In this approach an L1 norm minimization is used to express this sparsity property. Numerical simulations and phantom experiments are performed to demonstrate the superiority of this L1 minimization approach over the previous L2 minimization method. Preliminary brain imaging results in healthy subjects and in patients with intracerebral hemorrhages illustrate that QSM is feasible in practice.