Safety and activity of pembrolizumab in melanoma patients with untreated brain metastases.

Abstract

9009 Background: Brain metastases (BrMs) develop in 40% of metastatic melanoma (MM) patients (pts). Untreated BrMs exclude from most clinical trials. In prior trials, treatment of MM with pembrolizumab (pembro), an IgG4 antagonist of the immune checkpoint PD-1, produced response rates of > 30%. A phase 2 study (NCT02085070) was initiated to assess safety and activity of pembro in pts with previously untreated or progressing BrMs. Methods: Pts with BrMs from melanoma (reported here) or lung cancer are eligible if at least 1 asymptomatic 5-20mm BrM not requiring immediate local therapy or systemic steroids is present, and at least 1 BrM is amenable to biopsy or resection. Prior PD-1/PD-L1 inhibitors are excluded. Pembro 10mg/kg is administered every 2 weeks (wks). Brain MRI is repeated at 4 wks to assess safety and restaging is done every 8 wks. Primary endpoint is BrM response by modified RECIST (lesions ≥ 5mm are measurable on MRIs with 1mm slices; up to 5 BrMs are used to determine response). Results: Between April and December 2014, 17 pts were accrued, 6 with BRAF mutations, 10 previously received ipilimumab. Activity at interim analysis was sufficient to continue. Four were unevaluable for BrM response (3 due to rapid extracerebral disease progression (PD), 1 due to intralesional hemorrhage), and 1 was too early. Among 12 evaluable pts, BrM partial responses (PRs) were observed in 3 pts (1 with prior ipilimumab), stable disease in 2, PD in 7 (2 with a mixed response and 1 with PD by imaging but pseudoprogression on histology). BrM responses are ongoing at 7+, 6+ and 3+ months. One CR and 3 PRs were observed in extra-cerebral metastatic disease, 3 of these 4 with concordant BrM response. The only grade 3 adverse event clearly related to pembro was liver function abnormalities (1 pt). Two pts had seizures, 1 from perilesional edema, 1 from tumor growth, treated with anti-convulsants and a brief course of steroids. Conclusions: Early results from this ongoing trial suggest that pembro has promising activity in untreated melanoma BrMs. CNS symptoms were controllable with anti-convulsants and transient use of steroids. Accrual is ongoing and correlative studies from pre-treatment brain and extra-cerebral tumor samples are being conducted. Clinical trial information: NCT02085070.