Brain metastases develop in 40% of metastatic melanoma patients. Untreated brain metastases exclude from most clinical trials. In prior trials, treatment of metastatic melanoma with Pembrolizumab ( Keytruda ), an IgG4 antagonist of the immune checkpoint PD-1, produced response rates of greater than 30%.
A phase 2 study was initiated to assess safety and activity of Pembrolizumab in patients with previously untreated or progressing brain metastases.
Patients with brain metastases from melanoma or lung cancer were eligible if at least 1 asymptomatic 5-20mm brain metastasis not requiring immediate local therapy or systemic steroids was present, and at least 1 brain metastasis was amenable to biopsy or resection.
Prior PD-1/PD-L1 inhibitors were excluded.
Pembrolizumab 10mg/kg was administered every 2 weeks.
Brain MRI was repeated at 4 wks to assess safety and restaging was done every 8 weeks.
Primary endpoint was brain metastasis response by modified RECIST ( lesions greater than or equal to 5mm were measurable on MRIs with 1mm slices; up to 5 brain metastases were used to determine response ).
A total of 17 patients were accrued, 6 with BRAF mutations, 10 previously received Ipilimumab. Activity at interim analysis was sufficient to continue.
Four were unevaluable for brain metastasis response ( 3 due to rapid extracerebral disease progression, 1 due to intralesional hemorrhage ), and 1 was too early.
Among 12 evaluable patients, brain metastasis partial responses were observed in 3 patients ( 1 with prior Ipilimumab ), stable disease in 2, disease progression in 7 ( 2 with a mixed response and 1 with disease progression by imaging but pseudoprogression on histology ).
Brain metastasis responses are ongoing at 7+, 6+ and 3+ months. One complete response and 3 partial responses were observed in extra-cerebral metastatic disease, 3 of these 4 with concordant brain metastasis response.
The only grade 3 adverse event clearly related to Pembrolizumab was liver function abnormalities ( 1 patient ). Two patients had seizures, 1 from perilesional edema, 1 from tumor growth, treated with anti-convulsants and a brief course of steroids.
In conclusion, early results from this ongoing trial suggest that Pembrolizumab has promising activity in untreated melanoma brain metastases.
CNS symptoms were controllable with anti-convulsants and transient use of steroids. ( Xagena )
Kluger HM et al, J Clin Oncol 33, 2015 (suppl; abstr 9009)