Ctim-02. phase 2 trial of pembrolizumab for patients with brain metastases of diverse histologies

BACKGROUND Patients with brain metastases have limited treatment options.The PD-L1/PD-1 pathway is an immune suppressive mechanism in brain metastases. METHODS This was a single-arm phase 2 clinical trial evaluating the intracranial efficacy of pembrolizumab, a PD-1 inhibitor, in patients with brain metastases. The target accrual was 58 patients to achieve at least 52 evaluable patients. The primary endpoint was intracranial benefit (complete response, partial response, or stable disease by modified RANO criteria). The study design compared a null intracranial benefit rate of 10% against an alternative of 24%. If at least 8 patients among 52 had intracranial benefit, the primary efficacy endpoint would be met and pembrolizumab would be considered worthy of further study (type-I error of 10%, power of 89%). RESULTS In 57 evaluable patients, median age was 53 (range 28-80). Tumor histologies included breast (n = 35), NSCLC (n = 7), melanoma (n = 2), small-cell lung cancer (n = 2), sarcoma (n = 2), and other (n = 9). For patients with breast cancer, 16 patients had HER-2 positive, 17 had hormone-receptor positive and 11 patients had triple-negative disease. The study met its primary endpoint and achieved an intracranial benefit rate of 42.1% (90% confidence interval [CI]: 31-54%). Thirty-seven percent of breast cancer patients (90% CI: 24–52%) and 43% of NSCLC patients (90% CI: 13–77%) had intracranial benefit. All four breast cancer subtypes derived efficacy from pembrolizumab. Seven patients, who had either breast cancer, melanoma or sarcoma, had overall survival >2 years. The extracranial benefit rate in patients with evaluable extracranial disease based on RECIST 1.1 criteria was 45% (90% CI: 31-59%). Median overall survival was 8.0 months (90% CI: 5.5-8.7 months). Grade 4 toxicities at least possibly related to treatment were observed in 2 patients: cerebral edema. CONCLUSIONS Our study of pembrolizumab met overall primary endpoint for intracranial benefit in patients with brain metastases across diverse histologies.