Pembrolizumab in brain metastases of diverse histologies: phase 2 trial results

Abstract

Brain metastases (BMs) are an emerging challenge in oncology due to increasing incidence and limited treatments. Here, we present results of a single-arm, open-label, phase 2 trial evaluating intracranial efficacy of pembrolizumab, a programmed cell death protein 1 inhibitor, in 9 patients with untreated BMs (cohort A) and 48 patients with recurrent and progressive BMs (cohort B) across different histologies. The primary endpoint was the proportion of patients achieving intracranial benefit, defined by complete response, partial response or stable disease. The primary endpoint was met with an intracranial benefit rate of 42.1% (90% confidence interval (CI): 31-54%). The median overall survival, a secondary endpoint, was 8.0 months (90% CI: 5.5-8.7 months) across both cohorts, 6.5 months (90% CI: 4.5-18.7 months) for cohort A and 8.1 months (90% CI: 5.3-9.6 months) for cohort B. Seven patients (12.3%), encompassing breast, melanoma and sarcoma histologies, had overall survival greater than 2 years. Thirty patients (52%; 90% CI: 41-64%) had one or more grade-3 or higher adverse events that were at least possibly treatment related. Two patients had grade-4 adverse events (cerebral edema) that were deemed at least possibly treatment related. These results suggest that programmed cell death protein 1 blockade may benefit a select group of patients with BMs, and support further studies to identify biomarkers and mechanisms of resistance. ClinicalTrials.gov identifier: NCT02886585.

Extended Data Fig. 1 ∣. Kaplan-Meier Estimate for Intracranial Progression-free Survival, by Cohort.

The median intracranial PFS was 1.6 months for cohort A (blue line - 90% CI: 1.2-4.5 months) and 2.2 months for cohort B (red line - 90% CI: 1.4-3.1 months).

Extended Data Fig. 2 ∣. Kaplan-Meier Estimate for Extracranial Progression-Free Survival.

The median extracranial PFS was 4.5 months (90% CI: 2.7-8.0 months). Extracranial PFS was defined as the time of enrollment until the earlier of RECIST-defined disease progression or death. Patients who neither progressed nor died have follow-up that is censored at the date of last visit. CNS progression events are ignored. 53 of 57 patients (93%) experienced an extracranial PFS event. 18 patients experienced systemic progression and 35 additional died without systemic progression.

Extended Data Fig. 3 ∣. Kaplan-Meier Estimate for Extracranial Progression-Free Survival, by Cohort.

The median time to extracranial progression was 4.5 months (blue line - 90% CI: 1.2-6.7 months) for cohort A and 4.6 months (red line - 90% CI: 2.7-8.1 months) for cohort B.

Fig. 1 ∣. Trial schema.

A total of 58 patients with BMs were consented and enrolled to the study between October 2016 and October 2018. Cohort A enrolled 10 patients with at least one untreated BM, and cohort B enrolled 48 patients with progressive BMs.

Fig. 2 ∣. Kaplan–Meier estimates for overall survival.

Kaplan–Meier estimates for all patients enrolled on trial. The median OS was 8.0 months (90% CI: 5.5–8.7 months). Cohort A (9 patients) is shown by the dashed line. Cohort B (48 patients) is shown by the bolded line.

Fig. 3 ∣. Kaplan–Meier estimate for intracranial progression-free survival.

The median intracranial progression-free survival (PFS) was 1.6 months (90% CI: 1.4–2.9 months). Of 57 patients, 55 (96%) experienced an intracranial PFS event, and the remaining 2 patients were both lost to follow-up; 39 patients experienced CNS progression and 16 additional patients died without CNS progression. At 12 weeks, the intracranial PFS rate was 44% (90% CI: 31–57%), and at 18 weeks, the intracranial PFS rate was 26% (90% CI: 15–38%).