Outcomes With Pembrolizumab Monotherapy in Patients With Programmed Death-Ligand 1–Positive NSCLC With Brain Metastases: Pooled Analysis of KEYNOTE-001, 010, 024, and 042

Abstract

Introduction: We retrospectively evaluated outcomes in patients with programmed death-ligand 1 (PD-L1)-positive NSCLC to determine whether baseline (i.e., at study enrollment) brain metastases were associated with the efficacy of pembrolizumab versus chemotherapy.Methods: We pooled the data for patients with previously treated or untreated PD-L1-positive (tumor proportion score [TPS], !1%) advanced metastatic NSCLC in KEYNOTE-001 (NCT01295827), KEYNOTE-010 (NCT01905657), KEYNOTE-024 (NCT02142738), and KEYNOTE-042 (NCT02220894). Patients received pembrolizumab (2 mg/kg, 10 mg/kg, or 200 mg every 3 wk or 10 mg/kg every 2 wk); chemotherapy was a comparator in all studies except KEYNOTE-001. All studies included patients with previously treated, stable brain metastases.Results: A total of 3170 patients were included, 293 (9.2%) with and 2877 (90.8%) without baseline brain metastases; median (range) follow-up at data cutoff was 12.9 (0.1-43.7) months. Pembrolizumab improved overall survival versus chemotherapy in patients with or without baseline brain metastases: benefit was seen in patients with PD-L1 TPS greater than or equal to 50% (0.67 [95% confidence intervals (CI): 0.44-1.02] and 0.66 [95% CI: 0.58-0.76], respectively) and PD-L1 TPS !1% (0.83 [95% CI: 0.62-1.10] and 0.78 [95% CI: 0.71-0.85], respectively). Progression-free survival was improved, objective response rates were higher, and the duration of response was longer with pembrolizumab versus chemotherapy regardless of brain metastasis status. The incidence of treatment-related adverse events with pembrolizumab versus chemotherapy was 66.3% versus 84.4% in patients with brain metastases and 67.2% versus 88.3% in those without.Conclusions: Pembrolizumab monotherapy improved outcomes and was associated with fewer adverse events than chemotherapy in patients with treatment-naive and previously treated PD-L1-positive advanced/metastatic NSCLC regardless of the presence of baseline treated, stable brain metastases.

Navigate Towards the Immunotherapy Era: Value of Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer Patients With Brain Metastases

“…( 32 ) reported that no intracranial Grade≥3 adverse events (AEs) occurred, and the incidence of systemic Grade≥3 AEs was 14%. In the pooled analysis of KEYNOTE-001, 010, 024, and 042 ( 44 ), comparing pembrolizumab and chemotherapy, the incidence of intracranial Grade≥3 AEs was 9.7% vs. 26.7%, while the incidence of systemic Grade≥3 AEs was 14.8% vs. 45.6%. The Expanded Access Program from Italy included 466 NSCLC patients with BMs who were asymptomatic after radiotherapy.…”

“…Compared with chemotherapy, a higher systemic response has been observed in ICI monotherapy for patients with BMs. Recently, a pooled analysis based on KEYNOTE-001, 010, 024, and 042 ( 44 ) showed that systemic ORR with pembrolizumab was superior to chemotherapy in PD-L1≥1% NSCLC patients with BMs (26.1% vs. 18.1%). The single-arm FIR trial ( 45 ) enrolled 13 advanced NSCLC patients treated with atezolizumab into its cohort 3 (second-line with treated BMs).…”

“…Benefits in survival are relatively clear-cut for NSCLC patients with BMs. A pooled analysis of KEYNOTE-001, 010, 024, and 042 ( 44 ) showed that pembrolizumab improved overall survival (OS) versus chemotherapy (13.4 months vs. 10.3 months, HR=0.83). In the subgroup of NSCLC patients with high PD-L1 expression (PD-L1≥50%), the magnitude of benefit with pembrolizumab compared with chemotherapy increased to 19.7 months vs. 9.7 months (HR=0.67).…”

Immunotherapy in NSCLC Patients With Brain and Leptomeningeal Metastases

“…In the pooled analysis from Keynote 001, Keynote 010, Keynote 024, and Keynote 42 trials, Mansfield et al evaluated the efficacy and safety of pembrolizumab monotherapy versus chemotherapy in metastatic NSCLC patients with BM at baseline ( 14 ). Only patients with PD-L1 ≥1% were included in this post-hoc analysis.…”

“…In the pooled analysis from Keynote 001, Keynote 010, Keynote 024, and Keynote 42 trials, the patients had received pembrolizumab or standard chemotherapy in different settings, including as first-line treatment ( 14 ). After a median follow-up of 12.9 months, pembrolizumab provided a longer overall survival compared to chemotherapy regardless of the presence of BM at baseline (HR 0.83 and HR 0.78 in patients with and without BM, respectively) ( Figure 2 ).…”