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

Aaron S Mansfield,Roy S Herbst,Gilberto De Castro,Rina Hui,Nir Peled,Dong-Wan Kim,Silvia Novello,Miyako Satouchi,Yi-Long Wu,Edward B Garon,Martin Reck,Andrew G Robinson,Ayman Samkari,Bilal Piperdi,Victoria Ebiana,Jianxin Lin,Tony S.K Mok

doi:10.1016/j.jtocrr.2021.100205

Abstract

IntroductionWe retrospectively evaluated outcomes in patients with programmed death-ligand 1 (PD-L1)–positive non–small-cell lung cancer (NSCLC) to determine whether baseline (i.e., at study enrollment) brain metastases were associated with the efficacy of pembrolizumab versus chemotherapy. MethodsWe pooled data for patients with previously treated or untreated PD-L1‒positive (tumor proportion score [TPS], ≥1%) advanced or 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. ResultsA 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 ≥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 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. ConclusionsPembrolizumab 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.

Highlights

We retrospectively evaluated outcomes in patients with programmed death-ligand 1 (PD-L1)–positive non–small-cell lung cancer (NSCLC) to determine whether baseline brain metastases were associated with the efficacy of pembrolizumab versus chemotherapy
Patient Disposition Of the 3170 patients included in this pooled analysis, 293 (9.2%) had baseline brain metastases and 2877 (90.8%) had no known baseline brain metastases
Baseline characteristics were generally similar between patients with and without brain metastases (Table 1), the brain metastases group had a lower percentage of men (51.9% versus 66.9%), a higher percentage of patients with nonsquamous histology (86.0% versus 65.7%) and EGFR (11.3% versus 3.6%) genetic aberrations, and a lower percentage of treatment-naive patients (34.5% versus 59.4%)

Summary

Introduction

We retrospectively evaluated outcomes in patients with programmed death-ligand 1 (PD-L1)–positive non–small-cell lung cancer (NSCLC) to determine whether baseline (i.e., at study enrollment) brain metastases were associated with the efficacy of pembrolizumab versus chemotherapy. Recent evidence from patients with NSCLC receiving programmed death 1 (PD-1) or PD-L1 inhibitor monotherapy suggests that the presence of brain metastases was not associated with poorer survival on the basis of multivariate analysis.[9]. The efficacy of monotherapy with the anti–PD-1 monoclonal antibody pembrolizumab has been reported in patients with advanced NSCLC, including a phase 1 study of previously treated and untreated disease (KEYNOTE-001),[10] a phase 2/3 study (KEYNOTE-010) in Pembrolizumab in NSCLC and Brain Metastases 3 the second-line or later setting,[11] and two phase 3 studies in the first-line setting (KEYNOTE-024 and -042).[12,13] In the three randomized studies (KEYNOTE-010, -024, and -042), overall survival (OS) was significantly longer with pembrolizumab than chemotherapy. Each of the four studies permitted enrollment of patients with previously treated brain metastases provided the patients were clinically stable

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Discussion

Conclusion