Outcomes in Patients With Non–small-cell Lung Cancer With Brain Metastases Treated With Pembrolizumab-based Therapy

Abstract

Evidence for immunotherapy in metastatic nonesmall-cell lung cancer (mNSCLC) with brain metastases (BM) is limited. Within a cohort of 570 patients with mNSCLC undergoing pembrolizumab-based therapy, patients with (n [ 126) and without (n [ 444) BM did not have significantly different survival. Patients with mNSCLC with BM should be considered for pembrolizumab-based therapy; cranial irradiation can be administered either before or after pembrolizumab initiation. Background: Patients with metastatic nonesmall-cell lung cancer (mNSCLC) and untreated brain metastases (BM) have been excluded from most trials of immune checkpoint inhibitors (ICIs). Real-world evidence on efficacy and survival outcomes of ICIs in patients with BM is limited. Patients and Methods: We conducted a single-center retrospective study of patients with mNSCLC treated with pembrolizumab with or without chemotherapy and compared progression-free survival (PFS) and overall survival (OS) between patients with and without BM using Kaplan-Meier and Cox methodology. We also characterized systemic and intracranial objective response rate (ORR) and treatment details, including timing of cranial irradiation. Results: Between Augutst 2013 and December 2018, 570 patients with mNSCLC treated with pembrolizumab-based therapy were analyzed. Of 126 (22.1%) patients with BM, 96 (76.2%) had treated BM (local therapy prior to pembrolizumab), and 30 (23.8%) had untreated BM. Of patients with untreated BM, 17 (56.7%) underwent radiation within 30 days after pembrolizumab initiation. In the remaining 13 (43.3%) treated with pembrolizumab-based therapy alone, intracranial ORR was 36.4%. Patients with and without BM did not have significantly different systemic ORR (27.8% vs. 29.7%; P ¼ .671), PFS (mPFS 9.2 vs. 7.7 months; P ¼ .609), or OS (mOS 18.0 vs. 18.7 months; P ¼ .966). Factors associated with improved survival on Cox analysis included female gender, performance status, adenocarcinoma histology, and first-line therapy. Conclusions: Patients with BM did not have inferior survival to patients without BM after treatment with pembrolizumab-based therapy. In the current era, BM may not automatically confer inferior survival, and should not exclude patients from receiving pembrolizumab-based therapy.

Brain metastases, patterns of intracranial progression, and the clinical value of upfront cranial radiotherapy in patients with metastatic non-small cell lung cancer treated with PD-1/PD-L1 inhibitors

“…Moreover, univariate and multivariate analyses revealed that the presence of BMs did not carry independent prognostic value for PFS or OS. These observations echo those of earlier studies, in which the presence of BMs at baseline was not identified to be an independent unfavorable prognostic factor for the OS of patients with PD-1/PD-L1 inhibitortreated NSCLC (22,29,33). Therefore, when patients are treated with PD-1/PD-L1 inhibitors, the brain should not be considered an immune-privileged site, and in carefully selected patients with brain-metastatic NSCLC, anti-PD-1/ PD-L1 therapy may provide long-term survival benefit, which requires confirmation in future clinical trials.…”

“…To date, numerous studies have been published focusing on the impact and timing of cranial RT in relation to anti- PD-1/PD-L1 therapy for metastatic NSCLC (8,(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25).…”

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

“…Real-world evidence in patients with advanced NSCLC treated with first-line or later pembrolizumab, with or without chemotherapy, or secondline or later nivolumab parallels the clinical trial experience reporting similar benefits in patients presenting with and without brain metastases. [20][21][22] No new safety signals were identified in our analysis. The safety profile of pembrolizumab monotherapy was similar in patients with and without baseline brain metastases and was more favorable than that of chemotherapy.…”

“…Real-world evidence in patients with advanced NSCLC treated with first-line or later pembrolizumab, with or without chemotherapy, or second-line or later nivolumab parallels the clinical trial experience reporting similar benefits in patients presenting with and without brain metastases. 20 , 21 , 22 …”

Real-World Time on Treatment with First-Line Pembrolizumab Monotherapy for Advanced NSCLC with PD-L1 Expression ≥ 50%: 3-Year Follow-Up Data

“…Moreover, the findings may not be generalizable outside of the Flatiron Health network or for academic centers, as most patients were treated in the community oncology setting. Information was missing for clinically important variables, such as whether brain metastases were pretreated, although observational studies suggest that the survival benefit from pembrolizumab-based therapy may not be inferior for patients with brain metastases [ 40 ]. Finally, the KRAS subanalysis was limited to the 330 patients with available data, and no data were available regarding KRAS G12C mutations or the status of other mutations that have been associated with prognosis, such as STK11 , KEAP1 , and PTEN gene mutations [ 41 , 42 ].…”