The addition of bevacizumab to paclitaxel plus carboplatin in the treatment of selected patients with non-small-cell lung cancer has a significant survival benefit with the risk of increased treatment-related deaths. (ClinicalTrials.gov number, NCT00021060.)

The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates to the targeted therapy and immunotherapy sections in the NCCN Guidelines. For the 2018 update, a new section on biomarkers was added.

Background: We performed a phase II trial of pembrolizumab in patients with NSCLC or melanoma with untreated brain metastases to determine the activity of PD-1 blockade in the CNS. Interim results were previously published, and we now report an updated analysis of the full NSCLC cohort. Methods: This was an open-label, single-institution, phase 2 study. Eligible patients were ≥ 18 years of age with advanced NSCLC with ≥1 brain metastasis 5-20mm not previously treated or progressing after prior radiation, no neurologic symptoms or corticosteroid requirement, and performance status <2. Patients were treated with pembrolizumab 10 mg/kg IV every 2 weeks. Cohort 1 was for patients with PD-L1 ≥1% and cohort 2 PD-L1 <1% or unevaluable. The primary endpoint was the proportion of patients achieving a brain metastasis response. All treated patients were analyzed for response and safety endpoints. This study is closed to accrual and is registered with Clinicaltrials.gov, number NCT02085070. Here we report the updated results of the NSCLC cohort. Findings: Between March 31, 2014 and May 21, 2018, 42 patients were treated. Median followup was 8.3 months (IQR 4.5 to 26.2 months). Eleven of 37 patients in cohort 1 had a brain metastasis response (29.7% [95% CI, 15•9-47•0%]). There were no responses in cohort 2. Grade 3-4 AEs related to treatment included 2 patients with pneumonitis, and 1 each with constitutional symptoms, colitis, adrenal insufficiency, hyperglycemia, and hypokalemia. Treatment-related serious adverse events occurred in 6 (14%) patients and included pneumonitis acute kidney injury, colitis, hypokalemia, and adrenal insufficiency. There were no treatment-related deaths. Interpretation: Pembrolizumab has activity in brain metastases from NSCLC with PD-L1 expression ≥1% and is safe in select patients with untreated brain metastases. Further investigation of immunotherapy in patients with CNS disease from NSCLC is warranted.

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Combination chemotherapy improves response rate and failure-free survival compared with single-agent therapy, but there was no statistically significant difference in the primary end point of overall survival. The results in elderly patients were similar to younger patients. Performance status 2 patients had a superior outcome when treated with combination chemotherapy.

These NCCN Guidelines Insights focus on recent updates in the 2016 NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC; Versions 1-4). These NCCN Guidelines Insights will discuss new immunotherapeutic agents, such as nivolumab and pembrolizumab, for patients with metastatic NSCLC. For the 2016 update, the NCCN panel recommends immune checkpoint inhibitors as preferred agents (in the absence of contraindications) for second-line and beyond (subsequent) therapy in patients with metastatic NSCLC (both squamous and nonsquamous histologies). Nivolumab and pembrolizumab are preferred based on improved overall survival rates, higher response rates, longer duration of response, and fewer adverse events when compared with docetaxel therapy.

Although the trial closed prematurely and definitive statements regarding the efficacy of adjuvant gefitinib cannot be made, these results indicate that it is unlikely to be of benefit.

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