History and molecular features

Patients with nonsquamous cell histology, good performance status, no history of hemoptysis or other bleeding, or recent history of cardiovascular events may benefit from the addition of bevacizumab to paclitaxel and carboplatin. Patients with sensitizing variants in exon 19 or exon 21 of EGFR (particularly those from East Asia, never smokers, and those with adenocarcinoma) may benefit from EGFR tyrosine kinase inhibitors (TKIs) as an alternative to first- or second-line chemotherapy. Patients with tumors harboring ALK translocations, ROS1 rearrangements, or NTRK fusions may benefit from ALK, ROS1, or NTRK inhibitors as an alternative to first- or second-line chemotherapy.

Patients with tumors expressing PD-L1 (>50% by immunohistochemistry) have improved survival with pembrolizumab. The addition of pembrolizumab to carboplatin-plus-pemetrexed chemotherapy for nonsquamous advanced lung cancer improves survival irrespective of PD-L1 expression.[1][Level of evidence A1] For patients with stage IV or recurrent NSCLC and PD-L1 expression on at least 1% of tumor cells, frontline combination immunotherapy with nivolumab and ipilimumab increases overall survival (OS).[2][Level of evidence A1] Second-line systemic therapy with nivolumab, docetaxel, pemetrexed, or pembrolizumab for PD-L1−positive tumors also improves survival in patients with good performance status (who have not received the same or a similar agent in the first-line setting).[3][Level of evidence A1]

The role of systemic therapy in patients with an Eastern Cooperative Oncology Group (ECOG) performance status below 2 is less certain.

Patients with adenocarcinoma may benefit from pemetrexed [4] and bevacizumab, as well as from combination chemotherapy with pembrolizumab. Patients with unresectable, locally advanced or metastatic, well-differentiated, nonfunctional, neuroendocrine tumors benefit from the mTOR inhibitor, everolimus.