Management of advanced non-small cell lung cancer without a targetable driver mutation

PD-L1: programmed death-ligand 1; IHC: immunohistochemistry; CT: computed tomography; ECOG: Eastern Cooperative Group; PS: performance status; EGFR: epidermal growth factor receptor; ALK: anaplastic lymphoma kinase; ROS1: c-ROS oncogene 1; BRAF: B-Raf proto-oncogene; VEGF2: vascular endothelial growth factor receptor 2; NSCLC: non-small cell lung cancer.
* This is typically done at the time of diagnosis, along with next-generation sequencing for actionable driver mutations, including EGFR, ALK, ROS1, and BRAF. Those with actionable genetic driver alterations are managed with initial targeted therapy. Refer to UpToDate content on personalized, genotype-directed therapy in NSCLC for further details.
¶ Examples include bulky disease causing end-organ failure or unmanageable symptoms.
Δ Some patients and providers may opt for nabpaclitaxel over paclitaxel, given that steroid premedication is not needed with nabpaclitaxel, but is for paclitaxel. However, nabpaclitaxel is associated with higher rates of hematologic toxicity.
◊ Nivolumab plus ipilimumab is an acceptable alternative to pembrolizumab plus chemotherapy in select patients with either squamous or nonsquamous tumors, particularly for those who wish to avoid chemotherapy.
§ For such patients, we suggest pembrolizumab paired with a platinum doublet, although bevacizumab paired with a platinum doublet may be considered as an alternative.
¥ For patients with adenocarcinoma, we prefer pemetrexed rather than a taxane to pair with a platinum agent, given better tolerability and trends toward better survival, although a taxane is an acceptable alternative. For those treated with a taxane-containing regimen, it is not continued as maintenance.
‡ The combination of platinum-based doublet chemotherapy, bevacizumab, and atezolizumab, followed by maintenance therapy with atezolizumab and bevacizumab, is a potential alternative in patients with nonsquamous NSCLC.
† For patients with a good PS with nonsquamous NSCLC, the addition of bevacizumab to platinum-based therapy is associated with improved outcomes, but a small increase in frequency of severe toxicities, including hypertension, thromboembolism, and bleeding. If bevacizumab is used, it may be continued during the maintenance phase of therapy with pemetrexed, if tolerated. Refer to the UpToDate discussion on the addition of bevacizumab to systemic chemotherapy in advanced NSCLC.
** For such patients with a good PS, some but not all UpToDate experts add the VEGF2 antibody ramucirumab to docetaxel, which modestly improves survival, but is associated with increased rates of bleeding and hypertension.
¶¶ For patients with adenocarcinoma who have not already received pemetrexed, we opt for this agent rather than those listed.