Treatment of metastatic NSCLC is based on several factors: histology; performance status; presesence or absence or central nervous system involvement; PD-L1 expression (in tumor-, or surrounding-cells, or both); and presence or absence of actionable targets, including recurrent genomic alterations. A detailed description of all potential treatment strategies is beyond the scope of this article. But, it can be said that targeted therapy is the preferred initial option in patients with actionable mutations such as EGFR, ALK, and ROS1. Targeted therapy is also recommended in second-line therapy when appropriate. For patients without actionable mutations, use of immunotherapy has become the standard of care. Single-agent pembrolizumab is approved for NSCLC with high PD-L1 expression (≥50%); platinum-based chemotherapy plus pembrolizumab, regardless of PD-L1 expression, is approved for metastatic NSCLC. For non-squamous metastatic NSCLC, carboplatin plus paclitaxel plus bevacizumab plus atezolizumab is an option as first-line therapy in wild-type EGFR and ALK, and as the treatment of choice in mutated EGFR and ALK when targeted therapy is no longer an option. The combination of immune checkpoint inbitors, nivolumab plus ipilimumab, is also an option with level I evidence in advanced NSCLC. The median survival with these strategies has increased from about 1 year in the chemotherapy era, to about 3 years for EGFR and ALK mutated tumors treated with targeted therapy. Immunotherapy with or without chemotherapy has increased median survival to 17-30 months. It is very significant that about 14% of patients treated in second line with nivolumab, an immune checkpoint inhibitor, are alive after a 4-year follow-up. Cure is a distinct possibility for this subgroup.
Treatment of CUP is based first on recognition of specific good prognosis subgroups using clincal and pathological criteria. Treatment of good prognosis CUP can be homologated to a number of distinct treatment algorithms of corresponding cancers of known primary site. Treatment outcomes of said good prognosis CUP are identical to their known primary site counterpart. Remaining CUP patients belong to the poor prognosis group since median overall survival is only 11 months with combination chemotherapy (with a platinum plus a taxane, in most centers). Attempts to classify cell lineage using immunohistochemistry, or PCR-based gene expression assays, have not become standard of care for a number of reasons. Among these, is lack of robust data supporting cell lineage-directed therapy with well conducted clinical trials.
