Second-Line Chemotherapy and Beyond for Non–Small Cell Lung Cancer

Abstract

Keywordsnon-small cell lung cancer, chemotherapy, second-line treatment, docetaxel, pemetrexed, erlotinib Key Points• Docetaxel, pemetrexed, and erlotinib are approved for the second-line treatment of NSCLC.• The discovery of targetable mutations, the increasing use of maintenance strategies, and the introduction of immunotherapies has made the choice of second-line agents much more complicated.• Ramucirumab with docetaxel is the only combination regimen that has shown improved overall survival in the second-line setting.• Erlotinib is the only agent approved in the third-line setting for EGFR wild-type patients. First Line TreatmentIn patients without targetable genetic alterations, the standard first-line therapy for advanced (stage IIIB or IV) NSCLC is chemotherapy with a platinum doublet for 4-6 cycles with or without bevacizumab. 1 Historically, a number of drugs including paclitaxel, docetaxel, gemcitabine, and vinorelbine were considered acceptable platinum partners in the first-line metastatic setting with essentially no differences in progression free survival (PFS) or overall survival (OS). More recently, additional agents have been approved in combination with platinum in this setting including pemetrexed and nab-paclitaxel. [1][2][3] One particular advance in the last decade has been the recognition that histology should be considered in the choice of initial chemotherapy. This was discovered after an additional analysis of two studies showed pemetrexed to be more effective in non-squamous histologies and less active in squamous tumors. 3-5 Based on these findings, the choice of first-line agents in metastatic NSCLC is now strongly based on presenting histology, and this initial choice affects available second-line options. Maintenance TherapyHistorically, patients treated with first-line platinum doublet chemotherapy who had objective responses or stable disease were placed on surveillance following completion of 4-6 cycles. However, over the last decade, new data suggests that there is benefit to the addition of maintenance therapy following initial chemotherapy. There are two maintenance strategies including continuation of an agent used in the first-line setting or switching to a previously unused agent (switch maintenance). There is data supporting the use of bevacizumab, pemetrexed, and erlotinib in the maintenance setting either as single agents or in combination. [6][7][8][9][10][11] Prior maintenance therapy is of particular importance when discussing second-line chemotherapy options as the use of maintenance therapy, particularly when switch maintenance is employed, influences the availability of agents in the second-line setting and beyond. Chemotherapy as Second-Line TreatmentHistorically, nearly all patients received platinum doublet chemotherapy followed by single agent chemotherapy in the second-line setting. However, with the discovery of targetable mutations, the development of tyrosine kinase inhibitors (TKI), the increasing use of maintenance strategies, and the introduction of imm...

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