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Platinum-based chemotherapy regimens have been the mainstay of systemic chemotherapy in advanced NSCLC. However, substantial toxicity impairs the survival and symptom control advantages of cisplatin- and even carboplatin-containing regimens. With the advent of newer active agents in the 1990s, investigators began conducting clinical studies with the aim of potentially eliminating platinum from initial therapy for patients with advanced NSCLC. Conceptually, three major hypotheses were tested in phase III trials: (i) single, non-platinum agents are equal in efficacy to platinum in combination with these agents; (ii) non-platinum combinations are potentially more effective than platinum-based therapy; and (iii) non-platinum combinations are at least equally efficacious, but less toxic than, platinum-based therapy. An overall analysis of phase III data indicates that combinations of these newer agents with platinum are superior to the single agent alone and that combinations of non-platinum agents are no more effective than platinum-based therapy. Non-platinum therapy has a different and perhaps marginally improved toxicity spectrum compared with platinum-based therapy. In the few studies utilizing a formal quality-of-life analysis, no differences have been detected. Therefore, while several non-platinum regimens have been validated in phase III trials as reasonable alternatives to platinum-based therapy, they have not been proven to be clearly superior.