Combinations of three chemotherapeutic agents and two chemotherapeutic agents plus a targeted biologic agent in the treatment of advanced non-small-cell lung cancer

Lung cancer is the most common cause of cancer death in the world. In the United States, more than 28% of all cancer deaths are from lung cancer. In the past decade, a number of new drugs were introduced into the treatment of lung cancer including taxanes, gemcitabine, vinorelbine, and irinotecan. Combinations of one of these drugs with cisplatin, with carboplatin, or with one another were shown to be superior to best supportive care, to single-agent cisplatin, and in some instances, to a podophyllotoxin and cisplatin. Comparisons of the various two-drug combinations showed that they are equivalent in efficacy although there are differences in convenience, cost, and toxicity. Many of these two-drug combinations are less toxic than older combinations, which allowed for the development of three-drug combinations that could be given in full dose and with acceptable toxicity. Phase II trials of several three-drug combinations including carboplatin/paclitaxel/gemcitabine and cisplatin/vinorelbine/gemcitabine showed response rates and survival rates that were somewhat higher than anticipated with a two-drug combination. These data led to three randomized trials of a doublet combination versus a triplet combination. Each of these trials showed a higher response rate and higher toxicity rates with the triplet combination. The toxicity rates were still acceptable with the triplet combinations. The survival was also superior in the triplet arms of each of the randomized trials. Unfortunately, the sample size in each of these studies was small and the survival differences are not statistically significant. Therefore, additional larger randomized trials are sorely needed. During the past decade, new molecularly targeted agents were introduced into the treatment of lung cancer and completed phase I and II trials. Objective responses were noted with many of these new agents. Several combinations of doublet chemotherapy with a new targeted agent have completed phase II trials with encouraging results. Some of these new triplets are now in phase III randomized trials.