Non–small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality in the United States. Many patients present with symptomatic advanced metastatic disease and a significant proportion of patients with stage I-III relapse with metastatic spread. The use of platinum-based therapies, which have an acceptable toxicity profile, has been shown to prolong survival in patients who have a good performance status (PS). For many patients, platinum-based therapies are also effective at palliating disease-related symptoms. The benefit of platinum-based therapies occurs early, and several randomized trials have suggested that 3 to 4 cycles of therapy are just as effective as 6 or more cycles when considering overall survival (OS).1
After years of assuming that all platinum-based doublets including a third-generation agent (ie, paclitaxel, docetaxel [Taxotere], vinorelbine [Navelbine], gemcitabine [Gemzar], or irinotecan) were equally efficacious, studies showed that treating non-squamous NSCLC with a combination of pemetrexed (Alimta) and cisplatin improved OS compared with a doublet of gemcitabine and cisplatin.2
Other trials demonstrated that adding bevacizumab (Avastin)3
or cetuximab (Erbitux)4
to standard platinum-based chemotherapy in the first-line treatment of stage IV NSCLC prolonged survival. Despite these advances, stage IV NSCLC remains an incurable disease.
Second- and third-line treatments have been shown to improve survival and palliate symptoms,5,6
with pivotal phase III trials leading the FDA to approve docetaxel,5
and erlotinib (Tarceva)6
for this indication. Approval of these drugs ushered in the era of multiple-line therapy, changing the treatment paradigm for advanced NSCLC.MAINTENANCE OR IMMEDIATE THERAPY TRIALS
Second-line therapy has traditionally been administered at the time of objective disease progression following first-line therapy. Four recent trials have questioned whether this strategy is prudent in patients with advanced NSCLC. These trials were similarly designed. Each administered 4 cycles of a platinum-based chemotherapy regimen as first-line treatment for advanced stage IV NSCLC. Those patients who were non-progressive after first-line therapy were randomized to immediate or delayed treatment with a single agent approved as second-line therapy (Figure 1
). Three of the trials used the term maintenance8-10
to describe treatment administered immediately after completion of 4 cycles of first-line therapy, while the fourth used the term immediate.11
Delayed treatment was initiated only upon clear evidence of renewed progression. The single agents used after first-line therapy included pemetrexed, erlotinib, and docetaxel, all drugs that have available evidence suggesting they improve survival over best supportive care or placebo.
Three of the trials registered patients at the time of first-line therapy, and approximately 50% of study participants never made it to the randomization phase (Table 1
). The reasons for this dropout have not yet been presented, but presumably they related largely to early disease progression, toxicity, declining PS due to disease or treatment, or patient preference. This important observation needs to be considered as one interprets the benefit of maintenance therapy.
Only one trial11
dictated and exposed patients in the delayed cohort to the same agent patients in the maintenance or immediate arm received. The other 3 trials were placebo-controlled8-10
and allowed physicians to treat the patients in the placebo arms at their discretion, leading to an imbalance in exposure to second-line agents. Patients in the placebo-controlled trials were seen every 3 weeks, underwent scanning every 6 weeks, and had to demonstrate clear objective evidence of disease progression before transitioning from placebo to active treatment. Consequently, 30% to 50% of patients in the placebo arms never received second-line therapy. This has led many to interpret the results from these trials as affirmation of the value of second-line therapy, rather than as evidence that such treatment should begin immediately following 4 cycles of first-line therapy.
There is no consensus about the terminology to use when discussing the phenomenon of maintenance therapy. Other interpretations of the strategy used in these trials are prolonged duration of first-line therapy, sequential therapy, or earlier administration of effective second-line therapy. Because these trials (Table 1) used only FDA-approved agents with acceptable toxicity profiles in this setting, the trial summaries herein focus on efficacy outcomes and do not include specific toxicity data.Immediate or Delayed Docetaxel