In the last decade, the treatment of NSCLC has evolved very significantly, and one of the leading ways has been that we've gone from having no established role for treatment after initial, first line therapy to having multiple agents with a proven benefit. It's worth clarifying that as maintenance therapy is increasingly being considered as an option after first line therapy, a distinction between this and second line therapy. Maintenance therapy is given to prolong the period before someone who has achieved a response or stable disease on first line treatment demonstrates progression for the first time, while second line therapy is the term more commonly reserved for treatment after someone has demonstrated evidence of progression for the first time after first line therapy.

The first agent that demonstrated a survival benefit in the second line setting was Taxotere (docetaxel), which was tested in one trial against supportive care alone, and in another trial was tested against either Navelbine (vinorelbine) or ifosfamide. Both of these trials demonstrated that while a higher dose of 100 mg/m2 (meter squared) given IV every three weeks was associated with significant side effects and deaths from the treatment, a lower dose of 75 mg/m2 was associated with a significant improvement in overall survival. Importantly, the response rate (significant tumor shrinkage by specific criteria on consecutive CT scans) was below 10% in both of these trials, but nearly half of the recipients of Taxotere demonstrated stable disease, suggesting that a survival benefit may be achieved from prolonging the period before progression, even if significant tumor shrinkage doesn't occur. In addition, quality of life was favorable by multiple criteria with Taxotere, despite some challenging side effects, indicating that controlling the underlying cancer leads to improvements compared with less effective treatment or no anti-cancer therapy. A subsequent randomized trial of patients treated with one prior line of chemo for advanced NSCLC compared Taxotere at 75 mg/m2 given IV every three weeks with Alimta (pemetrexed) at 500 mg/m2 IV every three weeks. This trial showed remarkably similar efficacy for both, as measured by response rate (9% for each), progression-free survival, and overall survival. Alimta was noted to have less frequent need for transfusions and less severe side effects in terms of blood counts, and this along with a widely perceived easier tolerability overall (though not clearly demonstrated in the objective comparison of non-blood count-related side effects) led to an increasing use of Alimta as a second line agent of choice. Importantly, this trial looked at patients with all of the various NSCLC histologic subsets, but an unplanned subset analysis indicated that Alimta was more effective for patients with adenocarcinoma than for squamous NSCLC, while Taxotere appeared comparably effective in both major histologic subgroups. Subsequent work that confirmed the greater efficacy of Alimta in non-squamous NSCLC but with no real efficacy in squamous NSCLC led to a change in the FDA approval of Alimta as a second line agent, now specifying that Alimta is not indicated for patients with squamous NSCLC. The targeted therapy Tarceva (erlotinib), an oral inhibitor of the epidermal growth factor receptor (EGFR), was tested against placebo in patients who had received one or two prior lines of chemotherapy for advanced NSCLC. This study demonstrated a significant improvement in overall survival as well as progression-free survival, though again the rate of significant tumor shrinkage was under 10% but with about half of the patients demonstrating stable disease. The benefit in survival was comparable in woman and men and for patients with squamous NSCLC compared with adenocarcinoma NSCLC, though there was clearly a narrower subset who achieve a more profound and prolonged benefit. Such patients most typically have an activating EGFR mutaiton, but many patients who don't have an EGFR mutation receive a more modest but still meaningful improvement in survival with Tarceva. Though the other commonly used oral EGFR inhibitor, Iressa (gefitinib), failed to demonstrate a survival benefit compared to placebo in a large clinical trial of previously treated patients, these patients were probably a poorer risk population with early progression compared with the patients on other second line therapy trials, a subsequent trial that directly compared Iressa to Taxotere as second line therapy demonstrated no differences in efficacy and a more favorable side effect profile for Iressa. There was no patient subgroup defined by either clinical features or molecular markers that showed a significant difference in survival, indicating that Iressa is comparable to chemotherapy in its potential benefits. Nevertheless, in the US, only Tarceva is commercially available, reflecting the observation that only Tarceva demonstrated a significant improvement in overall survival compared to placebo. Other agents, such as standard chemotherapy drugs like Gemzar (gemcitabine), Navelbine, or perhaps other chemo agents may have some activity in previously treated patients, but they haven't been as well studied, don't have an established clinical benefit, and consequently remain poorly studied non-standard options in previously treated patients. Doublets have been shown to increase the response rate compared to single agent chemo, though this has been in the absence of any improvement in survival but associated with significant increase in clinically significant side effects, making sequential single agent therapy a current standard for previously treated patients at this time. For more information: Introduction to second line therapy for advanced NSCLC Selection of one treatment over another as second line therapy in advanced NSCLC Tarceva survival benefit in BR.21 trial Efficacy of Tarceva on BR.21 in many subgroups Iressa and the ISEL trial that failed to demonstrate survival benefit Alimta efficacy as a function of NSCLC histology Podcast by Dr. Julie Brahmer on second line NSCLC treatment options Podcast by Dr. West on second line chemo for advanced NSCLC Summary of INTEREST trial and molecular marker analysis