Although we are all frustrated by the relatively slow pace of progress in lung cancer, there are times when we can look back and feel that we have made a real impact. Six years ago there were no treatments that were FDA approved and appeared to benefit patients who had previously been treated with first-line chemo for NSCLC. Now there are several.

The first out of the gates was docetaxel, or taxotere. This was compared to placebo in one trial and showed a better survival, although the response rate, the likelihood of significant tumor shrinkage, was less than 10%. In that trial, the starting dose was higher, at 100 mg per m2 (meter squared), than we use now. They started at a higher dose and had problems with low blood counts, a risk of fevers with low blood counts, and up to a 10% of dying from treatment. The dose was then dropped to 75 mg/m2 and was much safer and more feasible. The overall survival with chemo was better, about a 10% higher likelihood of being alive one year out from treatment (19% vs. 29% for both doses, and up to 37% for just the lower dose). Importantly, patients receiving chemo also felt overall better than the ones who got a placebo, less likely to need higher doses of narcotics or radiation, less likely to lose significant weight or become less active over time. Importantly, because taxotere is similar to paclitaxel (taxol), this trial did not allow patients to have received taxol previously, although taxol is very commonly used in the initial treatment of advanced NSCLC. Because so many US patients get taxol, and because many patients in the US refuse to participate in a placebo-controlled trial, this was done mostly in Canada.

A different trial was done in the US, allowing patients to have received prior taxol. In this study, known as TAX 320, patients were randomized to receive taxotere at either the higher (100 mg/m2) or lower (75 mg/m2) dose or a different drug, navelbine (vinorelbine) or ifosfamide, generally navelbine. The response rate to navelbine or ifosfamide was very low, just 1%, and it was 8% at the lower dose, 12% at the higher dose. Survival a year out from the start of treatment was better at the lower dose than higher dose (31% vs. 21%), and was better than with the navelbine/ifosfamide alternative (19%). There was no suggestion that patients who received taxol and then taxotere did worse than patients who had not gotten taxol as first-lined therapy.

One key issue is that the survival benefit was seen despite such a low response rate. This is presumably because a much larger proportion, approaching 50% on the 75 mg/m2 dose of taxotere, had stable disease, sometimes for many months at a time, and that presumably translated to a survival benefit. These trials, and others since then, have shown that patients don't need to have significant tumor shrinkage to benefit. Just keeping a cancer from growing for several months can provide meaningful benefit. Including living longer and potentially feeling better.

Since then, Iressa (gefitinib) was approved initially and then shown to not have an overall survival benefit vs. placebo and is no longer available for new prescriptions. But the remarkably similar EGFR tyrosine kinase inhibitor, Tarceva (erlotinib) did show a significant survival benefit and is approved for second- or third-line treatment. It has not been directly compared to chemo in this setting, but overall appears to be similar in benefit when similar patients are being compared. And Alimta (pemetrexed) was directly compared to taxotere and shown to have essentially identical activity but a somewhat easier side effect profile, and for this it was also approved as a treatment option about two years ago. These agents will be described in more detail elsewhere.

In the meantime, it's great to see that there is a growing interest in building on the approaches we have in order to improve our outcomes for patients getting treated in second-line, third-line, and beyond. There are now growing options, in or outside of clinical trials, for patients who have received one or more kinds of prior treatment for advanced NSCLC.