As I mentioned in prior posts on the topic of second-line therapy, taxotere was the first treatment approved for second-line treatment of NSCLC. Back in 2000, first-line chemo with platinum-based doublets was becoming increasingly established as demonstrating a consistent survival benefit of several months for previously untreated patients with advanced NSCLC, and then a couple of trials came out that demonstrated a modest survival benefit that for second-line taxotere, compared to either supportive care alone or compared to alternative chemotherapy (navelbine or ifosfamide). However, even after these trials demonstrated a survival benefit and taxotere was approved by the FDA for treatment as second-line therapy, only a minority of patients were getting treated in this way. A large part of this was the concern about the challenging side effects of treatment with taxotere every three weeks. Although taxotere is clearly among the most active and effective agents available for treatment of NSCLC (and many other cancers), it can cause a lot of fatigue and decreased blood counts and other problematic adverse effects. Over the last few years, the alternative approach of Alimta (also known as pemetrexed) has become available and approved by the FDA for second-line treatment of NSCLC, and it is being studied in more and more treatment settings as a potentially appealing option in lung cancer.

Alimta, or pemetrexed, is a form of standard chemotherapy that is a newer version of old standard chemo like methotrexate. These drugs are called antifolates, and they inhibit the production of critical components of DNA that growing cells need to survive. Because cancer cells are growing faster than other cells, they are particularly susceptible to the damaging effects of antifolates and can lead to death of cancer cells. The "MTA" at the end of the name Alimta stands for multi-targeted antifolate, because, as its name suggests, it actually has several targets that are critical in DNA and protein formation (too complicated and not interesting enough to go into here). In truth, the distinctions between what is called standard chemotherapy and "targeted therapy" are actually not very clear. Even regular chemo is targeted, but we have generally had a better idea of the target for the newer molecular therapies.

Alimta was approved by the FDA in 2003 for the treatment of malignant pleural mesothelioma, a cancer of the lining around the lung that has been notoriously difficult to treat. In combination with cisplatin, alimta was associated with a clear improvement in survival, as well as a much better response rate and improvements in breathing capacity, compared with cisplatin alone (abstract here). It was also found during that early international trial that patients receiving Alimta did clearly better, with much less of a drop in blood counts and no decrease in efficacy (perhaps even an improvement), when vitamin B12 and folate were given to patients along with alimta. Since then, starting patients on B12 and folate before starting alimta has become the standard approach.

Alimta was tested in NSCLC in a large trial with nearly 600 patients treated in the second-line setting. In this trial, reported by Hanna and colleagues (abstract here), both of these drugs were given by vein one day every three weeks, and each was given along with decadron, a steroid, for a few days around the time of chemo in order to minimize acute side effects, most notably the risk of a hypersensitivity (allergic) reaction. The trial breakdown was as shown here:

(click to enlarge)

The trial was remarkable for how similarly the two drugs worked. In fact, they both had the same modest response rate (but consistent for the best we've been able to do in second-line) of 9%, with another 46% for each treatment achieving stable disease:

They also had the same progression-free survival of 2.9 months for each group, the exact same overall survival at one year of 29.7% (identical down to a tenth of a percent), and a median overall survival of 8 months on both arms:

The results of the two arms are so similar that it's hard to even see that there are two curves. So they had the same activity, and a quality of life analysis showed no significant differences in quality of life. However, there were differences that favored alimta in terms of several side effects. The patients receiving alimta were significantly less likely to have a serious drop in white blood cells (also known as neutropenia, which is associated with increased risk of infections), neutropenia with fevers, or infections even without low blood counts. They were also significantly less likely to require support with growth factors like G-CSF (neupogen), or, quite importantly, to need to be hospitalized for fevers with low blood counts (which generally requires patients to come into the hospital for IV antibiotics) or to be hospitalized for any cause. Although the impression I and many other oncologists get is that patients tend to tolerate alimta more favorably overall, the other side effects on this trial were not significantly different between the taxotere and the alimta arms. Regardless, with such limited treatment options available for previously treated patients with advanced NSCLC, and with one more active agent with an apparently more favorable side effect profile (although with a higher risk of abnormal liver tests on alimta and a small risk of developing a rash), the FDA approved alimta for second-line treatment in 2004.

Since that time, alimta has been widely used in this setting and also increasingly in other aspects of lung cancer. In the US, it is now used more commonly as second-line treatment than taxotere, because many patients have tolerated it very well, and it is given over 10 minutes every three weeks, which is a very convenient schedule for many people. It isn't asscociated with hair loss either, which is a nice feature for many patients. There are still plenty of patients who complain of significant fatigue and other side effects on it, but considering its activity, it often has a very favorable therapeutic ratio, the balance of efficacy vs. side effects. And since it has proven its value in previously treated lung cancer and in mesothelioma, two very high bars to show benefit, I expect that it will also prove itself to be a very active and useful drug in other settings of lung cancer and oncology in general in the coming years. The research is ongoing, and I"ll share results as they become available.