Maintenance therapy for advanced non-small cell lung cancer was certainly the big theme this year in the lung cancer presentations. Let's start with the Alimta data. Dr. West has outlined earlier results of this study after this data was presented at the 2008 ASCO meeting.

First, a little background on the study: patients with advanced NSCLC first received four cycles of standard platinum-based chemotherapy. Usual practice at this point would be to observe the patient without further treatment, performing clinical evaluations and CT scans at regular intervals. Treatment would be initiated only if a patient's cancer started to grow or symptoms of the cancer reappeared. This study sought to reassess this long-held paradigm by evaluating whether it would be better to initiate Alimta immediately after the first four cycles of chemotherapy rather than waiting to initiate treatment when a patient's cancer progressed.

Maintenance Alimta Trial Design

(Click on figure to enlarge)

This strategy has garnered many monikers (maintenance, early second-line, switching, sequential) but for simplicity, I will use maintenance. The recent maintenance studies have looked at a single chemotherapy drug or a targeted agent/combination because the toxicity tends to be milder than continuing on with a doublet. Alimta had already been FDA-approved as a second-line drug for NSCLC when this study was initiated. This study was not restricted to patients with non-squamous cancers because, when it was designed, Alimta was approved for all types of NSCLC rather than just non-squamous. We already knew, though, from retrospective analyses of earlier Alimta trials that patients with non-squamous cancers appeared to the ones benefitting most from this drug.

When this study was presented in 2008, the average length of time before cancer progressed was 4 months for those receiving Alimta compared to 2 months for those receiving placebo. There was also a trend towards improved overall survival at that time though it just missed being statistically significant. Once their cancer progressed, patients were taken off the study and could receive a second-line treatment (in the case of those who had been on the placebo arm) or a third-line treatment (for those who had been getting Alimta) at their doctor's discretion. When these results were presented, some oncologists took issue with justifying the use of a drug as a maintenance therapy based on the endpoint of progression-free survival.

Let's use an analogy to understand this: Two people have high blood pressure. One takes her medicine at 6 am, the other takes hers at 10 am. From 6-10 am, the first patient had better blood pressure control. But if the patient who takes her medicine at 10 am does just as well in terms of important outcomes like stroke or heart attack or death, who cares about the morning blood pressure? And she gets to sleep in!

The results presented this year by Dr. Belani showed that overall survival for patients treated withAlimta maintenance was 13.4 months, compared to 10.6 months for patients who got placebo initially.

JMEN Overall Survival Alimta vs. Placebo Maintenance

For non-squamous patients (who constituted the 3/4 of the patients), overall survival was 15.5 months compared to 10.3 months in the placebo group. As expected, patients with squamous cancers did not benefit from Alimta.

JMEN Trial Survival by NSCLC Histology

While the majority of patients (67%) on the placebo arm went on to receive a second-line therapy, only 19% of those received Alimta. Of the patients assigned to receive Alimta maintenance, 50% of patients went on to receive a third-line treatment later, most commonly with Taxotere or Tarceva.

Severe toxicity with Alimta was rare, and some patients were able to receive many cycles before their cancer progressed.

So what does this study tell us? It confirms that Alimta is an active drug for patients with non-squamous histology and that giving it in the maintenance setting can be a good strategy for increasing survival in these patients. What we don't know, given the relatively low percentage of patients who ever received Alimta in the placebo arm, is whether giving Alimta as maintenance is better than waiting until the cancer progresses to give Alimta. To figure this out, we would need a trial design like that of the Fidias Taxotere study. In this study, patients were randomized to Taxotere as maintenance versus Taxotere at the time of progression.

Fidias Trial Immediate vs. Delayed Taxotere

The other outstanding question is, now that Alimta is approved (along with cisplatin) in the first-line setting for non-squamous cancers, would giving maintenance Alimta still be valuable or should patients receive some other maintenance therapy?

Will this study change my practice? It already has. After this data was originally presented in 2008, I began to discuss it with patients and did give maintenance therapy to some patients. For which patients did I give maintenance therapy? Mainly those who had been very symptomatic at the time of their original lung cancer diagnosis (for instance, those with shortness of breath from large pleural effusions or masses compressing their airways) or those who really did not feel comfortable with watchful waiting. Did I suggest it to patients who were still having side effects of first-line therapy? No. Did I tell patients I thought a treatment break following front-line therapy was contraindicated? No, and I still wouldn't.

Who stands to gain the most from maintenance treatment? We don't know for sure but we think those patients whose cancer is likely to progress rapidly or result in significant symptoms before we detect progression. Those might be patients who would get sick enough that we might miss a window of opportunity for treatment. This was demonstrated with the Taxotere maintenance trial where 37% of those initially treated with placebo were never able to get the second-line treatment.

I was encouraged by the prolonged median overall survival (15.5 months!) of patients on the Alimta arm – it demonstrates that with sequencing of the active agents in this disease (remember that many of those on Alimta went on to receive other approved agents later in the course of their disease), patients can do better than they ever have before. I knew I wasn’t just imagining it.

Stay tuned for commentary on some of the other maintenance studies presented at ASCO! I'm looking forward to hearing your comments.