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Dr. Jack West is a medical oncologist and thoracic oncology specialist, and Executive Director of Employer Services at the City of Hope Comprehensive Cancer Center in Duarte, CA.

Impressions on the Trial of "Maintenance"/Early 2nd Line Alimta vs. Placebo
Fri, 06/06/2008 - 15:23
Howard (Jack) West, MD, Associate Clinical Professor, Medical Oncology, Executive Director, Employer Services, Founder, President and CEO of GRACE

A couple of weeks ago I described in a prior post the design and general results of a trial coded as JMEN by the sponsor company, Eli Lilly. This study randomized patients to either maintenance/early second line alimta (pemetrexed) or a placebo after four cycles of initial platinum-based doublet chemo with a drug other than alimta. The randomization was only for the patients who didn't progress after the first four cycles of chemo, and as described in the prior post, there was a very highly statistically significant improvement in progression-free survival with maintenance alimta, and while the overall survival benefit wasn't quite statistically significant, it was a very respectable difference of nearly three months (9 vs. 12 months) that was arguably quite clinically signficant and was associated with a "p-value" of 0.06 (meaning there was only a 6% chance that the difference could be by chance alone, while the standard cut-off we use is a p-value of 0.05, or a 5% or less probability of a difference being by chance alone) .

Combined with the results from a pretty similar trial of immediate vs. delayed second-line treatment with taxotere (docetaxel) that was presented at the ASCO meeting last year (see prior post), we now have two recent large studies that show major improvements in progression-free survival and a nearly significant improvement in overall survival. Taken together, these results are arguably enough to change our standard approach to moving second line treatment to right after first line, effectively blurring the edges so that non-progressing patients transition straight to maintenance therapy after 4 cycles of first line chemo (or possibly 6 as a variant that wasn't used in these two trials, but you'd likely have many patients show progression between the 4th and 6th cycles).

If you believe this, there are still several open questions for which we just don't have evidence to help provide an answer. For example, it's standard to give patients on first line chemo/avastin (bevacizumab) maintenance avastin alone after 4-6 cycles with the chemo. Should these patients now switch to alimta with avastin, or taxotere with avastin, as a new combination maintenance therapy? These combinations have been studied in small trials, but they aren't a standard approach at this time. The same issue of potentially overlapping maintenance strategies applies to the EGFR monoclonal antibody erbitux (cetuximab) if we consider the results of the recent FLEX trial to be worthy of making erbitux a standard of care for first line treatment, perhaps in avastin-ineligible patients or in other some other patients. We don't yet have any study results published that have reported the combinations of alimta or taxotere with erbitux, but there are large studies being done that are using these combinations.

Another question is whether maintenance tarceva (EGFR oral inhibitor erlotinib) after 4-6 cycles of initial first line chemo is a good idea. We don't have reported data on the issue of starting tarceva immediately after first line chemo in nonprogressing patients, but this research is being completed, and I suspect we may see results by next year. If positive, we'll again be thinking about various options that could include early/immediate second line chemo or tarceva, just as we have those options as "delayed" second line treatment that usually starts when a patient has shown progression. And tarceva could also be combined with avastin potentially as a maintenance strategy in avastin-eligible patients, as this combination has already been studied and has looked encouraging in a few trials (see prior post). We have very little data on tarceva with erbitux, but they've been combined in some small studies as well.

BUT there were plenty of skeptics at the ASCO meeting, and their concerns centered around one rather critical design flaw in the trial. That flaw is that the trial wasn't of immediate vs. delayed alimta, but rather that the arm of the trial that received placebo instead of alimta didn't necessarily get treated with alimta or anything else after progression. In fact, similar to the shortcoming from the taxotere trial of immediate vs. delayed second line chemo presented last year, many patients didn't receive any further treatment after progressing, so this alimta trial was partly a study of the patients on immediate maintenance alimta getting more opportunity for effective therapy than the patients on the placebo arm. In fact, 50% of the patients on the placebo arm received no additional chemo, and only 11% received alimta, with many others receiving agents without an established role in previously treated patients. This issue is a serious flaw in the trial, but my overall assessment is that the results suggest that immediate second line treatment also provides a greater opportunity for patients to get effective treatments and do better over time.

I wouldn't say that immediate transition to second line chemo is a clear standard that oncologists would be wrong not to pursue, but I'm likely to change my practice now to be much more inclined to offer and recommend maintenance chemo and believe the standard is now shifting. It's certainly still very appropriate to give a break to a patient who needs or just wants one, but I would say that the imperfect evidence supports the concept that survival is maximized by having patients on treatment for as much time as feasible, at least for the first 2-3 lines of therapy. And in someone who wants or needs a break, I'd be inclined to restart treatment within a month or two, as soon as they're up for it, rather than wait until they are definitely feeling worse from the effects of progressing cancer.

And while we don't have evidence yet with tarceva, I think it would be quite reasonable and tempting to substitute early/maintenance tarceva for chemo for patients with a minimal or no smoking history or with a known EGFR mutation, etc. But that will be a much stronger consideration once we see results from the ongoing studies looking at this.

One other significant issue that is worth noting is the JMEN trial of maintenance alimta showed a benefit that was only seen in patients with non-squamous tumors. This result really bolsters the idea put forth on the basis of another alimta trial (see prior post) that suggested that alimta is a significantly more effective agent for patients with adenocarcinomas and non-squamous NSCLC tumors compared with squamous tumors. We'll cover this issue more in the next post.

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