Last year, a provocative trial was presented at ASCO that compared early vs. later taxotere as second line therapy. I described that study here, and it showed a very significant improvement in progression-free survival (PFS) and a near significant improvement in overall survival (OS) for the recipients of taxotere immediately after four cycles of first line chemo for advanced NSCLC. These results were impressive enough that it would make us consider switching to a "maintenance" approach of giving second line treatment, in this case with taxotere, immediately after 4 cycles of first line chemo in non-progressing patients.

There were a few limitations to that work. First, some prior, generally smaller studies didn't clearly support the conclusion that maintenance or early second line chemo is definitely superior. Because of that, most experts felt that it would be helpful to get another study that supported maintenance chemo before we declared it a standard of care. Second, the prior trial waited a full three months before doing a repeat scan that would trigger a start of chemo in the delayed chemo arm -- and about 1/3 of the patients on that arm were too sick to get chemo by the time they were found to have progression. That's too long, in my opinion, to wait before checking for progression, which is often found radiographically before a patient gets too sick for chemo. With so many people in the delayed chemo arm not getting it, the trial was in some ways a study of everyone getting immediate chemo vs. 2/3 getting delayed chemo -- not fair.

But yesterday there was a press conference sponsored by ASCO to highlight the results of a trial sponsored by Eli Lilly and being presented at the oral presentation on advanced lung cancer at ASCO in two weeks (abstract here), and this result added to the prior study will likely change the standard of care, in my opinion. The new trial, called JMEN by Lilly (every common has their own cryptic coding for trial names, and I don't know if ANYONE really knows what JMEN refers to -- it's not an acronym), asked a very similar quesiton to the one from last year -- does maintenance chemo (or early second line chemo, depending on your point of view) improve progression-free survival, the time before someone shows cancer progression and needs to change treatment plans?

The schema is as shown here:

(Click on image to enlarge)

As shown in the figure, 663 patients who had received four cycles of initial platinum-based chemo (without avastin) and didn't show progression were randomized 2:1 to active chemo vs. an IV placebo every 3 weeks, and both groups received vitamin supplementation with B12 and folate, as is standard for alimta (who knows? maybe that leads to better results with a placebo as well).

The trial was clearly positive for demonstrating a benefit in progression-free survival as well as higher response rates achieved in patients overall who received an alimta "chaser" after initial platinum-based doublet:

As shown in the table, there was a nearly two month improvement in PFS overall, and a nearly 20% increase in response rate for the general population. These results were concentrated in the patients with non-squamous NSCLC, including adenocarcinoma, large cell carcinoma, and "other" (primilary histologies that couldn't be assigned because the tumor is poorly differentiated or there is too little tissue to clarify a particular NSCLC histology), and they look especially impressive in the adenocarcinoma patients.

In a prior study called JMDB that compared cisplatin/alimta to cisplatin/gemcitabine in previously untreated patients with advanced NSCLC (described in a post here), the cisplatin/alimta arm looked better for non-squamous NSCLC, while cisplatin/gemcitabine looked borderline significantly superior for patients with squamous NSCLC. Similar to that experience, in this maintenance trial there wasn't an improvement in the median PFS with alimta for squamous cell NSCLC patients. However, according to the table in the abstract the "hazard ratio" (abbreviated HR in most of the tables and abstracts) that reflects the overall improvement in PFS over the course of the entire time line was 30% better and statistically significant despite that. You can get a significantly better HR without improving the median if most of the improvement is before or after the median (which reflects just one spot in time, not the whole time course). The other explanation is that there was no improvement and that the number in their table from the abstract was an error. In any event, at the press conference, the lead investigator, Dr. Ciuleanu from Romania, said, "In the squamous population there was little change in progression-free survival with pemetrexed therapy, consistent with previous phase III trials". I'll let you know if the information in the table isn't correct, but it's fair to say that the results with maintenance alimta are at least less impressive in squamous NSCLC patients.

The trial hasn't collected enough long-term data to address any differences in overall survival, but the abstract and the press conference allude to a 20% improvement in OS with maintenance alimta, 13.0 vs. 10.2 months, that was just on the border of statistical significance (p = 0.06). Although I might have hoped for new and updated information at the meeting, the comments from the press conference sound like we won't learn more for another 6-12 months.

This does bring up the question of how important PFS really is compared with OS. I think this trial will be viewed as very influential because even if we consider OS to be far more important than PFS, the improvement by 2.8 months in the maintenance alimta arm is likely to be interpreted as very clinically valuable even if it isn't necessarily statistically significant. Combining these results with the Fidias trial of earlier vs. later taxotere, I believe that the new standard will be to use some kind of maintenance therapy after 4-6 cycles of first line chemo. We are already doing that as a standard of care with avastin for avastin-eligible patients, but we will likely see more people adding chemo or tarceva to avastin based on these results. While we don't have trial results yet on whether tarceva will provide a similar benefit to chemo as a maintenance therapy, the trials that will answer that question should be available and presented in the next year or so. And for the avastin-ineligible patients, I believe that while it will always be acceptable to give a treatment break to people who need it, our recommendation for patients without progression will be to transition immediately from first line chemo to a maintenance/early second line treatment.