I think one of the most important lead stories from ASCO 2008 got buried. Nobody's really talking about it yet, but they should.

Amidst the results that led to an arguable role for erbitux and more compelling evidence to move second line chemo to bridge first and second line chemo together, we also received what I would consider to be very convincing clinical evidence that we can identify populations of lung cancer patients who are far more or less likely to benefit from alimta (pemetrexed), one of our most commonly used drugs in advanced NSCLC. Although alimta is considered a conventional chemo and not a targeted therapy, we're getting increasing evidence of how to target our convention chemo (such as by using ERCC1 levels to predict sensitivity to cisplatin, as discussed in a prior post). The new data from the JMEN trial of maintnenance alimta vs. placebo provides what I'd consider to be downright convincing evidence that alimta is a quite effective treatment for patients with non-squamous NSCLC and also appears to be far less effective or even simply not effective for patients with squamous cell NSCLC.

As I described in my first post about the "JMDB" trial of cisplatin/alimta vs. cisplatin/gemcitabine after it was initially presented in Korea at the World Conference on Lung Cancer in September, 2007 (abstract here, and prior post here), the finding that was interesting wasn't that the two regimens had essentially the same overall efficacy but a better side effect profile with cis/alimta (another platinum-based doublet vs. doublet comparison trial -- yawn...), but rather that the patients with adenocarcinomas has a significantly better survival with cis/alimta:

The opposite was true for those patients with squamous cell NSCLC, in whom the survival was borderline significantly better with cisplatin/gemcitabine (survival curve on the right showing squamous results. compared with "non-squamous" cancers that include not only adenocarcinomas but large cell NSCLC and "other" tumors that couldn't be classified):

This was a pre-planned analysis of the data, not just a fishing expedition. Why would Eli Lilly, who ran this trial, think that they might see very different results in patients with squamous vs. non-squamous cancers? Because they had discovered in a prior study, the "JMEI" trial (abstract here) that compared alimta to taxotere (docetaxel) as second line treatment for advanced NSCLC (and showed completely superimposable results overall but a better side effect profile for alimta, leading to its FDA approval and widespread use), that the patients with non-squamous cancers did better with alimta, while those with squamous cancers did better with taxotere:

I believe that discovery was more of a fishing expedition just looking at various factors and whether there might be a signal of who would do better or worse with alimta.

Now, an unplanned, retrospective look at the second line data provides nothing conclusive, but the idea that there may be a clinically meaningful difference by NSCLC subtype was definitely bolstered by the prospective and planned analysis of the first-line data. Still, that hasn't yet become the gospel in the lung cancer community. After all, these were trials of one chemo (drug or combination regimen) vs. another, so the differences can be from the strengths of one drug as well as the weaknesses of another when they're compared to each other. And up to now, the first line JMDB trial is really the only one in which we had seen a difference by histology (the retrospectively obtained results in the second line trial really weren't highlighted, but rather were considered by Lilly to be grounds for further study).

So all of this is a preamble for one of the key observations of the "JMEN" trial (see ASCO abstract and prior post) of maintenance alimta vs. placebo after 4 cycles of first-line platinum-based chemo. Here, because there's a placebo control, we can really identify what alimta offers or doesn't, because there's no competing chemo as a complicating factor. And we see that the benefits in terms of the primary endpoint of progression-free survival (PFS) (the primary endpoint), overall survival (OS), and disease control rate (DCR: the percentage of patients with significant tumor shrinkage or stable disease) were all limited to the patients with non-squamous NSCLC:

When you compare the results of alimta to placebo, there simply isn't a benefit in patients with squamous cell NSCLC. And the benefits in those patients with non-squamous cancers becomes even more striking.

So these kinds of results appear to be reproducible in several large studies, but are they biologically plausible. Yes, actually, since a key target of alimta is an enzyme called thymidylate synthase, or synthetase (TS), and since alimta is supposed to inhibit this to successfully block DNA synthesis effectively in cancer cells, and TS appears to be expressed at much higher levels in squamous lung tumors than adenocarcinomas, at least:

This work remains preliminary, but it's consistent with the idea that alimta is going to have a harder time being effective in tumors with high TS expression. It's possible that beyond just looking at the tumor's histology, we could also test tissue from an individual cancer to help predict who's likely to benefit from alimta vs. better off pursuing another treatment. That's not an option today, but we're going to see these kind of tests built into more lung cancer studies in the next few years, and its use in clinical practice may follow after that.

So let me clarify that I now believe this difference is very real and very significant. I wouldn't say that I won't use alimta in a patient with a squamous cell NSCLC, but I'll be much more likely to consider taxotere or another option and relegate alimta to a late choice, if I recommend it at all. We don't really know what works better with squamous cancers, but gemcitabine remains a strong option (handily beating alimta in the JMDB trial, after all), and the taxanes may still be a perfectly good choice. Meanwhile, just as with the commonly acknowledged "targeted therapies" like EGFR inhibitors, finding a group who don't benefit means that the benefit in the right patients is even more pronounced -- I'd feel even more confident about recommending alimta in patients with non-squamous NSCLC tumors.

Finally, as noted in the slide/figure above, TS levels also appear to be high in patients with SCLC. We'll turn to a large study of alimta in SCLC next. Spoiler alert: my mention of high TS levels is what your high school literature teacher referred to as foreshadowing...