In my recent post on the JMDB trial that randomized patients between cisplatin/alimta and cisplatin gemcitabine in first line treatment of advanced NSCLC, the take home conclusions were that overall efficacy was very similar, with the cis/alimta arm looking a little better in several side effect parameters, most notably a less significant decline in blood counts and lower risk for fevers with a low white blood cell count. Also, the study showed the quite intriguing finding that those with adenocarcinoma and large cell tumors did signficantly better with cisplatin/alimta, while those with squamous cell carcinomas did notably (not quite statistically significantly) better with cisplatin/gemcitabine.

So a central question, first, is does this make sense? Actually, it very well might, because alimta works partly and potentially substantially by blocking a cellular enzyme called thymidylate synthase (or synthetase) (TS). There was a recent publication (abstract here) that demonstrated that levels of both messenger RNA (the code that is between the DNA and the protein it builds) and TS protein are significantly higher in squamous lung cancers than in adenocarcinomas, and also that the levels were higher in high grade cancers than lower grade ones. Higher TS levels would be expected to be associated with more resistance to alimta, while lower levels would be expected to correlate with sensitivity, as has been shown in some preclinical (lab-based) studies.

In fact, my understanding from a recent discussion with Dr. Nasser Hanna from Indiana University, who presented and published the important clinical trial that led to the approval of alimta in second line NSCLC (abstract here), is that they also saw considerably better results with alimta in the patients with adenocarcinoma on that study. I don't believe that's been published, but if true, it would corroborate the findings for the recent JMDB trial.

Does this mean that patients with adenocarcinomas should receive cisplatin/alimta? Well, many patients with adenocarcinomas are also eligible for Avastin, and the combination of carbo/taxol and avastin has also been shown to be signficantly superior in overall survival to another platinum-based doublet regimen. In the meantime, carbo/taxol/avastin is considered by most experts to be standard of care now for the people who don't have predominantly squamous cancer, or brain metastases, haven't coughed up significant blood and aren't on blood thinners. You couldn't presume that cisplatin/alimta would be better than carbo/taxol/avastin, and I think most of us would favor the chemo/avastin combination for appropriate patients. However, for patients with adenocarcinoma (or large cell NSCLC) who have brain metastases, or are on blood thinners or have had significant hemoptysis (coughed up blood), a non-avastin containing regimen that has shown a median survival of a year would make this regimen especially attractive. I would also consider it to be an especially strong alternative for patients who may technically be eligible for avastin but have a tumor right up against a big blood vessel, or a cavitating (hollowed out) tumor, or a borderline amount of hemoptysis. All of these patients may be at higher risk for serious or even fatal bleeding complications even if they are technically not excluded from receiving avastin.

I can almost hear the question people may be asking next: can we do even better by giving cisplatin/alimta with avastin? Perhaps, but that hasn't been tested. At the same time, carboplatin is far, far more widely used in the US than cisplatin, and it's unlikely that cisplatin will be embraced for advanced NSCLC over carboplatin anytime soon. We do have some data on the combination of carboplatin and alimta along with avastin, from my friend, Dr. Jyoti (pronounced JOE-thee) Patel, at Northwestern University outside of Chicago (abstract here). She reported on 39 patients with previously untreated advanced NSCLC who received carbo/alimta/avastin every 21 days and described an impressive response rate of 55% and one year survival of 58%, without new, fearsome side effects. While the results of this small trial would not be expected to be replicated in a much larger phase III experience, it certainly looks appealing. The discussant for this abstract, former ASCO president Dr. Larry Einhorn from Indiana University, raised the point that a terrific future study would include everyone starting with carbo/alimta and avastin (in patients without safety issues for getting avastin) for something like 4-6 cycles, followed by patients being randomized to avastin alone for a total of a year, continuing on alimta and avastin for up to a year, or stopping all treatment for a while and being monitored carefully:

(Click to enlarge)

As someone who has found the carboplatin/alimta regimen to be a very encouraging intersection of activity and often mild side effects, I agree that this is an attractive idea. But with the combination really only tested thus far in a few dozen patients, I would not be inclined to treat with this regimen outside of a clinical trial yet.

Finally, we shouldn't ignore that the cisplatin/gemcitabine arm demonstrated decidedly more favorable results for patients with squamous cancers. These patients are not generally considered good candidates for chemo/avastin combinations because of the bleeding risk, and because of that, chemo doublets remain the standard treatment for them. But as described in a prior post, we generally consider any of these platinum-based doublets to be almost completely equivalent, with little to recommend one over another. With cisplatin and gemcitabine now looking like one that might distinguish itself as particularly favorable for squamous cancers, it might be a tie-breaker among the many options. However, I wouldn't presume that the same favorable results would be seen with the more user-friendly and generally less toxic carbo/gemcitabine regimen.

It's not clear whether the results of this trial will have any lasting impact, but the findings do add to our growing story that we might continue to improve survival, one month at a time, by individualizing treatment. We'll have to see if thymidylate synthase levels as a predictor of benefit from alimta pans out. I'm sure this will be much more widely tested in the near future.