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.
posted by Dr. West @ 5:56 pm link to this post
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October 7th, 2007 at 7:48 pm
Dr. West: Here are the results that you said Dr. Hanna told you about regarding Alimta vs. Taxotere in second line setting. As you said you’d heard, Alimta did better for those with adenocarcinoma, and Taxotere did better for those with squamous cell. Is the magnitude of this difference about what you’d expected to hear? — Neil
http://newsroom.lilly.com/ReleaseDetail.cfm?ReleaseID=265678
October 8th, 2007 at 9:11 pm
Thanks for finding that, Neil. Yes, those numbers of about 1-1.5 month differences are very believable and consistent with the convincing but not staggering differences in the JMDB trial with cis/alimta or cis/gem. Most compelling is the fact that these results all corroborate each other. A single subset analysis probably shouldn’t be the definitive word, but if multiple trials in different settings all suggest the same thing, that’s probably a real finding.
-Dr. West
October 9th, 2007 at 8:32 am
Dr. West: I agree with you that the multiple results, combined with having a theoretical reason to expect them, means that this is probably a real finding. Two other points, one research-oriented and one a more practical question:
1. As you can see from the release, the Hazard Ratio for those on Alimta (versus Taxotere) was 0.78 for non-squamous cell patients. However, the upper bound of the 95% confidence interval was 0.997. (NOTE for those who are interested but not well-versed in statistics: this means that those on Alimta had an estimated 22% lower probability of dying than those on Taxotere. However, because this is a sample, that is only an estimate. The goal is is to be 95% sure that Alimta has at least SOME survival advantage over Taxotere in that setting. The range of Hazard Ratios means they just barely met that goal.) My concern is that medical researchers tend to treat this as an all-or-nothing issue. Had the upper bound of the confidence interval been 1.002 instead, we would see a report that says that they haven’t demonstrated the relationship in question. So, instead of two or three consistent results in different trials, the consensus would be that there were one or two positive results but that this one contradicts that to some extent. That would not be an accurate picture. I might also add that, given that there is a theoretical reason to predict that Alimta is superior in one case and inferior in another, a one-tailed test of significance is more appopriate than a two-tailed test. Indeed, the part of the curve that is above an HR of 1.00 is NOT a little less than 5%. It’s a little less than 2.5% (with the other 2.5% at the other end of the curve). Luckily, in this instance, this general problem did not matter, but I wonder how often it does.
2. On a more practical level, for someone like me who has adenocarcinoma, what are the practical implications of these findings. I’m convinced that Alimta is more likely to be a productive choice for me in either a combination setting or in monotherapy than would be Gemzar or Taxol (I’ve already had Taxotere). How to act on that finding is a question. I’m currently on Tarceva after showing mild progression on Carboplatin/Taxotere/Velcade. As indicated in an earlier post, if and when I progress on Tarceva, if my performance status is still very good, it is my intention to try a Cisplatin-based doublet, plus Avastin. My original thought was that I would try Cisplatin/Gemzar/Avastin. If that works, I would stay on maintenance Avastin. If that doesn’t work (or when I progress after success on that regimen), I would move to Alimta monotherapy.
The logic behind that is that Cisplatin/Gemzar/Avastin is a combination that has been studied (albeit in a first-line setting; there is, however, one very positive phase II study of Cisplatin/Gemzar in a third-line setting–even after progression on a Cisplatin-based doublet and Gemzar either as part of that doublet or as second-line therapy). Also, I note that there are three major NSCLC drugs that can be used in the long-term. I’m on one of them now (Tarceva). The others are Avastin and Alimta. I wouldn’t want to go with a combination that includes both of the others, as it would leave me with fewer options afterwards. Also, while Alimta appears to be superior to Gemzar in a cisplatin-based doublet, there is no evidence on how that doublet works with Avastin (but there is evidence that Cisplatin/Gemzar/Avastin is superior to Cisplatin/Gemzar). Finally, I recall (but can’t find right now) a report that “priming” with a platinum drug improves the response of Alimta (and that prior exposure to a taxane has a somewhat negative impact on the response of Alimta). Thus, I’d be tempted to do more priming (and take myself farther away from my minimal exposure to Taxotere) before trying Alimta.
I guess the question is whether this is being too cute for my own good. The more obvious approach might be to go with the doublet that is proven to be better in patients with adenocarcinoma and then figure something out in 4th line therapy.
I just thought of an analogy and then I’ll stop. It’s a little like the dilemma facing baseball managers in a 5 game playoff series (not that people in Pittsburgh or Seattle would know about that, and, sorry, Welthy, but the Cubs weren’t around long enough to face this dilemma). Down two games to one, managers face the question of whether to use their strongest starter (on less rest) in game 4 and then a solid starter in game 5 (if necessary). One school of thought is that you will need to win both games anyway so you save your strongest bullet for game 5. The other school of thought is that you should do everything possible to win game 4 and then figure out game 5 when you get there. The thought there is that it does no good to save a strong pitcher for game 5 if you’re eliminated in game 4.
Wow, the analogy really does make some sense, I think! What do you think? And are there any other practical implications for these findings? The obvious one would seem to be in choosing between Alimta and Taxotere as a second-line or third-line therapy if neither has been used already.
Sorry for being so long-winded.–Neil
October 11th, 2007 at 8:02 pm
Dr. West: Just giving this a bump. If you didn’t answer it because it’s too blathering, that’s fine. Just wanted to make sure you didn’t miss it accidentally.–Neil
October 11th, 2007 at 10:07 pm
Neil,
You were right that I missed this one. In terms of statistics, I think that while there’s always a danger of considering a trial simply “positive” or “negative”, we very often do put qualifiers on that. I described the trial of MAGE-A3 in the adjuvant setting as a very promising strategy, but that was technically a negative trial even though it generated a lot of attention and enthusiasm for the largest planned adjuvant trial in lung cancer ever. Or for the CALGB 9633 trial of carbo/taxol in stage IB, it was a negative trial, but we did look at subsets and put some serious consideration into the size of the tumor, based largely on the results of a subset analysis in this technically negative (but arguable just not positive enough) trial. I think there’s always a danger of throwing away the baby with the bathwater in separating trials simply as positive or negative, but I think oncologists often work to put the ambiguous results into context.
As for the second part, I think it’s a bit of a reach. It’s reasonable to consider cisplatin/gemcitabine/avastin as a salvage regimen, I suppose, but it’s more than I would personally be inclined to do. Instead, my generally approach would be to use a more sequential strategy, preserving more options longitudinally. But I think eventually we have to acknowledge that it’s like reading shapes of clouds, that your ideas are reasonable and mine are defensible too. I don’t think the data on priming are so compelling that I’d base treatment decisions on this work; really too speculative and intriguing than validated by many studies, in my estimation. I suspect that all of these approaches would lead to very similar results at the end of all of the treatment options.
-Dr. West