Alimta Sensitivity Correlates with Never- or Light-smoking, Not ALK+ Status - 1247227

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Here’s my takeaway notes from reading the full article:

- Alimta sensitivity appears to be better correlated with never-smoker/light-smoker (NS/LS) status than with ALK+ status.

- The responses seen in ALK+ patients and in NS/LS patients are a little shorter than previously reported, probably due to (1) the %mix of patients getting Alimta alone vs. with a platinum chemo vs. with a non-platinum chemo and/or (2) the %mix of patients getting Alimta as 1st line vs. 2nd or later line.

- The best incremental response to Alimta appeared to correlate with treatments which used both Alimta and platinum-based chemo (e.g., cisplatin or carboplatin) (7.3 month median PFS, 8.5 in 1st line), much longer than either Alimta plus non-platinum chemo (5.5 mo.) or Alimta alone (4.4 mo. in 1st line). Therefore the %mix of these variations can be significant to a calculation of an average.

- Alimta response duration was a little longer in 1st line treatment than 2nd or later lines of treatment by about a month. Therefore the %mix of 1st line vs. 2nd or later line can shift the calculation of an average by up to a month.

- The %mix of patients in any of these studies might also be affected by the fact that some cancer centers may attract more traveling patients who have characteristics making them more likely to respond longer. (I’d imagine examples might be being healthier in general or having a simpler or slower cancer.)

(see rest of this in next reply)

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- A very small amount of sidebar data was shown for the correlation of low thymidylate synthase (TS) level with longer response to Alimta. (Some researchers hypothesize that low TS might correlate with Alimta response and it’s often (usually?) low in adenocarcinoma, but usually high in squamous or SCLC). The two individuals with high TS had the shortest duration; those with low TS had a range of duration from weeks to years.

- Two large randomized phase III trials (already underway) should be able to add more data on this subject, and better than the retrospective study reported here.

Best hopes,

Craig

[Re-edited Reply]

DenderDender,

That summary bullet point was not referring to the prior point about thymidylate synthase. The content underlying the bullet was this: "While there may be improved efficacy with front-line platinum/pemetrexed in ALK-positive and other never/light smoking patients, we believe pemetrexed-based chemotherapy is unlikely to be equivalent to crizotinib therapy in terms of efficacy. This question will be directly address in two ongoing randomized phase III trials. In the first-line trial, the comparator is platinum/pemetrexed, while in the second trial the comparator is either pemetrexed."

Neither alluded-to study was named as far as I can see, but I assume that one is probably one that was reported at the 2012 ESMO conference on Oct 1:
http://www.oncologystat.com/news/Crizotinib_Changes_Practice_for_Advanc…
This study refers to the PROFILE 1007 study, and found . . . "crizotinib (Xalkori) remained superior regardless of whether chemotherapy contained docetaxel (Taxotere) (7.7 vs. 2.6 months, ...) or pemetrexed (Alimta) (7.7 vs. 4.2, ...). (This is in contrast to some gov't policies that preferred Alimta prior to crizotinib.)

Best hopes,

Craig

PS -- FYI, if you are interested in learning more about thymidylate synthase (TS) as possible indicator of possible Alimta effectiveness, I recommend the NIH's PubMed database search function:
http://www.ncbi.nlm.nih.gov/pubmed
But it's not as simple as just needing a TS test to determine if Alimta will work. For example, based on a foreign research study in a similar-but-different drug, I'd hypothesize (or speculate) that maybe dihydropyrimidine dehydrogenase (DPD) is another possible factor that might need to be considered along with TS. And DHFR & GARFT might be somehow involved in the mechanism of action, too.

DenderDender,

I've edited my prior reply after re-considering what you intended by your question.

But I also like Dr. West's answer if you are looking for info about trials that are testing whether TS status can help improve prediction of Alimta sensitivity or choice of treatment.

Best hopes,

Craig