During the entire time I’ve been commenting on the most evidence-based and commonly used agents for previously treated patients, I’ve focused on taxotere, alimta, and tarceva (example in prior post here). In fact, that overlooks an agent that has actually been tested in a large study and been found to have similar activity to taxotere, but it remains pretty much an afterthought. The drug is topotecan, tested in an oral form that is just becoming commercially available; here I’ll summarize the trial that illustrates that topotecan is a reasonable option but also suggests why it remains relegated to a lower priority than the other three options we tend to think of more readily.
At the ASCO meeting in 2005, Dr. Rodryg Ramlau from Poland presented the results of a large phase III international trial (ASCO abstract here) that directly compared oral topotecan to the standard of IV taxotere as a second line therapy for advanced NSCLC (subsequent publication abstract here). This study randomzed 829 previously treated patients enrolled from both Western and Eastern Europe to receive either taxotere at the typical dose of 75 mg/m2 IV one day every three weeks, or the altenative of topotecan by mouth at 2.3 mg/m2 for each of the first 5 days of a three week cycle. Treatment continued until there was evidence of progression or excessive side effects:
The study was designed to test whether topotecan was definitely inferior to taxotere or more or less similar, and it technically met the criteria to be considered not significantly worse than taxotere. However, at any given time point of follow-up, survival was better for the recipients of taxotere:
The response rate was 5% for both arms, which is just a little lower than some other studies of taxotere as second line treatment have shown.
The side effects of the two approaches were pretty comparable. While taxotere was associated with more frequent significantly low white blood cell counts (60% vs. 50%, so pretty common for both chemo regimens), topotecan was associated with a greater need for transfusions of both red cells (26% vs. 10%) and platelets (26% vs. 7%).
The study also evaluated several measures of quality of life (QoL), looking at a range of cancer-related symptoms to see how they changed over time. As we tend to see with treatment of advanced lung cancer, symptoms get worse over time even with treatment, but for every factor that was measured, the taxotere arm did better, with a slower rate of worsening than with topotecan:
So at the end of the day, topotecan was fairly comparable, but it was actually a little inferior to taxotere in both survival and QoL measures from start to finish, and it was associated with a greater need for transfusions. People came out of the original ASCO presentation less than blown away, since there was really nothing to recommend it over taxotere. Meanwhile, alimta had been shown to have nearly identical activity to taxotere but with significantly fewer side effects in terms of dropping blood counts, becoming a widely favored alternative.
Based on the findings from this study, I would relegate topotecan to the lower part of the list of agents that would be worth using for previously treated patients with advanced NSCLC. With taxotere, alimta, and tarceva appearing to have quite comparable activity overall (although we still don’t have the results of a head to head comparison of taxotere or alimta vs. tarceva, but that trial is being done), I think topotecan falls a little behind the rest. Nevertheless, it’s in a class of drugs that is similar to irinotecan (camptosar) but different from the taxanes (taxol, taxotere) or alimta or gemcitabine, so for the relatively uncommon patient who has already received the other options, it offers an altenative that is commercially available and actually has some evidence to show it belongs on the short list of drugs with established activity in patients who have already received chemo for advanced NSCLC.
posted by Dr. West @ 8:03 am link to this post
Loading ...
March 1st, 2008 at 7:33 pm
Is there really a scientific basis for calling a drug a 1rst, 2nd or 3rd line treatment or is it simply that most drugs haven’t been tested in phase 3 trials past first line. It seems like testing a drug in second or third line is mainly about finding a way to get FDA approval. In the trial discussed above the response rate to both topotecan and taxotere was only 5%. I would not be surprised if the response rate in previously treated NSCLC patients with any drug that has proven efficacy in NSCLC for first line treatment wasn’t similar(at least if not previously given). Are there studies with first line treatment such as taxol or cisplatin regiven to patients to see what the response rate is? I realize it is expected resistance has developed if a patient has progressed within a few months of a given cancer treatment but I wonder if this has been really tested or is just assumed. In my wifes case we are revisiting her first line treatment with carbo, taxol and avastin as it is a way to get the avastin past the insurance company and it resulted in a complete if temporary response two years ago. It is my wifes 4th line treatment. Her only treatment the last one and a half years was tarceva and hopefully if resistance developed it may have decreased due to continued mutations during this long period without chemo.
March 2nd, 2008 at 9:05 pm
That’s a very good point. Some agents have been better tested, and some less well tested, as second or third line treatments, but that doesn’t mean that other first line agents wouldn’t have comparable activity. We’ve seen that cisplatin/taxotere or carbo/taxotere has remarkably similar activity as various other platinum doublets in first line, and the same can now be said for cisplatin/alimta and carboplatin/alimta, so we could presume that other agents like gemcitabine or taxol that haven’t been well tested as second line or later treatments would be similar to the better tested agents. Yes, it’s largely based on getting approved and gaining market share, and the companies with drugs that are widely used and approved as first line treatments, such as gemcitabine or taxol, aren’t struggling to figure out how to move into the much smaller third or fourth line markets — so they don’t get tested.
Absence of proof isn’t proof of absence, so it’s not unreasonable to think that gemcitabine would be comparable to taxotere or alimta as second line treatment in patients who hadn’t received gemcitabine previously. But most people aren’t going to be able to get more than three kinds of treatment, so we generally just try to use the agents that have the best evidence and are approved for that indication, all other things being equal. But if we were to extrapolate, it’s reasonable to consider other unused altenatives with some kind of track record in lung cancer.
-Dr. West