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GRACE :: Lung Cancer

Abraxane Bests Taxol in Response Rate for NSCLC: What Might this Mean?

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In addition to developing new agents or refining which patients should or shouldn’t be given to particular patients, another way to potentially gain ground in fighting cancer is to improve the tolerability of a standard treatment in a way that either makes it more effective or reduces side effects, thereby making it possible to give higher doses. The drug Abraxane (nanoparticle albumin bound paclitaxel) uses the approach of coating taxol with albumin to reduce the side effects associated with standard taxol (paclitaxel), making it possible to give it without steroids (which can be a rather bothersome issue for many patients, causing problems from severe insomnia to very high blood sugars and more) and also reduce some other taxol-associated side effects like joint and muscle aches (see prior post on Abraxane for more background information). It’s also possible to give doses that may be high enough to work better than standard taxol. Abraxane has been approved in breast cancer since 2005, and it’s used here and there in lung cancer, but there is relatively little data about it in lung cancer. However, earlier this week, it was reported that a large trial of carboplatin/Abraxane vs. carboplatin/taxol for initial treatment of advanced NSCLC was “positive”, at least in terms of showing a significant improvement in response rate. But what does this mean for the field of lung cancer?

The short answer is that we don’t know because we need much more information, to be presented at the large ASCO meeting in early June, to really be able to assess the impact that this trial should have. For starters, response rate isn’t the most important endpoint in lung cancer, and I would consider it to be of relatively little importance compared with overall survival, tolerability/quality of life, and progression-free survival. Response rates represent the proportion of patients with tumor shrinkage beyond a strict set of criteria, but there are many reasons that the impact of a treatment may be dissociated from response rate. You’d definitely prefer to see major tumor shrinkage in more patients rather than fewer, but some treatments like the EGFR inhibitor Tarceva (erlotinib) or the investigational ALK inhibitor crizotinib (PF-02341066) may have a relatively or extremely low response rate in a broad population but be hugely effective in that group in which the cancer shrinks.

Still, it’s good to see more people with major tumor shrinkage, but a key issue is who the comparator group is (the control arm). In this trial, patients on the control arm received carbo/taxol, a perfectly acceptable and plain vanilla combination. It’s a very acceptable comparator because it’s essentially completely average. However, in North America today, many patients who are eligible for the anti-angiogenic agent Avastin (bevacizumab) receive that with carbo/taxol, because the three drug combination clearly beat carbo/taxol alone in terms of response rate, but also progression-free survival, and overall survival. That’s a combination of improvements that we’d hope to see. Importantly, the response rate in the trial of carbo/taxol with or without Avastin, the chemo alone arm had a response rate of only 15%. In contrast, carbo/taxol/Avastin had a response rate of 35% in that trial. Meanwhile, in a worldwide trial of cisplatin/Gemzar (gemcitabine) vs. cisplatin/Alimta (pemetrexed), the objective response rates were 28.2% and 30.6% respectively (the latter percentage including squamous cell NSCLC patients who are now known to not benefit from Alimta). My point is that carbo/taxol is completely fine, but beating it on response rate is not especially impressive. Meanwhile, we have many other treatments available now that can deliver on that (admittedly, comparing across trials in many cases), some associated with significant improvements in survival as well.

One other key advantage of Abraxane that is cited is that it doesn’t need to be given with steroids and spares patients some taxol-related side effects. That’s good, but we can already do that with Gemzar, Navelbine (vinorelbine), and some other readily available treatments.

Essentially, I’d say that this news is welcome, that it’s always good to get some positive trial results in lung cancer, but we really need to learn much more before we try to interpret the clinical significance of these results. The FLEX trial of chemo with or without the antibody against EGFR Erbitux (cetuximab) showed a rather marginal survival benefit along with an improvement in response rate, but it hasn’t been FDA approved and isn’t widely used or even felt to be especially appealing among many (probably most) lung cancer experts because of the lack of perceived significant benefit compared with the added side effects, requirement for weekly treatment, and very high cost. If Abraxane delivers only an improvement in response rate without even a significant improvement in progression-free survival or overall survival, I can’t imagine that the oncology world will be impressed. On the other hand, if it delivers a 2-3 month improvement in median survival, then it’s a legitimate contender as an attractive treatment for a broad range of patients. We’ll see when the actual data are presented.

As a few final points, I’ll mention that it’s relevant where the trial was conducted and how the patients do in absolute terms. One of the limitations of the maintenance therapy trials that have shown a survival benefit in advanced NSCLC is that only about 20% of patients on the placebo arms ever received the opportunity for the same active drug later, so access to what we’d consider optimal treatment was very questionable. I think that’s a problem with running trials in places with very disadvantaged health care systems just so that you can get the trials done quickly. If you run a trial primarily in central or eastern European countries where you’re lucky to get anti-nausea medication with your chemo and there’s no opportunity for second line therapy, are results generalizable to a health care system in which effective second and third line options are routinely available? If the Abraxane trial shows an improvement in median survival from 9.5 months with carbo/taxol to 12 months with carbo/Abraxane, that’s truly impressive. If it shows an improvement from 7.2 months with carbo/taxol to 9.0 months with carbo/Abraxane, that just means that carbo/Abraxane was average and beat very unimpressive results with carbo/taxol.

And then there’s cost. Abraxane is very, very expensive, and that’s perhaps justifiable if it offers major value. Avastin, Alimta, and Tarceva are also painfully expensive, and several other non-generic chemo agents aren’t exactly a bargain either. Taxol is available as a generic, so it’s cheap as an off-patent comparably effective chemo, and Abraxane is about an order of magnitude more expensive.

cup-of-ice-cream-w-sprinkles

A key question is whether a plain vanilla bowl of generic store brand ice cream (taxol) costs $1, and you add a few sprinkles, how much better is that? Even if it’s better than plain vanilla without sprinkles, is it worth $10? What if you can get Ben & Jerry’s Chunky Monkey for the same price or less? Carbo/Abraxane may beat the plain vanilla without sprinkles, but is it better than cisplatin/alimta, cisplatin/gemzar, carbo/taxol/avastin, or carbo/alimta/avastin? We don’t know whether carbo/Abraxane will be offer an improvement that is quite small (sprinkles) or pretty major (cookie dough and brownies) vs. plain vanilla, but it’s priced in the super-premium shelf of the ice cream section.

The press release doesn’t really provide us any meaningful information, and it provides yet another example of what seems like a marketing-driven hijacking of medical information that jacks up the price of the stock. We’ll see if actual evidence delivers, but right now I can tell you that a difference in response rate over carbo/taxol alone is not especially impressive on its own.


14 Responses to Abraxane Bests Taxol in Response Rate for NSCLC: What Might this Mean?

  • Derrick C says:

    I agree that the release of info from this study is rather sketchy. However what I find just as troubling about Abraxane vs Taxol in the taxane market is mounting evidence that Abraxane can likely be freely substituted for any treatment that that uses Taxol with as good or improved efficacy. The path to get to what appears rather obvious (versus proven) is clinically expensive as well.

    Evidence also suggests that the unique mechanism of albumin binding to SPARC in SPARC positive tumor expression is a reason Abraxane is superior. The survival gains in pancreas are seemingly there. The gemcitabine + ABraxane results speak loudly on this in pancreatic cancer. In the SPARC positive population the data is really much more impressive.

    From what I have seen the Abraxane SPARC combination is really impacting MDR (which is probably what has happened here) and attacking the stroma as well. The albumin seems better at getting the drug into the cells not just at eliminating the cremaphor poison and steroids.

    I really wish the clinical research was faster to get to the true benefits of Abraxane in dealing with albumin hungry tumors and MDR.

    One thing I do believe is there is evidence mounting for the research community to get to the point of embracing Abraxane more widely in Sparc positive cancers or trials. The data hasn’t caught up to the obvious mechanism reality because of trial cost burden I think.

    Hopefully more genetic profiling of tumors will speed up decision making to get the right drugs into the right patient tumors and trials. I hope the ASCO presentation again highlights the data with respect to SPARC status in this trial. Maybe then the NIH can help move Abraxane vs SPARC cancers along as well.

    On another point I am encouraged by the I-spy2 announcement because I believe this is exactly the type of approach that would have moved Abraxane from the slow lumbering path to new indications to a faster path for SPARC positive indications in a wider range of cancers.

    Anyway my fingers are crossed for survival data for the sake of lung cancer patients especially SPARC positive ones.

  • Dr. Weiss says:

    First, let me please thank Dr. West for this excellent commentary. We both thought that it was important to comment on this press release, but I did not want to be the first to do it. First, I have two major potential conflicts of interest: I just accepted a job at UNC working under Dr. Mark Socinski, the PI of the trial, and I have applied for funding for a trial with the company that makes the drug, Abraxis (although it’s a head and neck cancer trial, not lung). I felt between a rock and a hard place—I don’t want to have my objectivity questioned and also don’t want to offend my collaborators. Therefore, I am even more grateful to Dr. West than usual for writing the post. Now that he has, I’d like to also share a few thoughts, as this conversation could potentially take us way past one drug, but into a meaningful discussion of how drugs are approved, and how to think about trial results.

    First, I’d like to add to the explanation of why nab-paclitaxel (abraxane) MAY be a better drug IN LUNG CANCER. Getting rid of the cremaphor doesn’t just get rid of the steroid requirement. By eliminating cremaphor’s side effects, you can get a higher amount of the active drug in. Further, tumor cells like albumin and so the albumin binding may cause some selective uptake of the drug by tumor cells. Any differences in cell kill between taxol and abraxane may be tumor type dependent—in other words, the results from breast won’t necessarily be the same in lung (for better or for worse) or other tumor types. This difference, if it exists, may also vary by individual patients, and there may ultimately be markers to help us tell who will do better with abraxane, and who will do just as well with taxol.

    The trial asks an important question: In combination with carboplatin, is abraxane more effective than taxol? Dr. West argues that for metastatic disease, response rate is a poor measure of effectiveness, and I agree. I apologize for those who’ve heard me rant this important line too many times, but it’s worth repeating: There are two purposes, and two purposes only to treating cancer. 1) The patient should live longer. 2) The patient should live with a higher quality of life. For neoadjuvant therapy (chemo given to shrink cancer before surgery or some other curative-intention modality) response rate may be an important measure. For metastatic disease, overall survival, toxicity, and quality of life are the most important endpoints.

    So why did the company design the trial to look at response rate as the primary endpoint? It may not be as sinister as many think, but rather may come from the FDA. The FDA agreed in advance to the original trial design under a special protocol assessment. In particular, the application is via the 505(b)(2) process. This process smooths the path for a drug that is similar to an existing drug, in this case, taxol. My understanding (which I will freely admit is limited) is that the FDA may have preferred response rate, because it was the original endpoint of older studies looking at carbo/taxol, the similar regimen. I will also note that while response rate may be the 1st endpoint that we see, the trial was also powered to show, if present, a difference in progression-free survival and overall-survival, so we will eventually see these #s.

    One advantage of the press release, in terms of GRACE, is that it allows us to comment on what a meaningful advantage would be BEFORE data are announced, in effect keeping Dr. West and I honest. So what #s really matter? I think that the survival difference necessary to consider this a real advance depends a lot on toxicity. If abraxane ends up being more tolerable than taxol in this phase III trial, I’d accept a smaller survival advantage as the minimum that’s worth it. If it’s much more tolerable, I might even accept similar survival. Similarly, if it’s not much better tolerated, then I would demand a higher survival difference. Personally, I disagree with Dr. West that an improvement from 7.2 months to 9 months would not be meaningful. If most of the patients were enrolled in Eastern Europe where 2nd line therapy is less common, these #s would be reasonable, and enough to give me the idea that abraxane is more active in lung cancer than taxol. I agree with Dr. West is that this would not tell me where abraxane should fit in my arsenal, as I do have access to avastin, pemetrexed, gemcitabine, docetaxel, vinorelbine, tarceva, and soon , PF-02341066. However, if there is a one month survival advantage, and if abraxane were more tolerable than taxol, then at times where I currently reach for taxol, I’d have to consider instead reaching for abraxane.

    As far as cost goes, I fully acknowledge that abraxane is much more expensive than taxol. It will be up to the government and our policy makers how much they’re willing to pay for a given survival advantage. I’m trying to learn more about this, but at this time don’t consider myself enough of an expert to comment further.

  • Mark116 says:

    Is the review you provided above the same study shown here: http://www.slm-journals.com/news/current/single-news/date////loren-ipsum.html?tx_ttnewsbackPid=18&cHash=d125885fdd
    European Journal of Clinical & Medical Oncology Publishes Meta-Analysis of Phase II and Phase III Trials Supporting Tavocept’s Potential to Increase Lung Cancer Survival

    If it is it is interesting to see the differences in analysis and comment.

  • Dr West says:

    No, that agent has been studied occasionally as a potential protectant against neuropathy but hasn’t really appeared promising enough for the researchers I know who have worked with it to consider it promising enough to continue to study it. Despite the rather promotional comments from the head of the company, I don’t think there will be much enthusiasm for the drug described in the link above (BNP7787) unless or until it shows a statistically significant improvement in survival in a phase III trial. The authors of a CALGB trial that combined cisplatin/taxotere, and BNP7787 found that the investigational agent didn’t seem to reduce cisplatin-induced side effects in any meaningful way.

  • Dr West says:

    Derrick,

    I will be very interested to see the results as a function of expression of the biomarker SPARC (secreted protein acidic and rich in cysteine), which has been posited as a highly relevant variable for benefit with Abraxane, but the company didn’t mention anything about this in their press release, which wasn’t meant to be informative as much as promotional, I believe.

    We will have to see what the data show. In the meantime, I’m not a fan of speculating based on a presumed mechanism of action that doesn’t at this time have the clinical data to support it. I entirely agree that Abraxane, like Tarceva or crizotinib, could potentially be far more compelling if it becomes possible to identify subsets of patients far more likely to derive major benefit from it.

  • kaysey says:

    *Little squeaky voice from the peanut gallery*

    I’m on Abraxane as the result of targeted tumor v chemotherapy testing. I have no real basis of comparison – platinum based chemo didn’t affect me at all – there was some marker they found that showed platinum was unable to penetrate my cell wall or something. They found a bunch of different mutations – My Abraxane infusions are 260 mg once every 3 weeks – not weekly – and even though they say you can do without steroids, I’m a big sissy – take 4 mg dexamethasone before and after – otherwise I can’t walk! Sore bones and muscles are a big deal. And the neuropathy is terrible – actually Abraxane has the worst track record for neuropathy, but it’s probably because of the higher dose you get – the worst for me is getting off the steroids – they make me feel sooooo much better, but I know they’re not good for you. Thanks for looking into this article – it’s good to have a big hairy eyeball on these studies sometimes – you’re right – some are way more promo than education.

  • Dr. Weiss says:

    Dr. Socinski just presented the data from this phase III trial comparing carbo/taxol to carbo/abraxane at ASCO 2010. Response rate was 25% for carbo/taxol and 41% in carbo/abraxane. In squamous cell carcinoma, response rate for carbo/taxol was 24% and 41% for carbo/abraxane. For non-squamous histology, response rate was 25% for carbo/taxol and 26% for carbo/abraxane. With carbo/taxol there was more neutropenia and more neuropathy; with carbo/abraxane there was more thrombocytopenia (low platelets) and more anemia. Specific data are as follows:

    Abraxane G3/4 (514 pts) Taxol G3/4 (524 pts)
    Neuropathy 3/0 10/0
    Myalgia 0/0 2/0
    Thromocytopenia 13/4 6/2
    Anemia 22/5 6/0

    I find it interesting that the response rate advantage here was limited to patients with squamous histology. Abraxane may be taken up preferentially by tumor cells by a gp-60 caveolin mechanism and may be preferentially retained by a SPARC mechanism in the tumor microenvironment. It is possible that there are histology dependent differences in caveolin and/or SPARC. These difference could be key to predicting abraxane’s success in other squamous cell cancers, such as head and neck cancer.

    The decreased neuropathy is probably due to getting rid of the cremaphor solvent that is needed with taxol. Only patients (you!!!) can say how valuable the decreased infusion time (3 hours for taxol vs. 30 min for abraxane) and the lack of need for dex are.

    We should have PFS data later in the year and overall survival data sometime later. We are likely to never have biomarker data on a substantial number of patients from this trial.

  • catdander says:

    Thanks Dr. Weiss for your input on this trial. As wife of a squamous cell nsclc patient it is great news. Is abraxane FDA approved yet? and Would there need to be trials before it is given as a single agent? or Do we need to wait and see what the OS rate is before thinking about it as a next option even if a taxene is a next obvious line of treatment? breath

  • Dr. Weiss says:

    Abraxane is FDA approved for breast cancer, but not for lung cancer. After the ASCO report, I strongly suspect that Abraxis will be filing for an indication in lung CA. They will likely receive only a 1st line approval, not a later-line approval. In addition to not having survival data, we also don’t have phase III data for later lines of therapy. How oncologists use abraxane in later lines of therapy will depend on how willing they are to extrapolate and new trial data to come (clintrials.gov pulls up hundreds of taxol studies when I search for “abraxane” so I’m not sure what’s in the works). I have real hope that abraxane will be better than taxol in later lines; next I speak with the folks at Abraxis I’ll ask them about what’s being studied and will post it here.

  • 475blue says:

    Thank you Dr. West and Dr.Weiss, I had asked the question is Taxol the generic for Abraxane, the reason for the question is I have stage 4 metastatic breast cancer, spread to the lungs and t3, t4 & 5 spine, I was taking Abraxane once a week for 3 weeks one off, when I received a call from my doctors office stating that my insurance Keystone Hmo of Pa, will no longer pay for Abraxane at 100% that I will now be responsible for the 20%, I said ok and what would that be, they said it will cost me $500.00 a treatment and because it is so exspensive, I will have to pay the money up front, because of my back pain I can no longer work and am on disability, my check doesn’t even come close to the amount they want me to pay, my neice did some research and according to the blog Taxol is a generic to abraxane, one Dr. said that people that do not have the money, he puts on taxol, after reading your post I understand that the taxol is given in a 3hr dose where abraxane is 1hr and if I understand it, taxol has to have steroids given at the treatment, I guess what I wanted to know is should I try and change my insurance to cover the Abraxane or should I take the Taxol which is cheaper, the blog that I read was that they took a cheaper drug taxol made some enhancements and is charging 10 times more, that the death rate is the same, and that the other insurances will follow their lead, also is there anything else that I would have to take along with the taxol other than steroids, I really like my doctor, but it is good to be your own advocate and ask questions.

  • Dr West says:

    Of course it’s entirely appropriate to ask questions and look at many sources even if you’re happy with your own doctor.

    Yes, to answer your question, Abraxane in breast cancer does have some conveniences of a shorter infusion and a lack of a need for steroids, as well as a lower risk of problematic peripheral neuropathy over time, but it isn’t associated with a survival difference. Whether it’s worth a significant premium is really in the eye of the beholder, and how much someone can afford to pay the extra is certainly an issue. Abraxane really is a modified version of the generic drug Taxol (paclitaxel), and there is not an exceptional difference in efficacy. I think that to many doctors and patients, if the practical cost difference isn’t a major sacrifice, it’s preferred for breast cancer, but the incremental benefit isn’t so substantial that receiving Taxol instead would be missing out.

  • ts says:

    Hi 475Blue,

    You might also see if you qualify for the Abraxis Oncology Patient Assistance Program. I know I could not have afforded my last year of targeted therapy without assistance. Since it has been working well for you, it is definitely worth checking to see if they can make this available to you for free or a small copay!
    http://www.abraxane.com/patient-assistance.aspx

  • Dr. Weiss says:

    I would not consider abraxane to be the generic of taxol. Taxol is the brand name of a drug, paclitaxel that is now generic. Abraxane is nano-albumin bound paclitaxel. The extent to which the two drugs are the same or different may vary by tumor type and biology.

    While we’re commenting on abraxane, I will note that on Celgene’s investor conference call, they mentioned that PFS of the carbo/taxol vs carbo/abraxane trial did not meet statistical significance. They did not release the actual numbers and have not yet broken it down by histology.

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