Paclitaxel, marketed name Taxol, is among the most commonly used drugs in oncology in general, and definitely also for lung cancer, particularly NSCLC.  The combination of carboplatin/taxol is the most frequently prescribed combination for advanced NSCLC in the US and is also employed in many other settings for NSCLC as well.  However, there are several potential problems with taxol.  It is extremely hard to dissolve and requires a solvent called cremaphor (polyethoxylated castor oil — don’t worry, it’s not on the test!) and special tubing, as well as a three hour infusion time, to administer in its most common schedule.  Patients need to take multiple premedications that include steroids, which is a nuisance for lots of patients and a significant problem for some, such as those who have diabetes, because steroids can markedly increase the blood sugar levels of patients.  And despite premedications, it’s not uncommon for patients to develop significant hypersensitivity reactions that can be quite serious and, rarely, fatal.

   There are several novel formulations of paclitaxel and other chemotherapeutic agents that allow the same paclitaxel molecule to be delivered without the alcohol-based solvent, thereby eliminating the need for steroid premedications and a long “chair time” of patients having to spend most of their day getting chemo because it’s unsafe to give the chemo faster than that.  One of these is nanoparticle (tiny little particles) albumin bound (or nab) paclitaxel, which has the scientific name ABI-007 but is commonly known as Abraxane.  Not only is this special form of taxol faster to administer and doesn’t require the premedications that solvent-bound taxol does, there is also the possibility that this albumin-bound form may be delivered and picked up by the tumor than standard taxol.   In fact, there is some evidence that Abraxane may be superior in some ways to standard paclitaxel in breast cancer, where it has been studied much more than it has been studied in lung cancer thus far.  In a large trial with 460 predominantly (86%) chemotherapy pretreated women with breast cancer (abstract here), those who received Abraxane had a significantly higher response rate from Abraxane given every three weeks than standard taxol (21.5% vs. 11.1%), and they also had a significantly longer progression-free survival, but the overall survival was not significantly different.   It also had a no hypersensitivity reactions from the Cremaphor solvent, and lower neutropenia rates and severity of neuropathy (although the neuropathy with Abraxane remains a significant side effect challenge).  On the basis of this work, Abraxane was approved by the FDA in January, 2005 for recurrent or metastatic advanced breast cancer.

   Given that standard taxol is so widely used in lung cancer as well, particularly NSCLC, it made sense to also test Abraxane in advanced NSCLC.   There have been a few studies thus far.  Mark Green and colleagues published the experience in 43 previously untreated patients with advanced NSCLC who received Abraxane at the established breast cancer dose of 260 mg/m2 IV every three weeks, a 20 minute infusion (abstract here).  They reported the fairly encouraging result of a response rate of 16%, with one third of patients demonstrating stable disease for four months or longer, about half of the patients showed stable disease or better as their best response.  The median time to progression was 6 months, and the median survival was just under a year.  These results were considered particularly promising in light of the modest toxicity, with no grade 4 toxicity reported (side effects are graded from 1 to 5, with 1 being mildest, and 5 being fatal; most of our chemo treatments have some degree of grade 3 or 4, and sometimes grade 5, toxicity).  Another schedule for giving abraxane was reported by Naiyer Rizvi and colleagues from Memorial Sloan Kettering in NYC, who gave it to 40 previously untreated patients at 125 mg/m2 weekly for three weeks of every four, with a break in the last week (abstract here).  They noted a higher response rate of 30%, and another 23% with stable disease.   The median survival was again just a bit under a year at 10.9 months, and the main side effect they noted was cumulative neurotoxicity.

   It is the weekly approach that is being studied in combination with carboplatin, which is significant because platinum doublets, usually with carboplatin rather than cisplatin, are the cornerstone of most chemotherapy treatment plans in advanced NSCLC, at least in the US (I understand that much of Europe and the rest of the world are shifting increasingly from cisplatin to carboplatin doublets for advanced NSCLC).  Early results of a trial with 50 previously untreated patients who received carboplatin every four weeks and abraxane (100 mg/m2) weekly for three weeks out of four was presented at ASCO 2006 (abstract here).  The response rate was 50% with another 36% demonstrating stable disease; median survival was not reported.  Not surprisingly, with another drug added to abraxane, decreased blood counts were more of a problem, with 44% of patients having grade 3 or 4 neutropenia (low white blood cell count, very common with standard chemo combinations), but no serious neuropathy.  Another trial is being completed that is looking for the safe, optimal dose of Abraxane if carboplatin is given at the same standard dose (AUC, or area under the curve, of 6), IV every 3 weeks instead of every 4, and Abraxane is given weekly without a break.  The early results of this trial have apparently been submitted to ASCO this year, so I may have results to report back after that meeting in June (they are unavailable until the conference).

  Where will this lead to?  The company that makes this formulation of taxol, Abraxis Oncology, is developing a trial in which the identified best schedule for carbo with weekly abraxane on a three-week schedule is compared to standard carbo/taxol every three weeks in at least 1000 previously untreated patients with advanced NSCLC.  The trial will be looking for a significantly better response rate as the key difference (which the FDA has not always considered to be enough to approve a drug in a new setting, but I have to assume the company met with the FDA before committing millions of dollars to run this trial). 

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The trial will still be limited by the fact that it is not including Avastin, which is now generally considered to be a component of optimal treatment for the subset of patients who are eligible for it (see post on Avastin for restrictions, which probably amount to more than half of patients).  Ideally, a trial like this would include Avastin for either arm if the patient was eligible for it, but the safety of the combination of carbo/taxol/avastin hasn’t been tested.  Perhaps the company hopes that if carbo/Abraxane shows a significantly better response rate compared to standard carbo/taxol, people will switch to Abraxane over taxol even when avastin is included in the regimen, although I think it would be important to demonstrate the safety with Avastin, which can increase some toxicities when added to standard chemo regimens.

   And then there’s the issue of cost.  Although Abraxane has demonstrated some evidence of improved efficacy in breast cancer, namely a superior response rate and progression-free survival, it hasn’t taken the field of breast cancer by storm, and that’s partly because it is way, way, way more expensive than standard taxol.  How much of a difference?  A few hundred dollars vs. more than $10,000 per cycle, so oncologists and insurers and patients facing larger co-payments are asking whether, in the absence of a survival benefit at this point and in the presence of an ever-growing number of tragically expensive anti-cancer medications, the benefits are compelling enough to justify the costs.  As we get more information about Abraxane in lung cancer, we may consider the same “value judgment”.  In the meantime, Abraxane is a taxane that is readily used in breast cancer for patients who cannot tolerate other taxanes because of hypersensitivity reactions and has potential appeal far beyond that.  Although not FDA-approved and not standardly used in lung cancer, we will continue to gain more information about how best to use it in lung cancer as well.