A few new agents emerged from the ASCO 2007 meeting as very real potential players in lung cancer.  Probably at the lead of that list, in my opinion, was axitinib (AG-013736, now a Pfizer product).  Similar to agents like sunitinib and sorafenib, this is an oral agent that blocks a target called the Platelet-Derived Growth Factor Receptor (PDGFR) and also is a potent, and selective inhibitor of three different receptors in the Vascular Endothelial Growth Factor (VEGF) family: VEGFR-1, VEGFR-2, and VEGFR-3 (scientists are very clever and original with such names, as you can see).  As is typical for any complex biological process, there isn’t just one ligand, the protein that fits fits the target, and a single receptor for it, but rather a family of ligands and receptors that act in a coordinated fashion to balance a mechanism like blood vessel and lymphatic channels (the vessels that move lymph, a plasma-based filtering fluid, between lymph nodes).   Here’s a basic schema of the VEGF ligands and receptors (VEGFR-2 is the dominant one):

 (Click to enlarge)

   Axitinib connects to the intracellular, back end portion that has kinase activity, which basically means that it turns on an enzymatic signalling pathway inside the cell with multiple activities, which in this case ultimately promote blood vessel production that can benefit a growing tumor.   Like lots of promising drugs, it inhibits cancer cells in test tube and animal models, but more encouragingly, it’s been studied and looks like it has anti-cancer activity human patients with kidney cancers and some other oncology settings.  This year, Dr. Joan Schiller, who heads the oncology program at the University of Texas-Southwestern Medical Center and also chairs the ECOG Lung Cancer Committee, presented results of axitinib as a single agent in previously treated patients with advanced NSCLC (abstract here).

   This study was designed to test whether axitinib is active as measured by response rate, or more than 50% reduction in the volume of measured tumors in patients.  It was designed to first enroll 18 patients, and then if the drug showed activity, to continue to enroll to 32 patients.  To be included, people with advanced NSCLC had to have received prior chemo but not prior anti-angiogenic treatment like avastin, and they could have received prior EGFR inhibitor therapy like tarceva.  They also could not have any history of serious hemotysis, or coughing up blood, nor have tumor involvement of central blood vessels in the mid-chest.  Treatment started with 5 mg by mouth twice daily, with an unusual design of allowing patients to increase to 10 mg twice daily if axitinib was well tolerated.

   Of the 32 patients enrolled, the median age was 66, with at least one up to 80, and the majority had received one or two prior lines of treatment.  Three quarters had an adenocarcinoma subtype.  At the time of her presentation, two of 32 were still on treatment, and 30 came off, usually for progression.  There were no complete responses (very unusual in advanced NSCLC, especially previously treated patients), but 3 (9.4%), had a partial response, while another 10 (31%) achieved stable disease.  Below you can see the “waterfall plot”, that shows the degree of change in the size of measured tumors, in which bars going up represent growth, and bars going down represent shrinkage (the blue bars reaching the criteria for objective response):

  As you can see, about 2/3 to 3/4 of the patients with measurements available actually had some degree of shrinkage.  The overall survival was quite encouraging, with a median survival of 14.6 months.  As you might expect, the 9 patients who hadn’t received a prior regimen for metastatic disease (such as those who had a recurrence after adjuvant chemo following surgery for early stage NSCLC), did particularly well, but they’re a category of patient that really hasn’t been included in prior second-line treatment trials, and the lung cancer research community is still considering whether they should be considered as candidates for first-line metastatic disease trials or second-line.  They’ve already gotten treated with chemo, but never for metastatic disease.

   Of course, no cancer treatment is toxicity-free, and there were significant side effects to contend with.  About 3/4 of patients experienced fatigue, and about 1/4 of the whole group reported significant fatigue.  Half reported diminished appetite, none severe.  Other common, but usually mild to moderate, side effects included diarrhea, high blood pressure, nausea, hoarseness, and joint pains.  Importantly, there were no lethal or life-threatening bleeding events, as have been occasionally seen with avastin and other anti-angiogenic agents.

   Overall, this trial certainly showed that axitinib is an active drug in NSCLC, with a median survival that exceeded a year.  However, it’s a small study done at a single center that included several patients who had received less prior treatment than many other trials in the second- and third-line setting.  It clearly merits further study, and we should expect to see further clinical trials of axitinib in lung cancer over the next few years.