IASLC: Multi-Kinase Inhibitors Asserting Their Presence in NSCLC

SEOUL, South Korea, Sept. 7 -- Therapies that target several cancer pathways at once, such as multi-kinase inhibitors, might have an emerging role in non-small cell lung cancer.

"Traditional platinum-based chemotherapy has reached a therapeutic plateau," said Ulrich Gatzemeier, M.D., of Hospital Grosshansdorf in Grosshansdorf, Germany. And "agents working on single molecular targets may have limited long-term effectiveness because acquired resistance occurs in many tumors."

But, agents attacking tumors from multiple pathways have the potential to overcome these problems without the additive toxicity of combining single-target therapies, Dr. Gatzemeier and other oncologists at an industry-sponsored satellite symposium held in conjunction with the International Association for the Study of Lung Cancer' world conference here suggested.

Multi-targeted agents include sunitinib (Sutent), sorafenib (Nexavar), and ZD6474 (vandetinib), none of which are approved by the FDA for treating lung cancer.

Among them, sorafenib encompasses the most targets. It has been shown to have antiangiogenic effects by targeting vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR). It also acts against Raf kinase-mediated signaling involved in tumor progression and inhibits the receptor tyrosine kinases C-KIT and FLT3, Dr. Gatzemeier said.

This kind of multipronged approach makes sense because, although VEGF is "one of the lynch pins" of angiogenesis, "it's definitely not the only signaling pathway," added George Blumenschein, M.D., of the University of Texas MD Anderson Cancer Center in Houston.

Preclinical and clinical studies have shown sorafenib to have efficacy as monotherapy in non-small-cell lung cancer, he said, including one phase II study by his group in which 31% of patients had clear tumor shrinkage seen as cavitation on computed tomography imaging.

The drug gave similar response in second- and third-line monotherapy as other targeted therapies, Dr. Gatzemeier said. Findings across clinical trials were:

• 48% clinical benefit, defined as stable disease or partial response, and a median overall survival of seven months with gefitinib (Iressa).
• 44.9% clinical benefit and median overall survival 6.8 months with erlotinib (Tarceva).
• 59% clinical benefit and median overall survival 6.7 months with sorafenib.

The other multi-kinase inhibitors have also shown efficacy in advanced non-small-cell disease, said Nasser Hanna, M.D., of Indiana University in Indianapolis.

ZD6474 improved progression-free survival over gefitinib as monotherapy in second and third line disease in one trial (11.0 versus 8.1 weeks, hazard ratio 0.69, P=0.025). Sunitinib and the investigational multi-kinase inhibitor axitinib were shown to similarly yield 11.3- and 25-week progression-free survival, respectively, in trials.

Because the response rates and survival are similar between the multi-kinase agents and all target VEGF, "the difference in secondary targets will determine how they shake out in clinical trials," Dr. Blumenschein said.

Combining these agents with platinum-based chemotherapy regimens is likely the next stage, Dr. Hanna concluded. One such trial was recently completed, the phase III Evaluation of Sorafenib, Carboplatin, and Paclitaxel Efficacy in NSCLC (ESCAPE) trial of gemcitabine (Gemzar) and cisplatin (Platinol) with or without sorafenib.

"It's a challenge to know if manipulating single- or multiple-targeted agents is more effective than more general targeting," Dr. Hanna said.

Dr. Hanna reported financial conflicts of interest for Genentech, Lilly, Onyx, and Roche. Dr. Gatzemeier disclosed conflicts of interest with Bayer, Roche, Lilly, AstraZeneca, and Pierre Fabre. Dr. Blumenschein reported no conflicts of interest.