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's 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.
The satellite symposium was funded by an educational grant from Bayer Schering Pharma.
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. Primary source: International Association for the Study of Lung Cancer meetingSource reference: Hanna N, et al "The Emerging Role of Multi-Kinase Inhibitors in Non-Small Cell Lung Cancer" IASLC meeting 2007; Satellite Symposium.

PET Scans May Predict Response in NSCLC Treatment

ANN ARBOR, Mich., July 19 -- It may be possible to determine whether non-small cell lung cancer is responding to radiation therapy before the course of treatment is over, a small study evaluating the predictive value of PET imaging suggests.
Changes in peak [18F]fluorodeoxyglucose (FDG) activity in tumors on PET images obtained during radiation therapy correlated significantly with post-treatment outcomes (P<0.001), investigators reported in the July 20 issue of the Journal of Clinical Oncology.
FDG metabolic activity in the lung did not change significantly from pre- to post-treatment PET scans, said Feng-Ming Spring Kong, M.D., Ph.D., of the University of Michigan, and colleagues.
In addition to using PET scans to predict long-term outcomes, the correlation between PET scans during and after treatment suggests FDG-PET imaging might be used to alter planned treatment, they added.
Efforts to individualize treatment for non-small cell lung cancer continues to be handicapped by an inability to determine whether a patient has responded to a given therapy until after completion of treatment, the authors noted. Several studies have shown that changes in tumor uptake of FDG correlated with pathologic response and overall survival. Post-treatment normalization of the standard uptake value appears to be a marker of complete tumor response and an indicator of favorable prognosis.
Conventionally, FDG-PET scans to assess treatment response are performed at least six to eight weeks after completion of radiation therapy and two weeks after chemotherapy. However, such an approach has limited applicability in clinical practice because it affords no opportunity to alter first-line treatment.
The Michigan investigators hypothesized that tumor FDG activity decreases during radiation therapy, that no confounding FDG activity occurs during treatment in the irradiated lung, and that changes in tumor FDG activity during radiation therapy correlates with the ultimate response.
To test their hypotheses, the group performed FDG-PET imaging in 15 patients undergoing radiation therapy for stage I-III non-small cell lung cancer. Scans were performed two weeks before the start of therapy, after delivery of about a 45-Gy dose of radiation (of a planned 60-Gy total dose), and three to four months after completion of fractionated radiation therapy.
Each of the three scans was evaluated for tumor and lung response by a nuclear medicine specialist and a radiation oncology. Response was determined on the basis of peak FDG activity, which is a reproducible measurement commonly used in clinical practice, the investigators stated. The primary endpoint of the study was tumor response at three to four months after completion of therapy.
On the basis of changes in tumor FDG activity, the investigators determined that 11 patients had partial metabolic responses, two had complete metabolic responses, and two had stable metabolic disease (including one non-FDG-avid tumor). Peak FDG activity decreased in all 14 of the FDG-avid primary tumors but not in the non-FDG-avid tumor.
The mean normalized SUV decreased from 5.2 before radiation therapy to 2.5 during treatment and to 1.7 post-treatment. The change in mean normalized standard uptake value differed significantly for all time-point comparisons (P=0.002 to P<0.001).
Peak FDG activity in the irradiated lung did not change significantly between pre-treatment and during treatment. Post-treatment scans revealed a small but statistically significant increase in FDG activity compared with scans during treatment (P=0.01). The findings disproved "the traditional belief that radiation causes inflammatory changes in normal lung tissue during RT," the authors asserted.
The PET imaging was performed with a PET-CT scanner. Changes in tumor FDG activity during radiation therapy had a significant association with post-treatment CT assessment of tumor response (P=0.03).
Although encouraged by the results, the investigators noted the study's limitations: small sample size, heterogeneous study population, and non-uniform treatment regimens.
The authors indicated they had no potential conflicts of interest. The study was supported by the American Society of Clinical Oncology, the Radiological Society of North America, and the National Institutes of Health. Primary source: Journal of Clinical OncologySource reference: Kong F-M et al. "A pilot study of [18F] fluorodeoxyglucose positron emission tomography scans during and after radiation-based therapy in patients with non-small cell lung cancer." J Clin Oncol 2007;25:3116-3123.