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Four Drug Combination Helps in Lung Cancer


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http://www.reuters.com/article/healthNe ... OI20081113

Four drug combination helps in lung cancer: U.S. study

Thu Nov 13, 2008 12:52pm EST

By Maggie Fox, Health and Science Editor

WASHINGTON (Reuters) - Combining two chemotherapy drugs with two targeted therapies was safe and appeared to help patients with advanced lung cancer live longer, U.S. researchers reported on Thursday.

The combination of Roche and Co's Avastin, ImClone's Erbitux, carboplatin and paclitaxel appeared to add an average of two months to the lives of patients, from 12 months on average to 14 months, the team at the University of Texas M. D. Anderson Cancer Center said.

It was the first time two targeted therapies were used together with traditional chemotherapy in this way and M.D. Anderson's Dr. Edward Kim said the Avastin and Erbitux appeared to work synergistically.

"The rationale behind the study was the finding that Avastin enhances the efficacy of existing therapy, thereby possibly improving the carboplatin-paclitaxel-Erbitux regimen," Kim said in a statement.

"While early, this four-drug combination seems to show promising, yet modest improvement in efficacy without compromising patients' safety," Kim added.

He said his team would analyze the tumors to see if there were so-called biomarkers that can predict who would do best on this therapy.

Avastin, known generically as bevacizumab, is a monoclonal antibody, a genetically engineered immune system molecule, that targets vascular endothelial growth factor or VEGF. VEGF helps tumors grow a blood supply and Avastin is a so-called angiogenesis inhibitor that helps choke off that supply.

Erbitux, known generically as cetuximab, is also a monoclonal antibody and angiogenesis inhibitor but it targets a different blood-vessel-promoting molecule called epidermal growth factor receptor or EGFR.

The two older chemotherapy drugs, paclitaxel, sold under the brand name Taxol and carboplatin sold under the brand name Paraplatin, both by Bristol Myers Squibb, kill tumor cells directly.

Kim told the 2008 Chicago Multidisciplinary Symposium in Thoracic Oncology that his team tested 110 patients with stage 3 or 4 lung cancer in a phase II safety and efficacy trial.

The patients got six cycles of all four drugs and then as maintenance continued infusions of Avastin and Erbitux.

Four patients died from the treatment -- Avastin is known to sometimes cause internal bleeding -- and 40 patients had the usual side effects such as nerve pain and low blood counts.

But 53 percent had their tumors shrink and 24 percent had stable disease. On average patients enjoyed seven months before their tumors started growing again and lived 14 months.

Patients who previously got three drugs without Avastin lived an average of 5.5 months before their tumors started to grow again and 12 months overall.

Lung cancer is the leading cause of cancer death globally, with 1.2 million deaths a year and 114,000 annually in the United States, according to the American Cancer Society.

While many drugs are used to treat lung cancer, they almost all stop working eventually.

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A targeted drug agent refers to an antibody (chemical structure) that is only supposed to interact with one type of molecule in the body. The idea that a targeted drug can interact with only one pathway and work only on one cellular pathway is unlikely. Molecular pathways inside cells have an incredible amount of cross-talk. So blocking one molecule precisely is like keeping one person from talking and expecting that the rumor won't spread just as fast.

Targeted therapy halts the growth of certain cancers by zeroing in on a signaling molecule critical to the survival of those cancer cells. The drugs work specifically in patients whose cancers contain mutations in a gene that encodes the epidermal growth factor receptor (EGFR), vascular endothelial growth factor VEGF, or some other pathway. Although these targeted therapies are initially effective in a subset of patients, the drugs eventually stop working, and the tumors begin to grow again.

All the VEGF/EGFR mutation or amplification studies can tell us is whether or not the cells are potentially susceptible to this mechanism of attack. They don't tell you if one targeted drug is better or worse than some other drug which may target a specific pathway. There are differences. The drug has to get inside the cells in order to target anything.

The "cell" is a system, an integrated, interacting network of genes, proteins and other cellular constituents that produce functions. You need to analyze the systems' response to drug treatments, not just one or a few pathways. The cell "function" methodology measures the net effect of all processes within the cancer, acting with and against each other in real time, and it tests living cells actually exposed to drugs and drug combinations of interest.

The ultimate driver of the functional assay is the cell, composed of hundreds of complex molecules that regulate the pathways necessary for vital cellular functions. If a targeted drug could perturb any one of these pathways, it is important to examine the effects of the drug within the context of the cell. It allows for testing of different drugs within the same class and drug combinations to detect drug synergy and drug antagonism.

VEGF/EGFR-targeted drugs are poorly-predicted by measuring the ostansible targets, but can be well-predicted by measuring the effect of the drug on the function of live cells. True synergy is rather uncommon in most adult solid tumors. Most drug combinations in diseases are merely additive, where the whole equals the sum of its parts, and not synergistic.

The best combinations are those in which there is true synergy and in which the toxicities of the drugs in the combination are non-overlapping, so that full doses of each drug may be given safely.

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