Better Weapons in the Cancer War

New, tumor-specific drugs are starting to bear fruit. So far the gains in life expectancy are relatively small, but their significance is enormous

By Catherine Arnst

After two decades of development, a new generation of targeted cancer drugs is beginning to transform treatment of the nation's second-biggest killer. Even more encouraging, the next improvements in care won't take another 20 years. Already, a new class of multitargeted treatments is beginning to post promising results against some of the hardest-to-treat cancers.

The 25,000 attendees at the American Society of Clinical Oncology (ASCO) annual May 13-17 meeting in Orlando heard hundreds of presentations about new drugs that, unlike chemotherapy, take aim only at one specific gene or protein that promotes the growth of cancer, while leaving healthy cells alone. Though there are still only a handful of such drugs on the market so far, among them Genentech's (DNA ) Avastin and Tarceva, Novartis' (NVS ) Gleevec, and ImClone Systems's (IMCL ) Erbitux, almost all of the new drugs in development for cancer fall in this category.

By blocking only a certain tumor growth factor, they are much more easily tolerated than chemotherapy or radiation, which "flood" the body and are highly toxic. But so far the benefits of targeted therapies have been modest -- only a few have actually proven to help patients live longer, the brass ring in cancer care, and none are considered a cure. Scientists believe these targeted drugs will be of greatest benefits when used in combination, thus knocking out several cancer causing factors at once.


  The emerging class of mutitargeted drugs is putting this theory to the test. Referred to as multi-kinase inhibitors, they block blood-circulating proteins known as kinases that are responsible for tumor growth and for blood supply.

The two leading candidates in this class are sorafenib, jointly developed by Bayer Pharmaceuticals (BAY ) and Onyx Pharmaceuticals (ONXX ), and Pfizer's (PFE ) Sutent. Both drugs are being tested against several types of cancer, but their leading use is in kidney cancer, one of the deadliest forms of the disease.

The American Cancer Society estimates that some 36,000 people in the U.S. will be diagnosed with kidney cancer this year and 12,600 will die from it. If the disease spreads beyond the kidney, less than 10% of patients respond to chemotherapy -- and the treatment is highly toxic.


  Sorafenib and Sutent both gave oncologists attending ASCO some reason to hope that the outlook might change, based on interim data from ongoing clinical trials. Dr. Bernard Escudier, of Gustave-Roussy Institute in Paris, reported that sorafenib doubled the time that patients lived without their tumors growing larger, to a median of 24 weeks compared with 12 weeks on placebo. The data was pulled from an ongoing late-stage trial involving 768 patients. The patients had already failed standard therapies.

Sutent is in mid-stage trials against kidney cancer, and data from two of these studies showed that it also delayed tumor progression. Dr. Robert Motzer, of Memorial Sloan-Kettering Cancer Center in New York, reported that 40% of tumors shrank in 63 patients, and the tumor size remained the same in another 28%. A second study of 196 patients showed tumor shrinkage in 39% of patients, and another 23% were stabilized. Though still not a cure, "a 40% response rate in this disease is very significant," says Dr. Motzer. "These drugs represent a major shift in the paradigm of treatment for this disease."

Sutent is also garnering a lot of attention for a clinical trial testing the drug in patients with a rare form of stomach cancer who already failed Gleevec. Gleevec is possibly one of the most effective targeted drugs to date, knocking out the gene that causes gastrointestinal stromal tumors (GIST), which develop on the outside of the stomach, and a form of leukemia.


  But some patients eventually grow resistant to Gleevec, just as cancer patients usually do to traditional chemotherapies. If cancer is to be turned into a chronic disease, as many specialists hope, drugs are needed that patients can turn to once they fail their initial treatment.

Sutent may serve that purpose in GIST. In a late-stage trial of more than 300 patients resistant to Gleevec, Sutent delayed the time that tumors started growing again to 6.3 months, vs. 1.5 months for patients on a placebo, In another trial, the drug kept patients alive an additional 20 months. Dr. George Demetri of Dana-Farber Cancer Institute in Boston said the results substantiate the concept that multitargeted therapies can overcome resistance to other targeted drugs.

The two drugs have not been tested head to head, so researchers say it is difficult to know which might be superior. Motzer suggested that it may be possible to give the two drugs sequentially -- when a patient becomes resistant to one, they could shift to the other.


  The Bayer-Onyx drug, however, does have the lead in terms of time to market. FDA applications for both Suten and sorafenib will likely be filed by year end, Sutent in GIST and sorafenib in kidney cancer. Until a decision is reached, however, patients with advanced kidney and renal-cell cancers can get sorafenib on a compassionate basis, under an arrangement worked out with the FDA.

The arrangement means that just four years after Gleevec, the first targeted therapy, was approved by the FDA, patients have access to a multitargeted drug. Again, it's no cure, but at least measurable progress is being made in the war on cancer.

Arnst is a writer for BusinessWeek in New York

Edited by Beth Belton

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