Cancer: On Target Once More

Dec 01, 2010

With the advent of genomics and targeted therapy, bringing cancer to heel once seemed a viable, if distant, goal. But since then, Herceptin and Gleevec, models of the single mutation approach, have proved the exception rather than the rule. Over the past year or two, a handful of Phase III failures, including megablockbusters like Avastin and Sutent in trials for all kinds of common tumors, indicate that targeted therapy is generally a blunt instrument for the simple reason that most cancers are mutlifactorial, driven by abnormalities in many genes and pathways at the same time.

According to cancer geneticist Garth Anderson of the Roswell Park Cancer Institute, most common tumors are ruled by what he calls "genomic instability"—thousands of genetic errors causing massive DNA damage. The result is evident in the current state of cancer treatment: Tumors get a little smaller for a little while, and the benefit to the patient is measured in months.

The FDA and payers are pushing back at the barrage of drugs whose bar is so low and whose price is so high. And some pharmas are hedging their bets, investing increasingly in better, safer versions of chemotherapy. Still, 2011 will usher in four or five truly breakthrough—and, yes, targeted—therapies for cancers that have until now gone largely untreatable.

Topping the list is Sanofi-Aventis' iniparib, aiming to become the first treatment for triple-negative breast cancer, the most aggressive type and one that assaults 15 percent to 20 percent of all women with the disease. This molecule targets the PARP enzyme used by cancer cells to repair the damage to their DNA done by chemotherapy—thereby enhancing its effectiveness. When combined with standard chemo, iniparib increased overall survival to 12.3 months, almost five months longer than the chemo-only group. "That magnitude of the survival advantage is unusual in breast cancer and in metastatic tumors in general," says Dr. Joyce O'Shaughnessy, lead investigator of the study and co-director of the Breast Cancer Research Program at Baylor Charles A. Sammons Cancer Center.

Bristol-Myers Squibb's ipilimumab (ipi) is on deck to become the first treatment for malignant, or advanced, melanoma, one of the deadliest of cancers. A monoclonal antibody that amplifies the body's immune response by blocking a specific molecule on the surface of T cells, ipi is the first drug to show survival in Stage 3 and 4 melanoma. In Phase III trials, 23 percent of ipilimumab patients were alive after two years compared to 14 percent on standard treatment. Yet drugs that switch the immune system into high gear can have grave complications. After fast-tracking ipi, the FDA has postponed its big day until March 2011—to the fury of many patients.

Seattle Genetics' antibody drug conjugate (ADC) technology has at long last yielded a promising treatment for two types of rare lymphomas. SGN-35 (brentuximab vedotin) is an ADC delivery system that releases its anti-cancer payload upon entering the tumor. The FDA granted orphan drug designation to SGN-35 for the treatment of Hodgkin's disease and anaplastic large-cell lymphoma. In Phase II, 11 of 45 Hodgkin's patients saw a complete remission while six others received a partial remission. Based on these and other positive results, Seattle Genetics, in partnership with Takeda's Millennium, will file a BLA for both indications in the first half of 2011.

Exelixis is developing a compound that shows exceptional effects in bone cancer, for which no treatment exists. XL 184 appears to target the cancer in two ways, both by cutting off its blood supply and by blocking the MET protein that spurs tumor growth. New data from a Phase II prostate cancer study shows that 19 of 20 patients who had cancer that had metastasized to the bone had lesions shrink or disappear. "There's really no precedent for another drug that does this," says Dr. Matthew R. Smith, a prostate cancer specialist at Massachusetts General Hospital. This data may cause regret at GSK and BMS, both of whom passed on licensing Exelixis' lead candidate.

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