Cancer: On Target Once More
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.