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© Oxford University Press 2006.
NEWS |
Three New Drugs Available To Fight Kidney Cancer
More help could be on the way for the battle against renal cell carcinoma (RCC). Three new therapies showed promise in recent reports from the American Society of Clinical Oncology annual meeting. The benefits ranged from modest in a specific group of patients to potentially dramatic, which led the investigator to proclaim that a new standard of care has emerged.
The most impressive results came from a randomized trial comparing sunitinib to standard therapy with interferon-
in patients with metastatic RCC. Treatment with sunitinib led to a doubling of progression-free survival compared with the interferon group and a fivefold greater response rate.
"Sunitinib is the new reference standard for the first-line treatment of metastatic RCC," said Robert J. Motzer, M.D., of Memorial Sloan-Kettering Cancer Center in New York. "Sunitinib is a new treatment option, providing new hope for patients with metastatic RCC."
Sunitinib inhibits the tyrosine kinase (TK) in the receptor of both vascular endothelial growth factor and platelet-derived growth factor. Both of the growth factors are implicated in the pathogenesis and progression of RCC, said Motzer. These are especially important targets in clear-cell carcinoma, the predominant form of kidney cancer, where abnormalities in the von Hippel-Lindau gene lead to increased expression of both vascular endothelial growth factor and platelet-derived growth factor.
In previous trials involving patients with metastatic RCC, sunitinib was associated with response rates of 39% and 40%. In contrast, conventional RCC second-line therapies generally have response rates of 3%–4%, said Motzer. Even first-line therapies rarely have response rates greater than 10%–15%.
A preplanned analysis immediately after enrollment closed in October 2005 revealed a significant progression-free survival advantage in favor of sunitinib. When the trial ended, the median progression-free survival—the trial's main endpoint—was 11 months in the sunitinib group compared with 5 months in the interferon- group. Sunitinib maintained that difference in progression free survival in both intermediate-risk and low-risk patients.
The study's investigators found an overall response rate of 37% (137 of 374) with sunitinib and 9% (33 of 373) with interferon-. The independent central review committee confirmed the major difference in response rate, finding an overall response rate of 31% (103 of 335) with sunitinib versus 6% (20 of 327) with interferon-.
The trial involved 750 patients with metastatic RCC who were randomly selected to receive sunitinib or escalating-dose interferon-. The treatment continued until the disease progressed or the side effects became intolerable. Motzer said that the median overall survival has yet to be reached in either treatment arm.
Both therapies were well tolerated. Sunitinib was associated with higher rates of low neutrophil cell count (19%), low platelet count (12%), and elevated digestive enzyme (8%). Interferon- was associated with more cases of low lymphocyte cell count (17%).
"Sunitinib is superior to interferon- in achieving progression-free survival, the primary endpoint of the study," Motzer concluded. "Sunitinib also is associated with improved overall response and patient-reported outcomes compared with interferon and has an acceptable safety profile. The benefit was demonstrated in a relatively unselected general population of patients with metastatic RCC. The benefit translated across all prognostic subgroups that we studied."
Other New Options
Another kinase inhibitor demonstrated potential as a first-line treatment for patients with poor-risk advanced RCC. Temsirolimus, a mTOR kinase inhibitor, significantly improved survival compared with interferon- alone or the combination of both drugs.
Temsirolimus works by inhibiting mTOR signaling, which prevents translation of key proteins that regulate cell cycle progression and angiogenesis, said Gary Hudes, M.D., director of genitourinary malignancies at Fox Chase Cancer Center in Philadelphia. The agent also blocks the cellular response to several growth factors and nutrients.
The multicenter trial of temsirolimus involved 626 patients with advanced RCC at poor risk of survival. The patients were randomized to three treatment arms: temsirolimus, escalating-dose interferon-, or a combination of the two agents. The primary endpoint of the trial was the proportion of patients who achieved at least a 40% improvement in survival compared to interferon- alone—about 6.9 months, assuming a 4.9-month median survival for interferon-.
Patients in the temsirolimus arm had a median overall survival of 10.9 months, compared with 7.3 months with interferon-. The combination therapy patients showed a median overall survival of 8.4 months, which was not significantly different from interferon alone. However, the median progression-free survival was 3.7 months with both temsirolimus and combination therapy, which was significantly better the 1.9-month progression-free survival in the group taking interferon alone.
Temsirolimus was better tolerated than interferon- alone or the combination. Hudes reported that 69% of temsirolimus patients had grade 3–4 adverse events, compared with 85% of interferon- patients and 87% of patients who received combination therapy.
"Temsirolimus ... can be considered standard first-line therapy for patients with metastatic RCC and poor-risk features," Hudes concluded. "The results of this global phase III trial demonstrate that mTOR is an important therapeutic target in RCC. The efficacy of temsirolimus in patients with poor-risk features suggests the potential benefit of this agent in a broader RCC population."
Another multitargeted TK inhibitor demonstrated potential for at least a subgroup of RCC patients. Lapatinib, an oral small-molecule inhibitor of both the endothelial growth factor receptor (EGFR) and the HER2 receptor, was associated with improved overall survival in patients who had the highest baseline levels of EGFR expression.
The benefit emerged from a randomized trial involving 417 patients with advanced RCC who had not responded to treatment. The patients received either lapatinib or hormonal therapy (tamoxifen or megestrol acetate) for a median of 12 weeks. The primary endpoint was time to progression, and the secondary endpoints were overall survival and response rate.
The two forms of therapy led to virtually identical time to progression, 15.3 weeks with lapatinib and 15.4 weeks with hormonal therapy, reported Alain Ravaud, M.D., Ph.D., professor of medical oncology at University Hospital of Bordeaux and the University Victor Segalen in France. The overall survival also was similar, 46.9 weeks with the TK inhibitor and 43.1 weeks with the hormonal treatment.
An analysis based on EGFR expression revealed a better response in some patients. Patients with strongly positive expression, who accounted for 58% of the study population, had a median overall survival of 46 weeks when treated with lapatinib, versus 37.9 weeks with hormonal therapy. Treatment with lapatinib also resulted in a trend toward improved time to progression in those patients.
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