Click here to view as PDF.PHASE IIIThe Clinical Benefit of Bevacizumab in Metastatic Colorectal Cancer
The utility of vascular endothelial growth factor (VEGF) inhibitors in colorectal cancer may be affected by mutations of the KRAS gene; patients with metastatic colorectal cancer who have the KRAS mutation have been found to not gain benefit anticipated with use of endothelial growth factor inhibitors. Researchers from Duke University, Durham, North Carolina, and Genentech, South San Francisco, California, sought to determine if the outcome of patients treated with bevacizumab, a VEGF inhibitor, is affected by KRAS mutation status.
The researchers analyzed the results of a phase III, placebo-controlled study of 812 patients with metastatic colorectal cancer that tested the efficacy of a regimen of fluorouracil, irinotecan, and leucovorin. Patients in the study group also received bevacizumab, whereas patients in the control group also received a placebo. Samples from the tumors of 230 patients were evaluable for KRAS status.
In patients with mutated KRAS genotypes, median progression-free survival was 9.3 months in those receiving bevacizumab, compared with 5.5 months in those receiving the control regimen (P = .0008). In those with wild-type KRAS, study group had a mean progression-free survival of 13.5 months compared with the control group’s median of 7.4 months (,i>P < .0001). In terms of overall survival, the median survivals were 19.9 months and 13.6 months, respectively for those with mutant KRAS samples (P
= .26). For those with wild-type KRAS, the median overall survivals were 27.7 months and 17.6 months, respectively (P
The researchers concluded that KRAS status did not affect the benefit of bevacizumab treatment, even though patients with KRAS mutations experienced less benefit overall from treatment (both study and control). This means that KRAS testing in patients is unwarranted in patients who are candidates for bevacizumab treatment.
Hurwitz HI, Yi J, Ince W, et al: The clinical benefit of bevacizumab in metastatic colorectal cancer is independent of K-ras mutation status: Analysis of a phase III study of bevacizumab with chemotherapy in previously untreated metastatic colorectal cancer. Presented at the 2008 World Congress on Gastrointestinal Cancer, Zurich, Switzerland, July 1, 2008.PHASE IIIOnce-Daily Dasatinib Associated with Better Efficacy and Tolerability in Chronic Myeloid Leukemia
In patients with chronic-phase chronic myelogenous leukemia (CML) whose treatment with imatinib did not produce the desired remission, dasatinib 70 mg twice daily has proven effective and is the approved dosage. However, this dose schedule is associated with toxicity, which is thought to be related to continuous inhibition of Bcr-Abl gene expression. Can less-frequent dosing result in similar efficacy but with fewer tolerability issues? A team of international researchers conducted a phase III trial to better understand if toxicity can be reduced with oncedaily administration and what might be the best once-daily dose.
In this open-label study, the investigators randomly assigned 670 patients with imatinib-resistant or intolerant chronic-phase CML to one of four dasatinib treatment groups: (1) 100 mg once daily, (2) 50 mg twice daily, (3) 140 mg once daily, or (4) 70 mg twice daily.
After a minimum follow-up of six months and a median treatment duration of eight months, the clinicians examined response rates for hematologic (complete, 86% to 92%) and cytogenetic (major, 54% to 59%; complete, 41% to 45%) parameters from the four groups. Similar time to and duration of cytogenetic response were noted, as well as progression-free survivals. Disease progression or death occurred in 8% to 11% of all patients.
Patients taking dasatinib 100 mg once daily, when compared with the approved 70 mg twice-daily course of therapy, had significantly lower rates of pleural effusion (all grades, 7% vs. 16%, respectively; P
= .024) and grade 3 to 4 thrombocytopenia (22% vs. 37%, respectively; P
= .004). Fewer patients needed dose interruption (51% vs. 68%, respectively), treatment discontinuation (16% vs. 23%, respectively) and dose reduction (30% vs. 55%, respectively).
The researchers concluded that dasatinib 100 mg once daily remains the efficacy of 70 mg twice daily, but with less toxicity. They believe that efficacy may be preserved and adverse events reduced by intermittent target inhibition with tyrosine kinase inhibitors.
Shah NP, Kantarjian HM, Kim DW, et al: Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia.
J Clin Oncol 2008;26:3204-3212.New Mechanism Shows Promise in Patients With Non-Small Cell Lung Cancer
A new testing program is just getting underway to test the viability of another class of agents that address blood vessel supply to tumors. This class is distinct from an angiogenesis inhibitor, which tries to prevent tumors from growing new blood vessels; instead, a tumor-vascular disrupting agent will destroy blood vessels already created by the tumor.