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Targeted Therapies Formerly
BioOncology Watch www.tgt-therapies.com |
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APRIL 2005 BEVACIZUMAB THERAPY
FOR BREAST CANCER Bevacizumab plus
capecitabine vs capecitabine alone. A recently completed study demonstrated that the addition
of bevacizumab (Avastin; Genentech Inc), a monoclonal antibody directed
against vascular endothelial growth factor (VEGF), to first-line chemotherapy
for metastatic colorectal cancer prolonged overall and progression-free
survival (Hurwitz H, et al. N Engl J
Med. 2004; 350:2335–2342). Now,
Kathy Miller and associates report the results of a randomized phase III
study that compared the efficacy and safety of oral capecitabine (2500 mg/m2
daily for 14 days every 21 days) with or without bevacizumab (15 mg/kg
intravenously on LENALIDOMIDE Efficacy in
myelodysplastic syndromes (MDS). Alan List and coworkers treated 43
MDS patients with transfusion-dependent or symptomatic anemia with
lenalidomide, a novel analogue of the immunomodulatory drug thalidomide. All
patients were either refractory to recombinant erythropoietin therapy or had
high endogenous serum erythropoietin levels.
Three oral lenalidomide dosing schedules were sequentially evaluated:
25 mg daily, 10 mg daily, and 10 mg daily for 21 days every 28 days. Twenty-four (56%) patients achieved an
erythroid response, and 20 patients had sustained independence from red blood
cell (RBC) transfusions. The median
blood hemoglobin level achieved was 13.2 g/dL (range, 11.5 to 15.8 g/dL);
after a median follow-up of 81 weeks, the median duration of RBC transfusion
independence had not been reached. The erythroid response rate was highest
(83%) in patients in which the MDS clone had an interstitial deletion
involving chromosome 5q31.1 and in patients with lower-prognostic-risk
MDS. Among 20 patients with karyotypic
abnormalities at baseline, 10 patients achieved complete cytogenetic remissions
and 1 patient achieved a partial cytogenetic remission. Neutropenia and thrombocytopenia
necessitated a dose reduction in 25 (58%) patients. Other adverse events were mild and
infrequent. These data suggest that lenalidomide has hematologic activity in
patients with low-risk MDS. Further studies are warranted. (List A, et al. N Engl J Med. 2005;352:549–557) TYROSINE KINASE
INHIBITORS Mechanisms of
resistance. Acquired resistance to
kinase-targeted anticancer therapy has been most extensively studied in
cancers treated with imatinib. Secondary resistance in CML has been
associated with newly developed mutations in the ABL kinase domain that
interfere with imatinib binding to ABL. Crystallographic studies predict that
new BCR-ABL kinase inhibitors with less stringent structural requirements
than imatinib will retain activity against most imatinib-resistant BCR-ABL
mutants. Maria Debiec-Rychter and
coworkers screened 26 imatinib-resistant gastrointestinal stromal tumors and
detected secondary mutations in KIT that were sensitive to PKC412, a novel
small molecule that interacts with the ATP sites of KIT, VEGFR, PDGFR, PKC,
FLT3, and the CDK1/cyclin B complex.
Similarly, lung adenocarcinomas that respond to the tyrosine kinase
inhibitors gefitinib or erlotinib eventually develop acquired resistance. William
Pao and Susumu Kobayashi and their associates report cases of non–small cell
lung cancers that relapsed after responding to gefitinib or erlotinib and
were found to have second mutations in the EGFR kinase domain. These findings may help guide the development
of more effective anticancer therapies. (Debiec-Rychter
M, et al. Gastroenterology. 2005;128:270–279; Pao W, et al. PLoS Med. 2005;2:e73; and Kobayashi S,
et al. N Engl J Med. 2005;352:786–792) RITUXIMAB Optimizing therapy for
patients with low-grade non–Hodgkin's lymphoma (NHL). Recent studies have attempted to
define improvements in the administration of rituximab to NHL patients. John
Hainsworth and colleagues evaluated the feasibility of following standard
rituximab therapy (375 mg/m2 weekly ´ 4) with 3 instead of 6 cycles of
R-CHOP or R-CVP in 86 patients with previously untreated follicular NHL. Overall and complete response rates (93%
and 55%, respectively) were similar to those reported with chemotherapy and
rituximab combinations of longer durations of treatment. Thomas Witzig and
associates found that the administration of rituximab 375 mg/m2
weekly ´ 4 to 37 patients with advanced-stage, follicular grade 1
NHL showed a 72% response rate and was an acceptable alternative to
observation. However, rituximab
monotherapy was not recommended for patients with high serum LDH levels,
because they had low response rates (33%) and short times to progression
(only 6 months). In a randomized study of 114 patients with previously
treated indolent NHL, John Hainsworth and coworkers found that the duration
of rituximab benefit was similar in patients who received maintenance
rituximab therapy or rituximab re-treatment at the time of progression. Finally, Lucio Gordan et al utilized
pharmacokinetic data to demonstrate that a rational maintenance schedule is a
single dose of rituximab 375 mg/m2 every 3 to 4 months. These
studies may be used to individualize rituximab therapy so that efficacy is
maintained or increased and toxicity is minimized. (Hainsworth JD, et al. J Clin Oncol. 2005;23:1500–150; Witzig
TE, et al. J Clin Oncol. 2005; 23:1103–1108;
Hainsworth JD, et al. J Clin Oncol.
2005;23:1088–1095; and Gordan LN, et al. J
Clin Oncol. 2005;23:1096–1102) |
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