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Targeted Therapies Formerly
BioOncology Watch www.tgt-therapies.com |
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august
2004 NON-SMALL CELL LUNG CANCER (NSCLC) Identification of activating mutations that underlie
responsiveness to gefitinib. While response rates of only 10% to 19% have been demonstrated in initial
clinical studies of gefitinib treatment of patients with
chemotherapy-refractory NSCLC, responses to gefitinib have been rapid and
profound. These findings led Thomas Lynch and others in Bevacizumab plus carboplatin and paclitaxel. Carboplatin and paclitaxel show enhanced tumor growth
inhibition when combined with an antiangiogenesis agent. David Johnson and
associates randomized 99 patients with advanced or recurrent NSCLC in a phase
II trial to one of the following treatments: (1) the anti-vascular
endothelial growth factor (VEGF) monoclonal antibody bevacizumab 7.5 mg/kg
plus carboplatin (area under the curve = 6) and paclitaxel 200 mg/m2 every 3
weeks (n = 32); (2) bevacizumab 15 mg/kg plus carboplatin and paclitaxel
every 3 weeks (n = 35); or (3) carboplatin and paclitaxel alone every 3 weeks
(control arm; n = 32). Patients treated with bevacizumab 15 mg/kg plus
carboplatin and paclitaxel had a higher response rate (31.5% vs. 18.8%),
longer median time to progression (7.4 vs. 4.2 mo), and increased median
overall survival time (17.7 vs. 14.9 mo) compared to patients who received
carboplatin and paclitaxel alone. Five of 19 control-arm patients who crossed
over to single-agent bevacizumab therapy following disease progression
achieved stable disease and a 47% 1-year survival rate. Six
bevacizumab-treated patients experienced life-threatening hemoptysis or
hematemesis (4 events were fatal). Four of these hemorrhages occurred in
patients with squamous carcinomas. Thus, bevacizumab in combination with
carboplatin and paclitaxel may improve outcomes in patients with advanced or
recurrent NSCLC. However, serious bleeding adverse events were observed most
frequently in patients with squamous cell lung cancers. A randomized study of
carboplatin and paclitaxel with or without bevacizumab in patients with
nonsquamous carcinomas is underway. (Johnson DH, et al. J
Clin Oncol 2004;22:2184-2191)
COLORECTAL CARCINOMA Bevacizumab added to irinotecan, fluorouracil, and
leucovorin (IFL). Herbert Hurwitz
et al conducted a multicenter, double-blind trial in which 923 patients with
previously untreated metastatic colorectal cancer were randomized to either:
(1) IFL plus placebo; (2) IFL plus bevacizumab 5 mg/kg; or (3) fluorouracil
and leucovorin plus bevacizumab 5 mg/kg. Randomization to the third treatment
arm (fluorouracil, leucovorin, and bevacizumab) was halted after an interim
analysis that included the first 313 patients enrolled into the study. The
results of this group were not reported. The median durations of
progression-free and overall survival were greater for patients treated with
IFL plus bevacizumab compared to IFL alone (10.6 vs. 6.2 mo and 20.3 vs. 15.6
mo, respectively). Response rates were higher (44.8% vs. 34.8%) and the
median duration of response was longer (10.4 vs. 7.1 mo) in IFL plus
bevacizumab-treated patients. Grade 3 hypertension responsive to medical
management occurred more commonly in patients receiving bevacizumab (11% vs.
2.3 %). Thus, addition of bevacizumab to IFL chemotherapy improved survival
in patients with previously untreated metastatic colorectal cancer. (Hurwitz H, et al. N Engl J Med 2004;350:2335-2342) NON-HODGKIN'S LYMPHOMA (NHL) Ifosfamide-carboplatin-etoposide (ICE) plus
rituximab (RICE). Tarun
Kewalramani and colleagues administered 3 cycles of rituximab (375 mg/m2 each
cycle) plus ICE (RICE) to 34 patients with diffuse large B-cell lymphoma
(DLBCL) prior to autologous stem cell transplantation (ASCT). RICE therapy
resulted in a higher complete response (CR) rate compared to a historical
control group of 147 consecutive DLBCL patients treated with ICE only (53%
vs. 27%). The 2-year progression-free survival rate after ASCT was comparable
to that of ICE-treated patients (54% vs. 43%). Febrile neutropenia occurred
in 7.5% of delivered cycles of RICE. This study showed that RICE therapy has
acceptable toxicity and can result in a high CR rate prior to ASCT in DLBCL patients.
Further studies are warranted. (Kewalramani T, et al. Blood 2004;103:3684-3688) Extended rituximab treatments in follicular lymphoma
(FL). Michele Ghielmini et al administered
standard rituximab (375 mg/m2 weekly x 4 weeks) initially to 202
patients with FL (32% chemotherapy naïve). At week 12, non-progressors (n =
151) were randomized to no further treatment or extended rituximab (375 mg/m2
every 2 mo x 8 mo). At a median follow-up of 35 months, the median event-free
survival (EFS) time was longer in the patients given extended rituximab (23
vs. 12 mo). EFS gains were greatest in chemotherapy-naive patients and
patients who responded to induction rituximab treatment. The number of the
(14;18)-positive cells in peripheral blood and bone marrow at baseline was
significantly predictive of a clinical response to rituximab. These data show
that extended rituximab treatments improve EFS in patients with FL.
(Ghielmini M, et al. Blood 2004;103:4416-4423)
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