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Targeted Therapies Timely
Information for Practicing Hematologists and Oncologists www.tgt-therapies.com |
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FEBRUARY 2006 Glioblastoma Response
to kinase inhibitors. The epidermal growth factor
receptor (EGFR) is a receptor that is frequently overexpressed or mutated in
glioblastomas. However, only 10% to
20% of patients with glioblastoma have a response to the EGFR kinase
inhibitors erlotinib and gefitinib.
Previous studies have revealed that EGFR deletion mutant variant III (EGFRvIII), which persistently activates the
phosphatidylinositol 3' kinase (PI3K) signaling pathway, is often expressed
in glioblastomas. In addition, the
tumor-suppression protein PTEN, which inhibits the PI3K pathway, is commonly
lost in glioblastomas. Ingo Mellinghoff
and colleagues analyzed the expression of EGFR, EGFRvIII,
and PTEN in available pretreatment tissue obtained from 26 patients with
recurrent glioblastoma who had received EGFR tyrosine kinase inhibitor
therapy (gefitinib or erlotinib) since 2001.
Seven of these patients achieved a response and 19 patients developed
rapid progression during therapy. They
found that the coexpression of EGFRvIII and PTEN
was strongly associated with clinical response (p <0.001). Furthermore, these findings were validated
in a multicenter experience with 33 glioblastoma patients and in vitro
experiments which showed that coexpression of EGFRvIII
and PTEN sensitizes glioblastoma cells to erlotinib. A second tyrosine kinase inhibitor,
imatinib, has also been evaluated in glioblastoma patients due to an
overexpression of platelet-derived growth factor (PDGF) and PDGF receptor by
this tumor. David Reardon
et al report that the combination of imatinib and hydroxyurea achieved at
least stable disease in 51% of 33 patients with recurrent glioblastoma that
was associated with a 27% progression-free survival rate at 6 months. These studies represent important steps
toward the identification of rational, tumor-specific therapy for
glioblastoma. A perspective editorial
by Henry Friedman and Darell Bigner
concludes that future studies of agents that target genetic pathways in
glioblastoma will have to include analyses of genes and proteins in tumors
from patients enrolled in therapeutic trials.
(Mellinghoff IK, et al. N Engl J Med 2005;353:2012-2024; Reardon DA, et al. J Clin Oncol 2005;23:9359-9368; Friedman HS
and Bigner DD. N
Engl J Med 2005;353:1997-1999) Non-Hodgkin's Lymphoma (NHL) R-CHOP
vs. CHOP in advanced follicular lymphoma (FL).
Wolfgang Hiddeman
and others from the German Low-Grade Lymphoma Group conducted a study in
which 428 patients with previously untreated, advanced-stage FL were
randomized to receive standard CHOP chemotherapy or rituximab plus CHOP
(R-CHOP). CHOP was given in 3-week
cycles for 6 to 8 cycles and rituximab 375 mg/m2 was administered
on the day before each cycle to patients in the R-CHOP treatment group. A higher response rate (96% vs. 90%; p =
0.011) and a longer duration of response (p = 0.001) was achieved in the
R-CHOP compared to the CHOP treatment group.
In addition, both time to treatment failure and overall survival were
superior in R-CHOP-treated patients (p <0.001 and p = 0.016;
respectively). Severe granulocytopenia
occurred more frequently in the R-CHOP group (63% vs. 53%; p = 0.01). However, the proportion of patients with
severe infection was low and comparable between the R-CHOP and CHOP alone
treatment groups (5% and 7%). These
results demonstrate that the addition of rituximab to CHOP chemotherapy
improves clinical outcomes for patients with advanced, previously untreated
FL. (Hiddeman
W, et al. Blood 2005;106:3725-3732) Multiple Myeloma (MM) First-line
lenalidomide plus high-dose dexamethasone. Lenalidomide
(Len) is a new immunomodulatory drug (IMiD) that is
an analog of thalidomide. Len has
demonstrated more potent preclinical activity than thalidomide and has shown
significant efficacy in relapsed or refractory MM when given as monotherapy
or in combination with dexamethasone (Dex).
In the current study, S. Vincent Rajkumar
and others used Len/Dex to treat 34 patients with previously untreated
MM. Len was given orally 25 mg once daily
on days 1 to 21 of a 28-day cycle and Dex was given orally 40 mg daily on
days 1-4, 9-12, and 17-20 of each cycle.
Patients also received aspirin (81 mg or 325 mg once daily) as
thrombosis prophylaxis. Thirty-one
(91%) patients achieved a response (2 complete responses, 11 very good
partial responses, and 18 partial responses).
Among the 3 patients who did not have at least a partial response, 2
had minor responses and one had stable disease. Grade 3 or 4 neutropenia developed in 12%
of patients and grade 3 or 4 thrombocytopenia did not occur in any of the
patients. Overall, 47% of patients
experienced grade 3 or 4 nonhematologic toxicity, most commonly fatigue
(15%), muscle weakness (6%), anxiety (6%), pneumonitis (6%), and rash
(6%). One patient (3%) developed a
pulmonary embolism and recovered with therapy; no other patient developed
deep vein thrombosis or pulmonary embolism.
These findings indicate that Len/Dex is a highly active regimen in
patients with newly diagnosed MM and is tolerated with manageable side
effects. (Rajkumar
SV, et al. Blood;106:4050-4053) Renal cell Carcinoma (RCC) Activity of SU11248 in metastatic
RCC. SU11248 (sunitinab
malate; Pfizer Inc.) is a highly potent inhibitor of certain tyrosine
kinases, including vascular endothelial growth factor receptor (VEGFR) and
platelet-derived growth factor receptor (PDGFR). Antiangiogenesis and antiproliferative
effects were demonstrated in preclinical experiments. The recommended dose defined in phase I
trials was 50 mg orally once daily for 4 weeks of every 6-week cycle. Robert Motzer et
al. used this regimen of SU11248 in a multicenter phase II study to treat 63
patients with metastatic RCC. A
partial response was achieved in 25 (40%) patients and 17 (27%) patients had
stable disease. The median time to
progression was 8.7 months. The most
common adverse event was fatigue and the most common grade 3 or 4 laboratory
abnormalities were lymphopenia (32%) and elevated serum lipase (21%). Four patients were discontinued from the
study for a decline in cardiac ejection fraction. These results showed that the multitargeted
receptor tyrosine kinase inhibitor SU11248 is active against metastatic RCC
and is tolerated with manageable toxicities.
Further studies are warranted. (Motzer RJ,
et al. J Clin
Oncol 2006;24:16-24) |
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