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BioOncology Watch Timely Information for Practicing
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july 2003 highlights of the 39th ASCO Annual
Meeting May 31 to HER2-TARGETED THERAPY Cardiac safety of trastuzumab (T). M. Marty and colleagues pooled
data from 4 clinical trials in which left ventricular ejection fraction
(LVEF) was monitored in 259 patients treated with T. Five cases of symptomatic cardiac failure
were reported and 15 LVEF events were identified. Prior anthracycline use was associated with
a 5-fold higher risk of an event in patients treated with T. These findings support conclusions of prior
retrospective analyses of T-related cardiotoxicity and indicate that the
overall risk-benefit ratio for treatment of HER2-positive metastatic breast
cancer (MBC) remains favorable. A
second abstract by A.C. Wolff et al. reported interim results from a
multicenter ECOG trial (E3198) that is evaluating the cardiac safety of
patients with HER2-positive MBC treated with T in combination with pegylated
liposomal doxorubicin and docetaxel compared to that of patients with
HER2-negative MBC treated with doxorubicin and docetaxel alone. Data from 22 evaluable T plus doxorubicin
and docetaxel-treated patients showed an average drop of 3.6% and no >
grade 2 cardiac events after 4 cycles.
Accrual to this study remains ongoing.
A third study by H. Joensuu and the Finnish Breast Cancer Group
demonstrated that T in combination with vinorelbine or docetaxel adjuvant
therapy for early BC is not associated with short-term cardiotoxicity. High-risk BC patients (N = 606) were
randomized to receive adjuvant vinorelbine (8 weekly cycles) or docetaxel (3
cycles). HER2-positive patients were
also randomized to receive or not to receive T (9 weekly infusions) in
combination with vinorelbine or docetaxel.
Following these treatments, all patients were given 3 weekly cycles of
CEF60 and ER+ patients also received tamoxifen for 5 years. The mean LVEF at baseline, during the last
chemotherapy cycle, and 6 months after completing chemotherapy were 65%, 64%,
and 64%, respectively, for T-treated patients compared to 67%, 64%, and 64%,
respectively, for patients treated with vinorelbine or docetaxel alone. These 3 studies suggest a favorable
risk-benefit ratio for T treatment of HER2-positive BC. (Abstracts 72, 70,
and 74) Phase I study of pertuzumab. Pertuzumab is a humanized HER2
antibody that binds to a different epitope than trastuzumab and inhibits
intracellular signaling through MAP kinase and PI3 kinase pathways. Twenty-one patients with advanced solid
tumors received pertuzumab intravenously every 3 weeks at one of the
following doses: 0.5 (n = 3); 2 (n = 3); 5 (n = 4); 10 (n = 3); or 15 mg/kg
(n = 8). Only 2 grade 3 or 4 adverse
events were assessed to be possibly pertuzumab-related: a gastrointestinal
bleed and left ventricular failure following a myocardial infarction. Despite monitoring with 2-D echocardiograms
and serologic markers, no other evidence of cardiac dysfunction was
detected. Three (14%) patients
achieved partial responses and 8 (38%) patients had stable disease that
persisted for a median of 13.7 weeks (range, 6.1 to 24.4 weeks). These preliminary data show that pertuzumab
is well tolerated at doses up to 15 mg/kg and is potentially active
clinically. (Abstract 771) INHIBITORS OF EGFR GW572016. GW572016
is a novel small molecule inhibitor of EGFR and ErbB2. N. Spector and associates reported the
findings of a phase I study in which patients with metastatic carcinomas that
overexpress EGFR or ErbB2 were randomized to receive one of 5 doses of
GW572016 (500, 650, 900, 1200, or 1600 mg) administered orally once
daily. Twenty-eight patients were
accrued and of 10 evaluable patients, 2 trastuzumab-resistant BC patients had
objective responses. Toxicities were
primarily gastrointestinal (diarrhea) and dermatologic (transient rashes) and
were not dose dependent. In addition,
M. S. Berger et al. treated patients with trastuzumab-refractory MBC with
GW572016 1250 mg daily in a phase II study.
As of December 2002, 3 patients had been accrued and no cardiac
toxicity had been reported. Enrollment
is ongoing. (Abstracts 772 and 981) FLT3 INHIBITORS IN ACUTE MYELOID LEUKEMIA (AML) Phase II studies of 2 novel agents. CEP-701, an indolocarbazole
derivative that inhibits FLT3 with an IC50 in the range of 1-2 nM in vitro,
has been shown to cause cell death and prolong survival in an AML mouse
model. Early results of a phase II
study of CEP-701 treatment in patients with refractory or relapsing AML
expressing FLT3-activating mutations were presented by B.D. Smith and
colleagues. The CEP-701 dose was
increased from 40 to 60 mg BID after ex vivo analysis showed incomplete
inhibition of FLT3 autophosphorylation in the first 3 patients. Short-lived clinical responses (decrease of
peripheral blood [PB] blasts to <5% and in one patient, a decrease in bone
marrow [BM] blasts to <5%) were observed in 4 of the next 10 patients
enrolled. Except for neutropenic fever
(n = 11), CEP-701-related toxicity was rare.
A second oral FLT3 inhibitor, PKC412 (IC50 = 10 nM), was studied by R.
M. Stone and others in a phase II trial of relapsed or refractory mutant FLT3
AML. PKC412 was administered at a dose
of 75 mg TID and 12 of 14 patients experienced a >50% decrease in PB
blasts while 5 patients had a >50% decrease in BM blasts (including one
patient with <5% BM blasts).
Decreases in FLT3 autophosphorylation were found in 3 of 4 patient
samples. Further study of these new agents is warranted. (Abstracts 779 and
2265) CETUXIMAB Metastatic colorectal cancer (MCRC). D. Cunningham et al. conducted a
study in which 329 patients with EGFR-positive irinotecan-refractory MCRC
were randomized to receive the anti-EGFR antibody cetuximab (400 mg/m2 first
infusion, then 250 mg/m2 weekly) plus irinotecan (at the same dose and
regimen on which they had been progressing) (Arm A) or cetuximab alone
(option to add irinotecan after failure of cetuximab as a single agent) (Arm
B). Arm A patients achieved a response
rate of 17.9% and a median TTP of 126 days while those in Arm B had a
response rate of 9.9% and a median TTP of 45 days. Survival data is pending. These data suggest an additive interaction
for combination cetuximab/irinotecan therapy against MCRC. (Abstract 1012) BEVACIZUMAB Front-line therapy for advanced colorectal cancer
(advCRC). Bevacizumab
(BEV) is a chimeric monoclonal antibody directed against VEGF that inhibits
angiogenesis. B. J. Giantonio and
colleagues performed a phase II study in which previously untreated patients
with measurable advCRC were treated with BEV (10 mg/kg every other week) plus
irinotecan/5-FU/leucovorin (IFL) weekly for 4 weeks every 6 weeks. After the first 20 patients, the starting
doses of irinotecan and 5-FU were reduced to 100 mg/m2 (from 125 mg/m2) and
400 mg/m2 (from 500 mg/m2) due to a toxicity review of other IFL trials. With a median follow-up of 7.6 months, a
response (RECIST criteria) was achieved in 32 (45.7%) of 70 evaluable
patients (2 [2.9%] CRs). Of 83
patients evaluable for safety, grade 3 diarrhea occurred in 15 patients, one
patient had grade 4 epistaxis, and 9 patients had a thrombotic event. These findings suggest that BEV plus IFL
has substantial antitumor activity in previously untreated patients with
advCRC. (Abstract 1024) Phase III study of combination therapy with IFL. The results of a phase III study
in which 815 previously untreated patients with metastatic CRC were
randomized to receive either BEV plus IFL or IFL alone were reported by
Herbert Hurwitz et al. Patients in the
BEV treatment arm had a higher response rate (45% vs. 35%; p = 0.0029), a
longer response duration (10.4 months vs. 7.1 months; p = 0.0014), a greater
median time to tumor progression (10.6 vs. 6.2 months; p <0.00001), and an
increased overall survival time (20.3 months vs. 15.6 months; p = 0.00003)
compared to those patients treated with IFL alone. The addition of BEV was well tolerated in
combination with IFL chemotherapy.
Grade 3 hypertension developed in 10.9% of patients and was controlled
with oral agents. Although uncommon,
gastrointestinal perforation was observed to occur only in BEV-treated
patients. These findings demonstrate
that the combination of BEV and IFL therapy is tolerated with expectable
toxicity and improves outcomes, including overall survival time, for
previously untreated patients with metastatic CRC compared to IFL treatment
alone. (Abstract 3646) RITUXIMAB Combined with CHOP for HIV-associated non-Hodgkin's
lymphoma (NHL). L.D.
Kaplan and others from the AIDS Malignancies Consortium conducted a study in
which patients with AIDS-associated aggressive B-cell NHL were randomized in
a 2:1 ratio to receive standard CHOP plus rituximab (Arm A) or CHOP alone
(Arm B). All patients received G-CSF
support. The complete response rates
for Arms A and B were 58% and 50%, respectively (p = 0.371). Grade 3 or 4 neutropenia was reported in
39% of patients in Arm A and 17% of patients in Arm B (p =0.012). Death due to infection occurred in 7% and
2% of Arm A and Arm B patients, respectively.
These preliminary data do not show a response benefit for combination
therapy and suggest that the addition of rituximab to CHOP adds substantial
toxicity in patients with AIDS-associated NHL. (Abstract 2268) Concurrent versus sequential treatment with FND
chemotherapy (fludarabine, mitoxantrone, dexamethasone). P. McLaughlin and associates at
the Combination with hyper-CVAD in Burkitt (BL) and
Burkitt-like (BLL) leukemia/lymphoma. Cabanillas
and coworkers at M.D. Anderson treated 20 patients with newly diagnosed BL or
BLL with rituximab 375 mg/m2 on Days 1 and 11 of courses 1 and 3
of hyper-CVAD and Days 1 and 8 of courses 2 and 4 with high-dose methotrexate
and ara-C. The CR rate in 19 evaluable
patients was 89%. With a median
follow-up of 12 months (range, 3-30+ months), 2 relapses have occurred. Three deaths in HIV-BL patients in CR have
occurred while 12 of 14 non-HIV patients (86%) remain alive and
disease-free. The safety profile was
similar to that of hyper-CVAD alone and the addition of rituximab to
hyper-CVAD may improve outcomes for patients with BL or BLL. (Abstract 2309) BORTEZOMIB Phase II studies in NHL.
O. A. O'Connor et al administered the proteosome inhibitor bortezomib
(1.5 mg/m2 intravenously twice weekly for 2 weeks every 3 weeks) to 14
patients with relapsed or refractory indolent lymphomas in a phase II
study. Adverse events included
thrombocytopenia and peripheral neuropathy (N = 2). Seven patients have achieved objective
responses (1 CR). This trial is
ongoing. In a second study, A. H. Goy et al. gave bortezomib 1.5 mg/m2 on
Days 1, 4, 8, and 11 every 21 days to patients with relapsed or refractory
indolent and aggressive B-cell NHL.
Data were available for 11 patients.
Four patients developed grade 3 or 4 gastrointestinal toxicity, 4
patients had grade 3 or 4 thrombocytopenia, and neuropathy occurred in one
patient. Five patients have achieved a
response (1 CR; all responsive have been among 7 patients with mantle cell
lymphoma). These trials indicate that
further study of bortezomib therapy in patients with NHL is warranted. (Abstracts 2277 and 2291) |
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