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BioOncology Watch Timely Information for Practicing
Physicians |
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august 2001 Breast
Cancer
Trastuzumab therapy.
In 95 patients with measurable metastatic breast cancers that either
expressed HER2 normally (0-1+) or overexpressed HER2 (2-3+), Andrew Seidman
and colleagues investigated a weekly regimen of trastuzumab (4 mg/kg on week
1 and 2 mg/kg weekly thereafter) and paclitaxel 90 mg/m2. HER2 expression was evaluated by 4
different IHC assays (HercepTest, Pab 1, CB11, TAB 250) and by fluorescent in situ hybridization (FISH). According to the assay method utilized,
the objective tumor response rate for HER2-overexpressing tumors ranged from
67% to 81% while the response rate for HER2-normal tumors ranged from 41% to
46% (P<0.05). The median
left ventricular ejection fraction (LVEF) remained stable during the first
year on study. Seven patients
experienced a >20% decrease in LVEF from baseline and remained
asymptomatic. Serious cardiac complications occurred in 3 patients
(precipitous fall in LVEF [1 patient] and myocardial infarction [2
patients]). In a second phase II
study, Harold Burstein et al treated 40 women with HER2-overexpressing (2-3+)
breast cancers with a combination of weekly trastuzumab (4 mg/kg on week 1
and 2 mg/kg weekly thereafter) and weekly vinorelbine (25 mg/m2). The majority of these patients had
received prior chemotherapy (82%). An
objective tumor response rate of 75% was achieved. Thus, weekly trastuzumab combined with cytotoxic chemotherapy
is active in patients with metastatic breast cancer and this activity is
especially apparent in those tumors that overexpress HER2. R. R. Tubbs et al analyzed biopsy
materials from 400 primary infiltrating ductal breast carcinomas to
investigate the poor concordance observed in previous studies between genomic
amplification of HER2/neu (gene copy enumeration by FISH) and HER2 protein
detection by IHC methods. IHC
false-positive results (no corresponding HER2/neu gene amplification by
direct or digoxigenin-labeled FISH) occurred with both HercepTest (23%) and
CB11 (17%) assays and most (34 of 44) were scored as 2+. All 2+ false-positive cases were negative
for HER2/neu mRNA expression (by autoradiographic RNA:RNA in situ hybridization).
HER2/neu amplification was demonstrated in 79% of 3+ cases. These findings suggest that determination
of HER2/neu gene amplification by FISH is a more accurate method of selecting
patients for trastuzumab treatment. (Seidman AD, et al. J Clin Oncol
2001;19:2587-2595; Burstein HJ, et al. J Clin Oncol 2001;19:2722-2730;
Tubbs RR, et al. J Clin Oncol 2001;19:2714-2721) Acute
Myeloid Leukemia (AML) Mylotarg in first relapse.
Mylotarg is a humanized anti-CD33 monoclonal antibody conjugated to
calicheamicin, a highly potent antitumor antibiotic. Eric Sievers and coworkers recently
performed a phase II study in which 142 adult patients (median age of 61
years) with CD33+ AML in first relapse were treated with Mylotarg 9 mg/m2
administered intravenously at 2-week intervals for 2 doses. Complete remissions (£5% marrow blasts with recovery of
peripheral blood neutrophils to at least 1500/uL and RBC and platelet
transfusion independence) were achieved in 30% (42) of patients. The median
relapse-free survival time was 6.8 months and the 1-year survival rate was
31%. There were no reports of treatment-related cardiotoxicity, cerebellar
toxicity, or alopecia. Grade 3 or 4
hyperbilirubinemia and elevated transaminase levels were observed in 23% and
17% of patients, respectively. These
results demonstrate that Mylotarg has a favorable safety profile and can
induce remissions in patients with relapsing CD33+ AML. (Sievers EL, et al. J Clin Oncol
2001;19:3244-3254) Hairy-Cell Leukemia Efficacy of the Anti-CD22
recombinant immunotoxin BL22. Robert J. Kreitman and
associates tested the safety and efficacy of an immunotoxin directed against
the CD22 surface antigen that is strongly expressed by leukemic hairy
cells. RFB4(dsFv)-PE38 (BL22), a recombinant immunotoxin containing an
anti-CD22 variable domain (Fv) fused to truncated pseudomonas exotoxin,
was administered in a dose-escalation trial by intravenous infusion
every other day for a total of 3 doses. Of 16 patients who were resistant to
cladribine, 11 had a complete remission and 2 had a partial
remission with BL22. The 3 patients who did not have a response
received low doses of BL22 or had preexisting toxin-neutralizing
antibodies. Of the 11 patients in complete remission, 2 had
minimal residual disease in the bone marrow or blood. During a
median follow-up of 16 months (range, 10 to 23), 3 of the 11
patients who had a complete response relapsed and were retreated;
all of these patients had a second complete remission. In 2 of the
16 patients, a serious but completely reversible hemolytic–uremic
syndrome developed during the second cycle of treatment with BL22.
Common toxic effects included transient hypoalbuminemia and
elevated aminotransferase levels. BL22 can induce
complete remissions in patients with hairy-cell leukemia that is
resistant to treatment with purine analogues or pentostatin. (Kreitman
RJ, et al. N Engl J Med 2001;345:241-247) Phase
I Study Results
Novel agents.
Robert Vonderheide et al administered recombinant human CD40 ligand (rhuCD40L)
subcutaneously daily for 5 days every 6 weeks to patients (n=32) with
advanced solid tumors or non-Hodgkin's lymphoma (NHL). The maximum tolerated
dose (MTD) was found to be 0.1 mg/kg/day and the dose limiting toxicity (DLT)
was grade 3 or 4 elevation of serum transaminase levels. Two partial responses were observed
(laryngeal carcinoma [1] and NHL [1]).
OSI-774, an inhibitor of epidermal growth factor receptor (EGFR)
tyrosine kinase, was investigated by Manuel Hidalgo and associates. This trial
studied both escalating doses and progressively longer treatment intervals
(n=40). Findings: uninterrupted daily
administration was well tolerated; MTD was 150 mg/day; DLTs were severe
diarrhea and cutaneous toxicity; and daily administration did not result in
drug accumulation. An objective
response was achieved in 1 patient with metastatic renal cell carcinoma. (Vonderheide RH, et al. J Clin Oncol 2001;
19:3280-3287 and Hidalgo M, et al. J Clin Oncol 2001;19:3267-3279) |
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