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Targeted Therapies Formerly
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JULY 2004 Abstract Highlights of the ASCO 40th Annual Meeting LYMPHOMA Radioimmunotherapy
(RIT) for follicular lymphoma. Two studies investigated
the effectiveness of RIT in patients with follicular lymphoma following
induction chemotherapy. DL Shipley and
colleagues initiated 90Y-ibritumomab tiuxetan (Zevalin®) 5 weeks
after completing 3 courses of CHOP-R therapy for previously untreated
patients with stage II-IV follicular lymphoma. Thirty-three patients were evaluable and 10
patients with a PR to CHOP-R therapy converted to a complete response
(CR) after Zevalin treatment. At
the time of this report, 22 patients had completed therapy and been restaged;
19 patients (86%) were in CR and 3 patients had a PR. The most commonly reported grade 4 toxicity
was neutropenia (18%). In a second
study, B Link et al administered tositumomab and iodine I 131 tositumomab
therapy (Bexxar®) to 30 previously untreated patients with follicular
lymphoma within 56 days of completing 6 cycles of CVP. Nine
patients converted to a CR with Bexxar therapy, resulting in 24 patients who
achieved a CR and 6 patients with a PR after completion of all planned treatments. The median PFS had not been reached. Grade 4 neutropenia and thrombocytopenia
occurred in 33% and 32% of patients, respectively, and 1 patient developed
acute myeloid leukemia. These results
show that RIT following standard first-line treatment regimens for patients
with follicular lymphoma can induce high CR rates. (Abstracts 6519 and 6520) Intraventricular
rituximab administration. Previous studies in nonhuman
primates led JL Rubenstein and colleagues to utilize intraventricular
injections of rituximab via an Ommaya reservoir to treat 6 patients with
recurrent or refractory CD20+ leptomeningeal non-Hodgkin's lymphoma
(NHL). Nine injections of rituximab 10
mg or 25 mg were planned and high ventricular levels were achieved. Rituximab was detectable in the lumbar sac
within 4 hours of administration and these treatments were well
tolerated. Mild leukoencephalopathy
and paresthesias occurred in one patient.
Cytologic responses were achieved in 4 patients and 1 patient had a
complete resolution of parenchymal disease.
In a second study, HS Schultz et al gave 10 - 40 mg doses of
rituximab in 1 - 4 mL volumes either intrathecally (n = 2) or via an
Ommaya reservoir (n = 4) to patients with intracranial lesions and/or
leptomeningeal involvement due to CD20+ B-cell neoplasms. Intraventricular administration resulted in
rituximab concentrations that were several fold higher than those
obtained with intravenous rituximab.
Doses of rituximab up to 35 mg injected thrice weekly were well
tolerated in 5 of 6 patients.
Neurotoxicity related to rapid tumor lysis occurred in one
patient. Tumor cells were cleared from
the cerebrospinal fluid and clinical remissions were achieved in 4 patients
with leptomeningeal disease. No effect
on parenchymal disease was noted.
These preliminary data suggest that the intraventricular
administration of rituximab is a potentially promising means of therapy
for B-cell NHL patients with CNS involvement. (Abstracts 6593 and 1521) Maintenance rituximab. HS Hochster and others
in the Eastern Cooperative Oncology Group (ECOG) performed a phase III study
in which 322 patients with advanced follicular or small lymphocytic NHL
received CVP chemotherapy to maximum response (6-8 cycles) and were then
randomized to rituximab 375 mg/m2 i.v. weekly x 4 every 6 months
for 4 cycles or observation. The
2 study arms were well balanced for prognostic factors. The
estimates of progression-free survival (PFS) rates for 303 evaluable patients
at 2 and 4 years after randomization were 74% vs. 42% and 58% vs. 34% for
rituximab-treated and observation patients, respectively (p = 0.00008
[one-sided]). The estimated 2-year
survival rates were 95% for the rituximab-treated patients and 91% for the
patients in the observation group.
These data demonstrate that maintenance rituximab therapy after
CVP is associated with improved PFS in patients with advanced indolent NHL
and have resulted in an early termination of the study. (Abstract 6502) BEVACIZUMAB PLUS
GEMCITABINE Pancreatic cancer.
Preclinical studies suggest that anti-VEGF antibodies potentiate the
activity of gemcitabine. These
findings led HL Kindler and others to study the combination of bevacizumab
plus gemcitabine (BG) in previously untreated patients with advanced
pancreatic cancer in a phase II trial.
Among 42 patients with evaluable data, 9 patients (21%) achieved a
response and 19 patients (45%) had stable disease. The median duration of response was 9.4
months and the median time to progression was 5.8 months. The 6-month survival rate was 74% (median
overall survival time of 9.0 months).
Plasma VEGF levels have not been found to correlate with response or
survival. The most commonly reported
grade 3 and 4 toxicities have been neutropenia (33%), thrombocytopenia (7%), thrombosis
(12%), and bowel perforation (5%). These encouraging results warrant further
investigation. (Abstract 4009) BEVACIZUMAB PLUS
ERLOTINIB Combined VEGF and
EGFR inhibition. Preclinical studies have indicated that
combined blockade of VEGFR and EGFR pathways may enhance antitumor activity.
In addition, early phase studies have shown no pharmacokinetic
interaction between the anti-VEGF monoclonal antibody bevacizumab
(Avastin®) and the EGFR tyrosine kinase inhibitor erlotinib (Tarceva®). These findings led JD Hainsworth et al to
test combination bevacizumab plus erlotinib in a phase II study of patients
with metastatic renal cell carcinoma.
Among 40 evaluable patients, 10 (25%) patients had a partial response
(PR) and 25 (62%) patients had either a minor response or stable
disease. With a median follow-up of
4.4 months, 27 patients remained on study at the time of the
report and the actuarial PFS at 6 months was 71%. The combination regimen was tolerated well
by these patients. A second phase
II study conducted by M Dickler and associates evaluated the combination of
bevacizumab and erlotinib in patients with relapsed and refractory metastatic
breast cancer. In the first 9 patients
evaluable for response, 1 PR has been achieved and 2 patients have SD at 9
weeks of therapy.
These preliminary results indicate that combination
bevacizumab plus erlotinib has activity in metastatic renal cell carcinoma
and that further phase II investigation in patients with metastatic
breast cancer is warranted. (Abstracts
4502 and 2001) THALIDOMIDE PLUS
DEXAMETHASONE Multiple myeloma.
SV Rajkumar and colleagues in ECOG conducted a phase III study (Study
E1A00) in which newly diagnosed patients with advanced multiple myeloma were
randomized to receive induction therapy with 4 months of either thalidomide
200 mg daily plus dexamethasone 40 mg on Days 1-4, 9-12, and 17-20 or
dexamethasone alone. After 4 months of
treatment, patients went on to stem cell transplantation or they continued
study treatment. An analysis of 109
evaluable patients showed that the paraprotein response rate for the
combination arm was 80% compared to 53% for patients treated with
dexamethasone alone (p = 0.0023).
Among 192 patients evaluable for safety, a higher rate of grade 3 and
4 adverse events was observed in the combination arm (41% vs. 16%). In addition, deep vein thrombosis occurred
in 14% of patients treated with thalidomide plus dexamethasone compared to
only 3% of patients given dexamethasone alone. These findings demonstrate that treatment
with the all oral combination of thalidomide plus dexamethasone results in
high response rates that are comparable to those historically achieved
with VAD chemotherapy. The increased
incidence of DVTs observed in the combination arm suggest that studies
utilizing prophylactic anticoagulation in conjunction with thalidomide
plus dexamethasone therapy for multiple myeloma patients are warranted. (Abstract 6508) PACLITAXEL PLUS
TRASTUZUMAB Breast cancer.
AD Seidman and associates in the Cancer and Leukemia Group B (CALGB)
performed a phase III study in which patients with metastatic breast cancer
who had received 0-1 prior chemotherapy regimens were randomized to either
weekly or every third-week paclitaxel treatments. After the accrual of 171 patients, when
trastuzumab became a standard therapy for patients with HER2-positve breast
cancer, patients with HER2-positve disease received trastuzumab and patients
with HER2 normal disease were randomized for trastuzumab. A total of 577 patients were treated. Weekly paclitaxel was superior to every
third-week paclitaxel with respect to response rate (p = 0.017 and time to
progression (p = 0.0008). A trend
toward an increase in survival was also seen in the weekly paclitaxel group
(p = 0.17). Trastuzumab was not found
to increase efficacy in the normal HER2 group. Weekly paclitaxel was associated with
greater neurologic toxicity, but less grade 3 or 4 granulocytopenia. Five patients (0.8%) experienced
significant cardiac dysfunction. This
study demonstrated that weekly paclitaxel is more efficacious than every
third-week paclitaxel for the treatment of patients with metastatic breast
cancer. In addition, trastuzumab
treatment of patients with normal HER2 metastatic breast cancer was not
found to increase clinical benefit. (Abstract
512) Bcl-2 ANTISENSE Oblimersen sodium
treatment of advanced melanoma. Resistance of
malignant melanoma to chemotherapy has been linked to overexpression of
the anti-apoptotic protein, Bcl-2.
Oblimersen sodium (Genasense) downregulates Bcl-2 and may enhance
apoptosis when added to chemotherapy. In addition, previous studies
showed that oblimersen sodium has activity against melanoma. Thus, MJ Millward and coworkers conducted a
phase III study in which patients with stage 4 or unresectable stage 3
melanoma were randomized to receive DTIC (1,000 mg/m2 i.v. every 3
weeks) plus oblimersen sodium (7 mg/kg/day for 5 days prior to DTIC by
continuous i.v. infusion) or DTIC alone.
A higher response rate (11.7% vs. 6.8%; p = 0.019) and a
longer time to progression (74 vs. 49 days; p = 0.0003) was
observed in the patients treated with combination therapy. A
trend toward increased overall survival was also noted for the oblimersen
sodium-treated patients (median survival of 9.1 vs. 7.9 months; p =
0.18). Hematologic toxicity and acute
phase reaction adverse events occurred more frequently in the combination
therapy group. These data suggest that
oblimersen sodium may enhance the effect of DTIC against melanoma. (Abstract 7505) ERLOTINIB Non-small-cell lung
cancer (NSCLC). In phase II studies erlotinib (Tarceva®)
has demonstrated single-agent activity in patients with NSCLC. FA Shepherd and colleagues from the
National Cancer Institute of Canada Clinical Trials Group now report the
results of a double-blind phase III study in which stage IV or IIIB NSCLC
patients were randomized in a 2:1 ratio to receive either erlotinib or
placebo after failing first or second line therapy (N = 731). The response rate to erlotinib was 8.9% and
the median duration of response was 34.2 weeks. Improved overall and
progression-free survival times were observed in the erlotinib-treated
patients compared to those who received placebo (6.7 vs. 4.7 months; p =
0.001 and 2.23 vs. 1.84 months; p < 0.001, respectively). The times to the development of
tumor-related symptoms were also longer in the erlotinib group. These results
demonstrate that erlotinib therapy prolongs survival compared to placebo treatments
in previously treated patients with advanced NSCLC. (Abstract 7022) CETUXIMAB Combined with
chemotherapy in colorectal cancer (CRC). The findings of 2 trials
investigating the combination of cetuximab (Erbitux®) with standard
chemotherapy regimens in patients with CRC were reported. P Rougier and colleagues
combined weekly i.v. cetuximab at doses of either 400 or 250 mg/m2
with FOLFIRI (irinotecan, 5FU, folinic acid) in a phase II study of
previously untreated patients with metastatic EGFR+ CRC. Dose-limiting toxicity (DLT) was not experienced
in the lower dose cetuximab group while 3 patients in the high-dose group had
DLTs consisting of diarrhea, an allergic reaction, and neutropenia. Among 22 evaluable patients, 10 patients
(46%) achieved a PR and 9 patients (41%) had stable disease. The median time to progression was 10.9
months. These results indicate that
the combination of cetuximab with chemotherapy regimens is feasible in
patients with metastatic CRC. S
Badarinath et al reported a preliminary safety analysis of a phase III study
in which patients with metastatic EGFR+ CRC were randomized to receive
second-line therapy with cetuximab (400 mg/m2 initial dose
followed by 250 mg/m2 weekly) plus FOLFOX4 (5FU, leucovorin,
oxaliplatin) or FOLFOX4 alone. This
analysis of 40 patients indicated that cetuximab did not increase the
toxicity associated with FOLFOX4 and that the authors were continuing to
accrue the target sample size of 1100 patients. (Abstracts 3513 and
3531) Squamous cell
carcinoma (SCC) of head and neck. JA Bonner et al
conducted a phase III study in which patients with locoregionally advanced
SCC of the oropharynx, hypopharynx, or larynx were randomized to receive
weekly cetuximab plus radiation or radiation alone (N = 424). The median survival for patients given
cetuximab plus radiation was 54 months compared to 28 months for patients who
received radiation alone (P = 0.02).
Toxicity was similar between the treatment groups except that an
increased incidence of grade 3 and 4 skin reactions occurred in the cetuximab-treated
patients (34% vs. 18%; p = 0.0003).
These data show that the addition of cetuximab to radiation improved
survival in patients with locally advanced SCC of the head and neck and
suggest that cetuximab should be studied in other tumors associated with EGFR
overexpression. (Abstract 5507) SIGNAL TRANSDUCTION
INHIBITION Renal cell carcinoma
(RCC). RJ Motzer et al investigated the use
of an orally administered tyrosine kinase inhibitor, SUO11248, as treatment
for 63 patients with metastatic RCC.
SUO11248 was given at a dose of 50 mg once daily for 4 weeks every 6
weeks. The early best-response data
revealed that 15 patients (24%) achieved a PR, 29 patients (46%) had
stable disease, and 19 patients (30%) developed disease progression. With a median follow-up of 6+ months,
32 patients remained on study treatment.
SUO11248 was tolerated with acceptable toxicity. The most commonly reported grade 3 or 4
adverse events were lymphopenia (30%) and elevated lipase levels (21%). Eight percent of patients had increased
levels of amylase without pancreatitis and 2 patients developed a decrease in
left ventricular ejection fraction. In
a second investigation, MJ Ratain et al. studied Bay 43-9006 (BAY), a novel
agent that inhibits tumor proliferation and angiogenesis through blockade of
the Raf/MEK/ERK pathway at the level of Raf kinase and the receptor kinases
VEGFR-2 and PDGF-b.
The authors enrolled 397 patients with advanced solid tumors in a
placebo-controlled, randomized discontinuation phase II trial. Tumor regression was noted in multiple
tumor types. Among 63 evaluable
patients with RCC, 25 patients responded to treatment and 18 patients
had stable disease. The most common
toxicities were rash, hand-foot syndrome, fatigue, diarrhea, anorexia,
and hypertension. These studies
demonstrate early evidence of antitumor activity for these novel agents. (Abstracts 4500 and 4501) |
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