|
|
BioOncology Watch Timely Information for Practicing
Physicians |
|
|
july 2001 highlights of the 37th
ASCO Annual Meeting May 12-15, San Francisco Non-Hodgkin's Lymphoma (NHL) Rituximab therapy of post-transplant lymphoproliferative disorder
(PTLD). Steve Horwitz and
colleagues used rituximab 375 mg/m2 weekly for 4 weeks in 14
patients with CD20+ PTLD unresponsive to reduction in immunosuppression
therapy. Eight (62%) patients
achieved a response (3 CRs and 5 PRs) and 1 patient had stable disease while
4 patients progressed on therapy. All
8 responders remained progression free after a median follow-up of 10 months
(range, 1-21 months). Rituximab was
well tolerated and these results show rituximab to be active against CD20+
PTLD. (Abstract 1134) Zevalin radioimmunotherapy (RIT). Ian Flinn et al conducted a phase II trial
in which 57 patients with NHL (95% were of follicular histology) refractory
to rituximab were treated with Zevalin (ibritumomab tiuxetan; IDEC
Pharmaceuticals), an anti-CD20 murine monoclonal antibody covalently bound to
tiuxetan, which forms a chelate with 90Yttrium. The objective response rate was 74%
including 15% CRs. All 14 patients
with tumors £ 5 cm in
diameter achieved a response, and 5 of 10 patients with bulky tumors (>10
cm) also responded. The median
duration of response was longer for Zevalin than for prior rituximab (8.4+ vs
4 months; P=0.008). Zevalin
treatments were tolerated well and the most common toxicity was transient
marrow suppression. These results
show that Zevalin RIT is safe and effective therapy for patients with
rituximab-refractory follicular NHL.
(Abstract 1141) Tositumomab therapy of mantle cell lymphoma (MCL). Ajay Gopal and associates treated 15
patients with relapsed/refractory MCL with a combination of I-131-tositumomab
(20-25 Gy) (Coulter Pharmaceuticals) followed by high-dose chemotherapy
(etoposide 30-60 mg/kg and cyclophosphamide 60-100 mg/kg) and ASCT. Of 11 evaluable patients, 8 achieved a CR
(73%), 1 achieved a PR, and 2 remained progression free. All 15 patients were alive and progression
free with a median follow-up of 12 months (range, 1-47 months). Toxicities were comparable to standard
transplant regimens with a median time of absolute neutrophil count <500/mL of 12
days (range, 9-19 days). These
results from a small number of patients suggest that I-131-tositumomab
combined with high-dose chemotherapy and ASCT may provide an effective
therapeutic option for patients with relapsed/refractory MCL. Further studies are warranted. (Abstract 1118) Hu1D10 monoclonal antibody. Hong Wang et al analyzed the reactivity of the 1D10 antigen in
various human malignant tissues and found the antigen to be expressed in many
hematological tumors as well as several solid tumors including colorectal,
ovarian, renal cell, and breast carcinomas.
These findings suggest that Hu1D10 may be useful in the treatment of
solid tumors. Another trial led by
Brian Link studied 4 doses of Hu1D10 (0.15, 0.5, 1.5, and 5.0 mg/kg)
administered as 4 weekly infusions in patients with relapsed B-cell lymphomas
expressing the 1D10 antigen (n=20).
Hu1D10 was tolerated at all dose levels; frequent grade 1 and 2
infusion-related toxicities were experienced while grade 3 adverse events,
including hypotension (n=2) and nausea/vomiting (n=2), were infrequent. Partial responses have been observed in 3
of 6 follicular NHL patients. These
responses occurred late (median time to response of 106 days) and
progressively improved up to 400 days after treatment, suggesting a possible
unique mechanism of action. Phase II
studies are under way. (Abstracts 1181 and 1135) Chronic
Lymphocytic Leukemia (CLL) Therapy with
rituximab. John Byrd and colleagues reported phase II
trial results in which previously untreated CLL patients were randomized to
receive fludarabine (25 mg/m2 days 1-5 every month for 6 months)
followed 2 months later by rituximab 375 mg/m2 weekly for 4 weeks
(n=21; Flu then Ritux) or Flu + Ritux 375 mg/m2 on days 1 and 4 of
the first cycle and day 1 of cycles 2-6 (n=21). All 21 patients receiving Flu + Ritux achieved a tumor response
(10 CRs and 11 PRs) and 18 patients receiving Flu then Ritux had a response
(8 CRs and 10 PRs). Six Flu + Ritux
patients (29%), compared to 1 Flu then Ritux patient (6%), developed grade 3
or 4 infusion toxicity during the first treatment with Ritux. Infusion reactions were uncommon during
subsequent infusions of Ritux. Grade
3 or 4 hematologic toxicities and grade 3 infections were comparable in both
treatment arms. Longer follow-up is
needed, however, both regimens of Flu and Ritux appear to be active with
acceptable toxicity in previously untreated CLL patients. (Abstract 1116) Treatment of residual disease with
Campath-1H. Susan O'Brien et al investigated the
effect of Campath-1H therapy on minimal residual disease in 29 patients with
CLL who had achieved a stable PR (n=14), a nodular PR (n=12), or a CR (n=3)
after chemotherapy. The first 24 patients
received Campath-1H 10 mg tiw for 4 weeks and after a 4-week rest, patients
were re-evaluated. A second cycle of
Campath-1H was administered if disease was still present. Subsequent patients
were given a single cycle of Campath-1H at 30 mg tiw for 4 weeks. Nine patients (41%) at the 10mg dose and 3
of 5 patients at the 30 mg dose have responded. Four patients with a PR improved to a nodular PR (3) or a CR
(1) and 6 patients with a nodular PR achieved a CR. Campath-1H was well tolerated, however, CMV reactivation
occurred in 3 of 24 patients (13%) treated with the 10mg dose and in 3 of the
patients treated at the 30 mg dose. Campath-1H is a potentially effective
therapy for residual CLL following chemotherapy. (Abstract 1132) Hairy Cell Leukemia (HCL) Anti-CD22 recombinant immunotoxin BL22. Robert Kreitman and coworkers conducted a
dose escalation trial of an anti-CD22 recombinant immunotoxin (an anti-CD22
Fv fused to truncated Pseudomonas exotoxin) in HCL patients resistant
to purine analogs (n=16). The maximum
tolerated dose was 40 mg/kg qod
for 3 days and common toxicities included transient hypoalbuminemia and
transaminase elevations. A CR was
achieved in 11 patients (minimal residual disease was detected in only 1
patient by bone marrow immunohistochemical analysis) and a PR in 2
patients. Pancytopenia resolved in
all responders. None of the
responding patients has developed disease progression after a median
follow-up of 7 months (range, 3-15 months).
These results demonstrate that this agent has activity in resistant
HCL and may produce long-term remissions. (Abstract 1119) Epidermal Growth Factor Receptor (EGFR)
Inhibitors
Squamous cell carcinoma of the head
and neck (SCCHN). Neil Senzer and coworkers treated 114
patients (no patient had received more than 1 prior treatment) with advanced
SCCHN with an oral antagonist of the EGFR-tyrosine kinase (OSI-774; OSI
Pharmaceuticals and Pfizer) in a phase II study. Patients with EGFR-positive and EGFR-negative tumors were
eligible for study participation.
Patients received 150 mg of oral OSI-774 daily. This dosing regimen achieved serum levels
of OSI-774 (500 ng/mL) that correlated with drug concentrations associated
with antitumor effects in preclinical models. Of 78 evaluable patients, there were 10 patients with partial
responses (13%), 23 patients with stable disease (29%), and 45 patients who
developed disease progression (58%).
An acneiform rash occurred in 82 patients (72%), which was severe in 9
patients (8%). Other adverse events
included diarrhea, nausea, vomiting, headache, and fatigue. OSI-774 has activity in SCCHN and with
acceptable toxicity. Further studies
are warranted. (Abstract 6) Cetuximab for colorectal cancer.
Cetuximab (IMC-C225; ImClone Systems), a chimeric monoclonal antibody
that targets EGFR, has been shown to have synergistic/additive effects in
preclinical studies when combined with chemotherapeutic agents. Leonard Saltz and colleagues investigated
the activity of the combination of cetuximab and CPT-11 in patients with
EGFR-positive colorectal cancer refractory to 5-fluorouracil and CPT-11
(n=121). The median time from the
demonstration of disease progression on CPT-11-based therapy to the
initiation of cetuximab/CPT-11 therapy was 30 days. CPT-11 was administered at the same dose and schedule with
which the patient had previously been treated and cetuximab was given as a
400 mg/m2 intravenous loading dose followed by infusions of 250
mg/m2 weekly. A partial
response was achieved in 21 patients (17%; 95%CI, 11%-25%). The median duration of response was 84
days (range, 42-210 days). An
additional 37 patients (31%) had stable disease. Toxicities associated with
cetuximab were allergic reactions and an acne-like rash. Toxicities commonly associated with CPT-11
were not exacerbated by the addition of cetuximab treatments. Cetuximab is well tolerated and may
produce objective tumor responses when combined with CPT-11 in patients with
advanced colorectal cancer that is both refractory to CPT-11 and is EGFR-positive. (Abstract 7) Anti-HER2/neu
Optimal patient selection for
Herceptin therapy. RD Mass et al performed fluorescence in situ hybridization (FISH) analysis
on available histologic material obtained from 458 patients enrolled in a trial
of Herceptin plus chemotherapy as first-line treatment for patients with
metastatic breast cancers that overexpressed HER2 at the 2+ or 3+ level by
standard immunohistochemistry assays to investigate the prognostic effect of
HER2/neu amplification. Amplification
was detected in 76% of patients; 89% of the 3+ patients and 31% of the 2+
patients. Tumor response rate (54% vs
31%; P<0.0001) and survival (P=0.009) were improved by the
addition of Herceptin to chemotherapy compared to chemotherapy alone in the
FISH+ group while no differences were observed in the FISH- patients. In addition, GL Vogel et al
retrospectively analyzed 2 large trials of Herceptin therapy in patients with
advanced breast cancer and found that patients selected by FISH positivity
compared to immunohistochemistry positivity had a trend toward higher
response rates and longer survival.
These findings suggest that FISH testing may identify those patients
who are most likely to derive clinical benefit from Herceptin therapy. (Abstracts 85 and 86) HER2 and cardiotoxicity.
Animal studies indicate that HER2 plays an important role in
cardiogenesis and myocardial protection.
Ilka Beate Fuchs et al analyzed 60 heart biopsies from patients with cardiac
dysfunction and myocardium from 25 breast cancer patients with or without
previous anthracycline exposure to study the pathophysiologic role of HER2 in
damaged myocardium. HER1 expression
was not noted and only faint staining for HER2 was detected. In addition, FISH analysis did not reveal
HER2 gene amplification. These findings suggest that a direct antibody
interaction does not contribute to the cardiotoxicity associated with
Herceptin. Other mechanisms, such as cytokine release, should be
examined. (Abstract 176) Adjuvant Treatment of Colon Cancer
Edrecolomab (a murine monoclonal
antibody). C JA Punt and associates conducted a phase
III, multicenter, randomized trial of edrecolomab/5-fluorouracil
(5-FU)/leucovorin (LV) vs 5-FU/LV vs edrecolomab alone as adjuvant therapy
for patients with surgically resected stage III colon cancer (n=2761). The addition of edrecolomab to 5-FU/LV did
not improve clinical outcomes while treatment with edrecolomab alone was
associated with shorter survival and disease-free survival times compared to
patients treated with 5-FU/LV. These
data from a large, well-controlled trial show that adjuvant edrecolomab
therapy did not result in clinical benefit for patients with stage III colon
cancer. (Abstract 487) |
||
|
Produced by Market Development Group through an
educational grant from Genentech, Inc. and IDEC
Pharmaceuticals. Comments and inquiries can be e-mailed to webmaster@biooncologywatch.org |
||