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Targeted Therapies Formerly BioOncology Watch www.tgt-therapies.com |
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APRIL 2004 NON-SMALL CELL LUNG CANCER (NSCLC) Standard combination chemotherapy plus gefitinib. Two phase II studies in patients with
previously treated advanced NSCLC have shown that single-agent gefitinib 250 mg daily is active (response rates were
11.4% and 18.4%). Thus, Giuseppe Giaccone and colleagues conducted a multicenter,
double-blind phase III trial (INTACT 1) in which 1,093 previously untreated
patients with unresectable stage III or IV NSCLC
were randomized to cisplatin 80 mg/m2 on
Day 1 and gemcitabine 1,250 mg/m2 on
Days 1 and 8 every 3 weeks plus either gefitinib
500 mg daily, gefitinib 250 mg daily, or placebo
for up to 6 cycles. Gefitinib/placebo was then continued until disease
progression. Patients in both of these
studies were not selected on the basis of the presence of tumor EGFR. There
were no differences in overall survival, time to progression, or response rate
between the treatment groups. Roy Herbst et al performed a second multicenter,
double-blind phase III study (INTACT 2) in which 1,037 previously untreated
patients with unresectable stage III or IV NSCLC
were randomized to receive paclitaxel 225 mg/m2
and carboplatin area under the concentration/time
curve of 6 mg/min/mL on Day 1 every 3 weeks plus
either gefitinib 500 mg daily, gefitinib
250 mg daily, or placebo for up to 6 cycles.
Gefitinib/placebo was then continued until
disease progression. Again there were
no differences observed in overall survival, time to progression, or response
rate between the treatment groups.
These large double-blind, placebo-controlled trials showed that the
addition of the EGFR tyrosine kinase inhibitor gefitinib to standard combination chemotherapy doublet
regimens did not result in greater clinical benefit than standard
chemotherapy alone. (Giaccone G, et al. J
Clin Oncol
2004;22:777-784 and Herbst RS, et al. J Clin Oncol 2004;22:785-794) RENAL CELL CANCER (RCC) Randomized phase II study of CCI-779. CCI-779 (Wyeth Research)
is a novel mammalian target of rapamycin (mTOR) kinase inhibitor. In a phase I study CCI-779 was well
tolerated over a wide range of doses and one patient with advanced RCC
achieved a partial response (PR).
These preliminary findings led Michael Atkins and associates to
conduct a phase II study in which 111 patients with advanced RCC (previously
treated or those who were not considered to be an appropriate candidate for
first-line IL-2-based therapy) were randomized to receive 25, 75, or 250 mg
of CCI-779 weekly. Neither efficacy
nor safety was found to be influenced by CCI-779 dose level. The overall objective response rate was 7%
(7 PRs and 1 complete response), the median time to
progression was 5.8 months, and the median survival was 15.0 months. The most common CCI-779-related toxicities
were maculopapular rash (76%), mucositis
(70%), asthenia (50%), and nausea (43%).
These findings suggested that CCI-779 has modest clinical activity against
advanced RCC and further studies are warranted. (Atkins MB, et al. J Clin Oncol
2004;22:909-918) MYELOFIBROSIS WITH MYELOID
METAPLASIA (MMM) Phase II study of thalidomide. MMM is the most severe among Philadelphia-negative myeloproliferative
disorders. Potentially curative therapies, i.e., stem-cell transplantation,
are held in reserve and standard treatment consists of supportive therapies
or cytoreductive approaches aimed at reducing tumor
burden. Thalidomide has been evaluated
in MMM patients based on its anti-angiogenic
properties (D'Amato RJ, et al. Proc Natl Acad Sci
USA 1994;91:4082-4085)
and the prominent neo-angiogenesis that occurs in MMM.
Pilot
studies have suggested that thalidomide may be an effective therapeutic agent
for MMM. These findings led Monia Marchetti et al to administer oral thalidomide, starting
at 50 mg daily and increasing to 400 mg daily as tolerated, to 63 patients
with MMM. Half of the patients were
maintained on a thalidomide dose >100 mg daily and the drop-out rate was
51% at 6 months. Splenomegaly
was decreased by >50% in 19% of patients.
An increase in platelet count of ³ 50 x 109/L was
achieved in 22% of patients and an improvement in anemia was observed in 22%
of patients. Thirty-nine per cent of red blood cell transfusion-dependent
patients became transfusion independent with thalidomide treatments. Improvements in overall disease severity
score occurred in 31% of patients and were associated with reduced fatigue. Thus, low doses of thalidomide have palliative
activity in some patients with MMM and further investigations with controlled
trials are warranted. (Marchetti M, et al. J
Clin Oncol
2004;22:424-431) NON-HODGKIN'S LYMPHOMA (NHL) Rituximab adjuvant therapy following
high-dose therapy. Steven Horwitz
and colleagues investigated the use of rituximab
treatments following high-dose therapy (HDT) supported by autologous
hematopoietic cell transplantation (HCT) in
patients with relapsed or refractory aggressive NHL. Starting at Day 42 after HCT, 4 weekly
intravenous infusions of rituximab 375 mg/m2
were administered to 35 patients with relapsed or refractory B-cell lymphoma
(25 patients with DLCL, 3 patients with mantle-cell lymphoma, 3 patients with
transformed B-cell lymphoma, and 4 patients with other subtypes of B-cell
lymphoma). In addition, patients 5
through 35 received a second 4-week course of rituximab
6 months after HCT. In 29 evaluable patients with a median follow-up of 30 months,
the 2-year overall and event-free survival rates were 88% and 83%,
respectively. All patients who
received 2 courses of rituximab did not have
measurable B-cell counts at 12 months.
However, B-cell numbers were recovering by 18 to 24 months after HCT
and serious infections were not observed despite delayed B-cell recovery. Grade |
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