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Targeted TherapiesÔ Timely
Information for Practicing Hematologists and Oncologists www.tgt-therapies.com |
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JUNE 2005 HIGHLIGHTS OF THE 2005 AMERICAN
SOCIETY OF CLINICAL ONCOLOGY ANNUAL MEETING TYROSINE KINASE INHIBITORS Addition of erlotinib (Tarceva®)
to gemcitabine improves survival in advanced pancreatic cancer. MJ Moore and others from the
NCIC-CTG conducted a double-blind study in which 569 patients with previously
untreated, unresectable, advanced pancreatic adenocarcinoma were randomized
to receive gemcitabine (1,000 mg/m2 iv weekly x 7 for 8 weeks then
weekly x 3 for 4 weeks thereafter) plus erlotinib (100 mg po
daily) or gemcitabine plus placebo. At the time of the analysis, 485 patients
(85%) had died. Erlotinib-treated
patients achieved improvements in overall survival (OS) and progression-free
survival (PFS). The 1-year survival rates were 24% and 17% in the erlotinib
and placebo groups, respectively. In addition, among patients who experienced
a ≥ grade 2 erlotinib-induced rash, the 1-year
survival rate was 43%. No difference in response rate was observed between
the treatment groups (8.6% vs 8%). Rates of grade 3 and 4 toxicities were
comparable in both arms. These results demonstrated that the addition of
erlotinib to gemcitabine improved OS and PFS in patients with advanced
pancreatic cancer. (Abstract 1) Imatinib in polycythemia rubra vera
(PCV). Increased
mRNA for c-kit has been demonstrated in CD34+ cells in patients with
PCV. CM Jones reported on 16 PCV
patients treated with imatinib. The starting dose was 400 mg/day, and dose escalations to 600 and 800 mg daily were allowed. Five
patients treated with imatinib 400 mg daily achieved a complete response, and
7 patients have required dose escalation. These data suggest that imatinib is
an effective treatment option for patients with PCV. (Abstract 6517) BMS-354825 treatment of imatinib
resistant/intolerant disease. Unlike
imatinib, BMS-354825 binds the ABL kinase domain in both active and inactive
conformations and is predicted to have activity in most imatinib-resistant
CML and Ph+ ALL cases. Clinical data from 2 phase I
dose-finding studies confirmed that BMS-354825 can achieve hematologic responses
in patients with chronic- phase CML resistant to imatinib and in patients
with Ph+ ALL. BMS-354825 was well tolerated in
these studies; myelosuppression was reversible. A correlative study by N.
Shah and colleagues showed BMS-354825 to be active in patients with a wide
range of imatinib-resistant BCR-ABL kinase domain mutations. However, the
T315I mutation is an exception that is responsible for the development of
resistance to both imatinib and BMS-354825. Additional studies have
identified pharmacogenomic markers that are useful for predicting response to
BMS-354825 in cell lines. (Abstracts
6519, 6520, 6521, 3010) MONOCLONAL ANTIBODIES High-dose bevacizumab (Avastin®)
plus FOLFOX4 improves survival in advanced colorectal cancer. BJ Giantonio
et al. performed an ECOG trial in which 829 patients with advanced colorectal
cancer previously treated (with a fluoropyrimidine and an irinotecan-based
regimen) were randomized to receive one of 3 treatments: FOLFOX4 (iv
biweekly) alone, high-dose bevacizumab (10 mg/kg iv biweekly) alone, or
FOLFOX4 plus high-dose bevacizumab. Response rates were higher in patients
treated with combination therapy (21.8%), as compared with patients treated
with FOLFOX4 alone (9.2%) or bevacizumab alone (3.0%). With a median follow-up of 18.7 months,
patients in the combination arm had a longer median PFS and OS (7.2 and 12.9
months, respectively) than did patients receiving FOLFOX4 alone (4.8 and 10.8
months, respectively) or bevacizumab alone (2.7 and 10.2 months, respectively).
A higher incidence of ≥grade 3 hypertension,
bleeding, and neuropathy occurred in bevacizumab-treated patients. Thus, the
addition of high-dose bevacizumab to FOLFOX4 resulted in improvements in
response rate, PFS, and OS in patients with previously treated advanced
colorectal cancer and was tolerated with acceptable toxicity. (Abstract 2) Paclitaxel (P) plus carboplatin (C)
with or without bevacizumab in advanced nonsquamous non–small cell lung
cancer (NSCLC). In this
ECOG study (E4599), 878 patients with previously untreated advanced nonsquamous
NSCLC without brain metastases were randomized to receive treatment with P
(200 mg/m2), C (AUC=6), and bevacizumab (15 mg/kg) every 3 weeks
or with PC alone every 3 weeks. At the time of the analysis, 484 patients
(55%) had died. Patients treated with PC plus bevacizumab had a higher
response rate than did patients treated with PC alone (27% vs 10%; P<0.001). The PC plus bevacizumab
group also achieved a longer median PFS (6.4 vs 4.5 months; P<0.0001) and a longer median OS
(12.5 vs 10.2 months; P=0.007).
Neutropenia (24% vs 16.4%), hypertension (6% vs 0.7%), and ≥grade 3
hemoptysis (1.9% vs 0.2%) occurred more frequently in patients who received
bevacizumab. These results showed that the addition of bevacizumab to PC
improved PFS and OS compared with PC alone in patients with advanced nonsquamous
NSCLC. (Late Breaking Abstract 4) First-line therapy with bevacizumab
plus paclitaxel in metastatic breast cancer.
In this ECOG phase III study (E2100), 715 patients with previously
untreated metastatic breast cancer were randomized to receive paclitaxel (90
mg/m2 on days 1, 8, and 15 every 4 weeks) plus bevacizumab (10
mg/kg on days 1 and 15 every 4 weeks) or paclitaxel alone. The response rate
was greater in the combination group (28%) than in the single-agent
paclitaxel group (14%) (P<0.0001).
Median PFS and OS times were longer in patients in the combination therapy
arm (P<0.001 and P=0.01, respectively). Bevacizumab-treated patients had a higher
incidence of ≥grade 3 hypertension, proteinuria, and neuropathy. These
data demonstrated that therapy with bevacizumab and paclitaxel provided
greater response rates and longer PFS and OS times than paclitaxel alone in
patients with metastatic breast cancer. Further follow-up is needed to
confirm the survival benefit of combination therapy in these patients. (Miller KD, et al.) Addition of rituximab (Rituxan®)
to CHOP-like regimens used in diffuse, large B-cell lymphomas (DLBCL)
equalizes results. In the
MABTHERA International Trial Group (MIntT) study of
patients with DLBCL, CHOEP-21 was found to be better than CHOP-21 with
respect to complete response (CR) rate (75% vs 62%; P=0.02) and 2-year time to treatment failure (TTF) rate (65% vs
55%; P=0.04) but not 2-year
survival rate (86% vs 83%; P=0.67).
Rituximab increased the efficacy of both CHOEP-21 and CHOP-21 such that
differences in CR rate (87% vs 87%) and 2-year TTF rate (80% vs 83%) were no
longer detected. The 2-year survival rates of R-CHOEP-21 and R-CHOP-21 were
93% and 97%, respectively. (Abstract
6529) EPOCH plus rituximab (EPOCH-R) in
DLBCL. WH Wilson
and others conducted a phase II study in which 78 patients with previously
untreated CD20+ DLBCL were given dose-adjusted EPOCH-R plus filgrastim for 6
to 8 cycles, based on response. The pharmacodynamic endpoint of grade 4
neutropenia occurred in 96% of patients (febrile neutropenia developed in 33%
of patients). All patients achieved an
objective response to treatment (68% CR rate). At 18 months, PFS and OS rates
were 80% and 88%, respectively. Thus, dose-adjusted EPOCH-R is feasible in
DLBCL patients. Phase III studies are warranted. (Abstract 6530) Trastuzumab in breast cancer. In one
study of 66 patients with HER2+ metastatic breast cancer, the combination of
vinorelbine and trastuzumab yielded a response rate of 61%, with a median response duration of 12 months. In a second
trial, 31 patients with locally advanced HER2+ breast cancer were treated
with 6 cycles of docetaxel, vinorelbine, and trastuzumab prior to surgery,
achieving a response rate of 88% (clinical CR in 65% and pathologic CR in 45%
of patients). In addition, PK Marcom and coworkers
treated 32 patients with metastatic breast cancer (ER and/or PgR+ and HER2+) with the combination of letrozole and
trastuzumab and achieved a median time to progression of 32 weeks (range, 6–180+
weeks). However, a retrospective review by F Montemurro
and others of 120 patients with advanced breast cancer who had progressed
during trastuzumab therapy revealed that clinical outcomes were similar
whether or not trastuzumab was continued. Finally, Brian Leyland-Jones and
coworkers used a loading regimen to provide high steady-state levels early in
the course of trastuzumab therapy. This schedule has potential for improved
efficacy. Such studies aid in further defining the role of trastuzumab in the
treatment of breast cancer. (Abstracts 587, 591, 593, 594, 596) Adjuvant breast cancer therapy with
trastuzumab; presentations. Combined
analysis of 2 large cooperative group studies was reported. Patients with
resected HER2+ breast cancer received adjuvant therapy with 4 cycles of
doxorubicin and cyclophosphamide (AC) followed by 12 weeks of paclitaxel (P).
Patients in N9831 received paclitaxel 80 mg/m2 weekly ´ 12; in
B-31, they received paclitaxel 175 mg/m2 every 3 weeks ´ 4. Patients
in N9831 were randomized to one of 3 arms: the AC-followed-by-P control arm
(arm A); AC followed by P, followed by weekly trastuzumab ´ 52 weeks
(arm B); or AC followed by P, plus weekly trastuzumab ´ 12,
followed by weekly trastuzumab ´ 40 (arm C). Patients in B-31 were randomized to
the AC-followed-by-P control arm and to AC followed by P plus weekly
trastuzumab ´ 12
followed by weekly trastuzumab ´ 40. The design of B-31 allowed for analysis of
N9831 arm A and arm C data (N>3300). Joint analysis showed that
disease-free survival (DFS) and OS were significantly longer in arm C than in
arm A. Further follow-up is needed to confirm these preliminary results and
to determine the effect of combined versus sequential trastuzumab therapy
(arm B). ♦ An interim analysis of the HERA study was also reported. In
this study, HER2+ breast cancer patients following the completion of adjuvant
chemotherapy were randomized to one of 3 arms: 1 year of trastuzumab therapy,
2 years of trastuzumab therapy, or observation. The 2-year DFS rate was 86%
in the 1-year trastuzumab arm, compared with 77% in the observation arm (P<0.0001). OS was similar between
these 2 treatment groups at this time. A decrease in LVEF by >10 EF points
to <50% was observed in 2.2% of observation patients and in 7.4% of
patients treated with trastuzumab for 1 year. Further follow-up is needed to
determine 2-year results for trastuzumab treatment. These studies demonstrate
that trastuzumab is effective adjuvant therapy for patients with HER2+ breast
cancer. (Miller KD et al, Romond EH et al, and Piccart-Gebhart MJ, et al.) EPIGENETIC
MODULATING THERAPY Suberoylanilide
hydroxamic acid (SAHA) treatment of cutaneous T-cell lymphoma (CTCL). SAHA, an
oral inhibitor of class I and II histone deacetylases, has been shown to
induce apoptosis in CTCL cell lines. These data led M Duvic
and colleagues to administer SAHA 400 mg daily to 37 patients with CTCL
unresponsive to conventional therapies.
Partial responses were achieved in 10 (27%) patients. Additionally,
lymphadenopathy decreased by >50% in 15 of 26 patients, and pruritic
symptoms were reduced in 21 of 31 patients. Grade 4 thrombocytopenia
developed in 4 patients. The most common adverse events were fatigue and
gastrointestinal symptoms. Confirmatory studies are ongoing. (Abstract 6571) ANTISENSE THERAPY DTIC with or without oblimersen
sodium in advanced malignant melanoma (MM).
In the current study, 771 patients with advanced MM were randomized to
receive DTIC plus oblimersen sodium or DTIC alone. After 6 months of
follow-up, the survival difference between the 2 arms was not significant. However,
after 15 and 18 months of follow-up, landmark survival analysis demonstrated
significant survival differences in favor of combination therapy (P=0.036 and 0.012, respectively). After 21 months of follow-up, a trend
toward improved survival remained for the antisense therapy arm (P=0.057). These data indicate that
oblimersen sodium enhanced the effectiveness of DTIC in patients with
advanced MM. However, longer follow-up is needed. (Abstract 7506) |
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