Annual Meeting Proceedings Part 1 - American Society of Clinical ...

632s Sarcoma
LBA10008 Oral Abstract Session, Mon, 3:00 PM-6:00 PM
Randomized phase III trial of regorafenib in patients (pts) with metastatic
and/or unresectable gastrointestinal stromal tumor (GIST) progressing
despite prior treatment with at least imatinib (IM) and sunitinib (SU): GRID
trial. Presenting Author: George D. Demetri, Dana-Farber Cancer Institute,
Boston, MA
The full, final text of this abstract will be available at
abstract.asco.org at 12:01 AM (EDT) on Monday, June 4,
2012, and in the Annual Meeting Proceedings online
supplement to the June 20, 2012, issue of Journal of
Clinical Oncology. Onsite at the Meeting, this abstract will
be printed in the Monday edition of ASCO Daily News.
10010 Poster Discussion Session (Board #2), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Phase III, placebo-controlled trial (SUCCEED) evaluating ridaforolimus as
maintenance therapy in advanced sarcoma patients following clinical
benefit from prior standard cytotoxic chemotherapy: Long-term (> 24
months) overall survival results. Presenting Author: Jean-Yves Blay, University
Claude Bernard Lyon I, Centre Léon Bérard, Lyon, France
Background: The mammalian target of rapamycin (mTOR) regulates cell
growth and proliferation and is abnormally activated in many sarcomas.
Ridaforolimus, an oral mTOR inhibitor, demonstrated clinical activity in
previous nonrandomized trials in advanced sarcomas following failure of
prior chemotherapy. Methods: An international, multicenter, placebocontrolled,
phase 3 trial was conducted to evaluate maintenance therapy
with ridaforolimus in patients with metastatic soft-tissue or bone sarcomas
who achieved disease control from prior chemotherapy. Patients were
randomized (1:1) to receive oral ridaforolimus (40 mg) or placebo once
daily for 5 days each week. The primary endpoint was progression-free
survival (PFS); secondary endpoints included overall survival (OS) and
safety and tolerability. For OS, patients were to be followed at 3-month
intervals for at least 24 months and up to 60 months after randomization.
Results: 702 of 711 randomized patients received treatment. At the time of
the data cutoff for OS (386 deaths), patients in the study population had
been followed for at least 15 months. Median OS was 93.3 weeks with
ridaforolimus vs 83.4 weeks with placebo (hazard ratio [HR]�0.88; 95%
confidence interval [CI]: 0.72, 1.08; P�0.23). Ridaforolimus significantly
improved PFS vs placebo (HR�0.72; 95% CI: 0.61, 0.85; P�0.0001;
median PFS: 17.7 weeks vs 14.6 weeks); PFS improved across all
prespecified baseline characteristics. As expected from the class of mTOR
inhibitors, the most common adverse events with ridaforolimus were
stomatitis, thrombocytopenia, noninfectious pneumonitis, hypertriglyceridemia,
hyperglycemia, infections, and rash. Conclusions: Oral ridaforolimus
was generally well-tolerated and significantly improved PFS in
metastatic sarcoma patients with benefit from prior chemotherapy, offering
an effective treatment alternative to surveillance alone. Results of a
long-term OS analysis (prespecified to occur at 67% mortality, 24 months
minimum follow-up) in the intent-to-treat population will be available in
early 2012.
10009 Poster Discussion Session (Board #1), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
PALETTE: Final overall survival (OS) data and predictive factors for OS of
EORTC 62072/GSK VEG110727, a randomized double-blind phase III
trial of pazopanib versus placebo in advanced soft tissue sarcoma (STS)
patients. Presenting Author: Winette T.A. Van Der Graaf, Department of
Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen,
Netherlands
Background: At ASCO 2011 we presented an increase in median progressionfree
survival (PFS) of pazopanib of 13 weeks (median 7 to 20 weeks; HR
0.31) in a randomized double-blind, placebo-controlled phase III trial in
advanced non-adipocytic STS patients pretreated with chemotherapy. Now
we present final OS data and predictive factors for OS, such as ethnicity,
ancestry and well-known prognostic and predictive factors in STS patients
treated with chemotherapy. Methods: At clinical cut-off median follow-up
was 25 months. Comparison of both treatments for OS was performed using
a two-sided log rank test stratified for number of prior lines of systemic
therapy for advanced disease and WHO performance status (PS). HR was
calculated with a 2-sided CI. A Kaplan-Meier OS curve was used. Baseline
characteristics as potential predictive factors for OS were: PS (0 vs 1),
number of lines of prior therapy for advanced disease (0-1 vs 2�), age
(�55 yrs vs � 55 yrs), gender, ethnicity (Hispano or Latino vs other),
geographic ancestry (White Caucasian, Asian, other), tumour grade (1-2 vs
3), histology (leiomyosarcoma vs synovial sarcoma vs other). A Cox model
was fitted with the investigated factor, treatment arm and associated
interaction factor. Data of all 369 randomized patients (123 placebo, 246
pazopanib) were used for the analyses. Results: Median OS (95% CI) was
10.7 (8.7-12.8) in the placebo versus 12.5 (10.6-14.8) months in the
pazopanib group, HR: 0.86 (0.67-1.1). Post study protocol systemic
treatment was administered in 63% of placebo, and in 49% of pazopanib
treated patients. None of the investigated factors showed any statistical
significant predictive value for OS. Conclusions: Although pazopanib
demonstrated a statically significant increase in PFS compared to placebo,
final OS analysis, which showed a trend in favor of pazopanib in patients
with metastatic non-adipocytic STS, did not reach statistical significance.
The factors studied were not predictive for OS.
10011^ Poster Discussion Session (Board #3), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Phase I study of neoadjuvant chemoradiation (CRT) plus sorafenib (S) for
high-risk extremity soft tissue sarcomas (STS). Presenting Author: Janelle Marie
Meyer, Oregon Health & Science University Knight Cancer Institute, Portland,
OR
Background: We previously reported a regimen of epirubicin/ifosfamide (E/I) and
hypofractionated radiation (RT) followed by surgery and postoperative E/I. We
hypothesize that S � CRT is safe and augments activity through anti-angiogenic
mechanisms. We performed dynamic contrast-enhanced MRI using shutter
speed pharmacokinetic analysis (SSM DCE-MRI) to assess preoperative therapy
effect. Methods: Subjects with �5 cm, grade 2-3 extremity STS were treated in
cohorts of escalating S dose using a 3�3 design based on dose-limiting toxicity
(DLT) during the first 8 weeks. Daily S was initiated 14 days prior to E/I (E 30
mg/m2 /day days 1-3 and I 2.5 g/m2 /day days 1-3 every 21 days for 3 pre- and 3
postoperative cycles). 28 Gy preoperative RT was administered in 8 fractions
during cycle 2 (E omitted). Primary objective was to determine maximum
tolerated dose (MTD). DCE-MRI was performed at baseline, after 2 weeks S, and
prior to surgery. Results: 16 subjects were enrolled. Histologies included
pleomorphic (5), synovial (5), liposarcoma (3), other (3). All were extremity (12
lower, 4 upper) tumors. Median tumor size was 11.7 cm. The MTD of S was 400
mg daily (see table). Most common grade 3/4 adverse events among all dose
levels were neutropenia (94%), anemia (75%), hypophosphatemia (69%),
thrombocytopenia (56%), neutropenic fever/infection (50%), and hypokalemia
(31%). 38% developed wound complications requiring surgical intervention
including amputation in 1 subject. 44% had �95% histologic necrosis at
surgery. No subjects have recurred with median follow-up of 15 (6-27) months.
8 subjects underwent DCE-MRI. Changes in SSM DCE-MRI biomarkers after 2
weeks S correlated with histologic response (R2�0.71). Conclusions: The
addition of S to CRT is feasible with promising activity that warrants further
investigation. Rate of wound complications is similar to other reports of
preoperative radiation. SSM DCE-MRI detected changes in tumor perfusion after
only 2 weeks of S and may prove useful to assess early drug effect in STS.
S (mg) #DLTs/subjects DLT Grade
200 1/6 Mucositis 3
400 1/7 Syncope 3
800 3/3 -Neutropenic sepsis, thrombosis, HFS
-Rash, HFS
-Rash
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