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

274s Gastrointestinal (Noncolorectal) Cancer
TPS4144 General Poster Session (Board #53G), Mon, 8:00 AM-12:00 PM
A phase II study of afatinib (BIBW 2992) in patients with advanced
HER2-positive trastuzumab-refractory esophagogastric cancer. Presenting
Author: Yelena Yuriy Janjigian, Memorial Sloan-Kettering Cancer Center,
New York, NY
Background: Trastuzumab, approved by the FDA, has been the standard of
care for patients (pts) with HER2-positive esophagogastric cancer. Acquired
and de novo resistance to trastuzumab is an important clinical issue.
Afatinib, an oral irreversible inhibitor of the ErbB-family of tyrosine kinase
receptors, EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4), in combination
with cetuximab, demonstrated a 40% partial response (PR) rate, with
clinical benefit in �90% in lung cancer patients with acquired resistance
to erlotinib. (Janjigian Y. ASCO 2011). MSKCC data in a HER2-positive
NCI-N87 gastric cancer xenograft showed that while trastuzumab alone
was minimally effective, single-agent afatinib resulted in near complete
tumor regression by inducing apoptosis and downregulation of HER2,
p-HER2, EGFR, p-EGFR with minimal additive benefit of trastuzumab. In
light of these data and the efficacy of afatinib in patients with trastuzumabrefractory
breast cancer, we designed a phase II study to determine if
afatinib will benefit patients with trastuzumab-refractory HER2-positive
esophagogastric cancer. We hypothesize that simultaneous inhibition of
ErbBB receptor family components with afatinib will overcome trastuzumab
resistance. Molecular bases of trastuzumab resistance will be
examined. Methods: Pts with metastatic HER2-positive (IHC 3� or FISH
�2.0) esophagogastric cancer with disease progression on a trastuzumabcontaining
regimen will receive afatinib 40 mg once daily. Primary
endpoint RECIST 1.1 response (SD�CR�PR) at 4 months, with imaging
every 8 wks. 13 pts will be enrolled in the 1st stage and if �1 responses are
observed, additional 14 ps (total of 27) will be treated. An initial biopsy
prior to the start of therapy, a second biopsy after 1 wk of afatinib, analysis
of archival pre-trastuzumab tissue and blood sample for matched normal
DNA control are mandated. Changes in signaling following afatinib therapy
will provide insight into response heterogeneity. Degree of target inhibition
will be correlated with responses. Archival baseline (pre-trastuzumab) and
pre-afatinib tissue will be assessed for abnormalities in pathways implicated
in trastuzumab resistance.
TPS4146 General Poster Session (Board #54A), Mon, 8:00 AM-12:00 PM
A multicenter, randomized, double-blind, phase III study of ramucirumab
(IMC-1121B; RAM) and best supportive care (BSC) versus placebo (PBO)
and BSC as second-line treatment in patients (pts) with hepatocellular
carcinoma (HCC) following first-line therapy with sorafenib (SOR). Presenting
Author: Andrew X. Zhu, Division of Hematology and Oncology, Massachusetts
General Hospital, Boston, MA
Background: Blockade of vascular endothelial growth factor (VEGF) signaling
in HCC has been shown in preclinical models with monoclonal
antibodies and small molecule multikinase inhibitors, and in clinical trials
with SOR, to have anti-tumor activity and improve survival. RAM, a fully
human monoclonal antibody, binds to the VEGF receptor-2 (VEGFR-2),
potently blocks the binding of the VEGF ligand to VEGFR-2, inhibits
VEGF-stimulated activation of VEGFR-2, and neutralizes VEGF-induced
mitogenesis of human endothelial cells. In a single-arm, Phase 2 study of
RAM as 1st-line monotherapy in 42 pts with advanced HCC (Zhu, ILCA
2010, abstr. O-033), preliminary results included median progression-free
survival (PFS) of 4 months (m), time to progression (TTP) of 4.2 m, overall
survival (OS) of 12 m and disease control rate of 70% (best overall
response: 10% partial response, 60% stable disease). Methods: Pts with
HCC with disease progression during or following 1st-line therapy with SOR
(or who were intolerant to SOR) are randomized 1:1 to receive RAM (8
mg/kg) or PBO once every 2 weeks, with BSC, until disease progression or
intolerable toxicity. Eligibility includes prior SOR as 1st-line systemic
treatment for HCC, Child-Pugh A, B7 or 8 cirrhosis, ECOG PS 0-1, bilirubin
� 3 mg/dL, transaminases � 5 � upper limit of normal (ULN), creatinine
� 1.2 � ULN, and platelets � 75�103 /�L. The primary endpoint is OS.
Secondary endpoints include PFS, best objective response rate, TTP,
patient-reported outcome measures of disease-specific symptoms and
health-related quality of life, safety, and RAM pharmacokinetics, pharmacodynamics,
and immunogenicity. With 544 patients, this study is designed
to detect an increase in OS (median 6 m with PBO to 8 m with RAM;
1-sided �� 2.5%, 85% power). As of 18 January 2012, approximately
52% of planned pts have been randomized. The IDMC reviewed this study
on 21 June and 3 November 2011 and recommended the study to continue
unmodified.
TPS4145 General Poster Session (Board #53H), Mon, 8:00 AM-12:00 PM
DOCTOR: A randomized phase II trial of preoperative cisplatin, 5-fluorouracil,
and docetaxel with or without radiotherapy based on poor early response
to standard chemotherapy for resectable adenocarcinoma of the esophagus
and/or OG junction. Presenting Author: Andrew Barbour, University of
Queensland, Brisbane, Australia
Background: Surgery forms the mainstay of curative treatment for oesophageal
and gastro-oesophageal junction adenocarcinoma (OAC). Preoperative
chemotherapy (CTX) with or without concurrent radiotherapy (CRT) have
resulted in modest improvements in outcome. Patients who demonstrate a
histological response in the resected specimen following pre-operative
therapy (CTX or CRT) have consistently better survival than non-responders.
Recent data suggests that early metabolic response, assessed by FDG-PET
scan performed 14�/-1 days after the start of CTX compared with a
baseline PET scan, is predictive of a histological response and improved
survival. Increasing the proportion of responders to pre-operative therapy
remains one of the major challenges facing patients with localised OAC.
Methods: 150 patients with resectable adenocarcinona of the oesophagus
or GOJ will be registered and given 1 cycle of cisplatin and 5FU (CF).
Patients will undergo a series of baseline tests including endoscopy,
endoscopic ultrasound and 18FDG-PET. At Day 15 of the initial CF cycle
the PET will be repeated. Patients with a PET response (� 35% reduction
in SUVmax) to initial treatment will continue with CF as standard treatment
prior to surgery. PET non-responders (� 35% reduction in SUVmax) will be
randomized equally to receive either docetaxel, cisplatin and 5FU (DCF) or
DCF plus radiatiotherapy. Following completion of the preoperative chemotherapy
/chemoradiotherapy patients will have their cancer surgically
removed. The primary end point is major histological response (�10%
residual viable tumour) and secondary endpoints of progression-free and
overall survival, toxicity, quality of life and feasibility of response-based
therapy. Eligibility: T2 or greater tumours (by EUS or CT), or T1 tumours
that are poorly differentiated, or T1 node positive, histologically proven
invasive adenocarcinoma of the oesophagus or GOJ, technically resectable
tumour which is sufficiently FDG avid on the initial PET staging scan.
Status: Opened to accural 2009.
TPS4147 General Poster Session (Board #54B), Mon, 8:00 AM-12:00 PM
An open-label, randomized phase II study comparing first-line treatment
with dovitinib (TKI258) versus sorafenib in patients with advanced hepatocellular
carcinoma. Presenting Author: Ann-Lii Cheng, National Taiwan
University Hospital, Taipei, Taiwan
Background: Hepatocellular carcinoma (HCC) is a highly vascularized tumor
that may rely on tumor angiogenesis for growth, invasion, and metastasis.
Inhibition of the vascular endothelial growth factor receptor (VEGFR) and
platelet-derived growth factor receptor (PDGFR) pathways temporarily
prevents HCC tumor progression. However, because the fibroblast growth
factor receptor (FGFR) pathway can serve as an escape pathway for these
tumors, simultaneous inhibition of FGFR may be required to provide a
sustainable antitumor response. Dovitinib (TKI258) has been shown to be a
potent oral tyrosine kinase inhibitor that inhibits multiple angiogenic
factors, including FGFR, VEGFR, and PDGFR, with IC50 values of � 20 nM.
Preclinical studies in HCC xenograft models have demonstrated that the
antitumor effects of dovitinib are superior to those of the kinase inhibitor
sorafenib, which is approved for use in advanced HCC. These data support
additional testing of dovitinib in advanced HCC patients. Methods: This
study (NCT01232296) is an open-label, randomized phase II trial being
conducted at multiple centers in the Asia-Pacific region. Adult patients are
eligible if they have advanced HCC (Barcelona Clinic Liver Cancer stage C)
with Child-Pugh class A cirrhotic status. Patients must also have an Eastern
Cooperative Oncology Group (ECOG) performance status of 0 or 1 and
cannot be eligible for (or have had disease progression after) surgical or
locoregional therapies. Patients are randomized 1:1 to receive dovitinib
(500 mg/day on a 5-days-on/2-days-off dosing schedule) or sorafenib (400
mg twice daily). Patients will be treated until disease progression, unacceptable
toxicity, death, or discontinuation for any other reason. No treatment
crossover will be permitted. The primary end point of this trial is overall
survival. Secondary end points include time to tumor progression, disease
control rate, time to definitive deterioration in ECOG status, safety, and
pharmacokinetics. The pharmacodynamic effects of dovitinib and sorafenib
on plasma/serum biomarkers will also be explored. As of 30 January 2012,
93 of the planned 150 patients have been enrolled.
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