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

258s Gastrointestinal (Noncolorectal) Cancer
4079 General Poster Session (Board #45F), Mon, 8:00 AM-12:00 PM
Phase II study of oxaliplatin and sorafenib in advanced gastric cancer after
failure of cisplatin-fluoropyrimidine-based (PF) treatment. Presenting Author:
Rosa Gallego, Hospital Clinic, Barcelona, Spain
Background: PF-based chemotherapy is the standard first line treatment in
advanced GC. Although some drugs as taxanes or oxaliplatin (Ox) have
shown efficacy in combination with P or F, no established second line
exists. RAF/MEK/ERK pathway activation as well as VEGF expression have
been related with more advanced GC. Sorafenib (S) is a potent Raf and
VEGFR inhibitor and Ox has demonstrated non-cross resistance with P.
Methods: A multicenter phase II to evaluate the efficacy of OX- S
combination in gastric or GEJ adenocarcinoma (pts) with progressive
disease after CF based first line chemotherapy, was planned. Other
inclusion criteria: ECOG 0-2, measurable disease and adequate organ
function. Treatment doses were Ox 130mg/m2 /3 weeks and S 800
mg/bid/d until progression or toxicity. CT scan evaluation every 3 cycles.
The study followed a A-Hern single-stage design (HR � 1.67, median
expected PFS of 4.3m if treatment ineffective, sample size: 43). The study
was closed with the inclusion of 40 pts, maintaining a power � 87%. Ten
pts would have to be alive and free of progression at 12m to consider the
study positive. Results: Forty pts were included and evaluable for PFS.
Thirty-six pts were evaluable for response. Median age was 63 ( range 39 -
76) years, ECOG 0/1/2 in 36/59/5 % of pts. PFS to 1st line was � 6m in
59% of pts. One CR and, 47.2% of SD were observed. Gr ¾ toxicity (%)
was: neutropenia (9.8), thrombocitopenia (7.3), neurotoxicity (4.9) and
diarrhea (4.9). Median PFS was 3 (95 %CI: 2.3-4.1 )m and median OS was
6.5 ( 95% CI: 5.2-9.6)m. PFS at 12 m was 0%. Median OS in pts with PFS
to 1º line � 6m/ �6m was 9.7m and 5.6m respectively (p0.04).
Conclusions: The combination of Oxaliplatin-Sorafenib in advanced GC
patients previously treated with CF shows a safe profile but these results do
not support the implementation of a phase III trial. Our results show that
PFS under a CP-based first line therapy determine subgroups of GC
patients with different clinical behaviors.
4081 General Poster Session (Board #45H), Mon, 8:00 AM-12:00 PM
Safety of everolimus (EVE) in Asian patients (pts) with advanced gastric
cancer (AGC) enrolled in the phase III GRANITE-1 study. Presenting
Author: Kun-Huei Yeh, National Taiwan University Hospital, Taipei, Taiwan
Background: Previous subanalyses of the RECORD-1 (Jpn J Clin Oncol
2011;41:17-24) and RADIANT-3 (GICS 2011; abs. 289) studies of the
oral mammalian target of rapamycin inhibitor EVE showed that incidences
of stomatitis, rash, infections, and pneumonitis were greater in Asian pts;
however, the number of Asian pts enrolled was small. GRANITE-1 provides
an opportunity to evaluate EVE safety in a broader Asian population.
Methods: In the randomized, double-blind, phase 3 GRANITE-1 study, pts
aged �18 y with confirmed AGC and disease progression after 1 or 2 lines
of systemic chemotherapy were randomized 2:1 to EVE 10 mg/d � best
supportive care (BSC) or placebo � BSC. Randomization was stratified by
region (Asia [China, Japan, Korea, Taiwan, Thailand, Hong Kong] vs rest of
world [ROW]) and previous lines of chemotherapy (1 vs 2). Study drug was
continued until disease progression or unacceptable toxicity. Adverse
events (AEs) were collected throughout the study and for 28 d after final
dose of study drug and assessed according to the Common Terminology
Criteria for Adverse Events, v 3.0. Primary endpoint was overall survival.
Safety was a secondary endpoint. Results: Of the 656 pts in the study, 363
(55%) were enrolled in Asia and received EVE (n�243) or placebo
(n�120). EVE did not significantly reduce the risk of death in the overall
(HR 0.90; 95% CI 0.75-1.08), Asian (HR 0.96; 95% CI 0.75-1.23), or
ROW (HR 0.85; 95% CI 0.65-1.10) populations. The most common
any-grade AEs among EVE-treated pts (Asia vs ROW) were decreased
appetite (45% vs 51%), stomatitis (44% vs 35%), and fatigue (34% vs
35%). Among EVE-treated pts, rates of any-grade rash, infections, and
pneumonitis (Asia vs ROW) were 22% vs 18%, 24% vs 28%, and 4% vs
2%, respectively; rates of grade 3/4 stomatitis, rash, infections, and
pneumonitis (Asia vs ROW) were 4% vs 6%, 0% vs 0.5%, 6% vs 9%, and
0.4% vs 1%, respectively. No grade 4 pneumonitis was observed. Only 1 pt
(from Asia) discontinued due to pneumonitis (grade 3). Conclusions: The
safety profile of EVE in Asian pts with AGC was similar to that observed in
ROW pts with AGC and with EVE in other cancers. No new safety signals
were identified. Pneumonitis was relatively uncommon in Asian and ROW
pts.
4080 General Poster Session (Board #45G), Mon, 8:00 AM-12:00 PM
Feasibility of perioperative chemotherapy with infusional 5-FU, leucovorin,
and oxaliplatin with or without docetaxel, in elderly patients with locally
advanced esophagogastric cancer. Presenting Author: Sylvie Lorenzen,
National Center for Tumor Diseases, University of Heidelberg, Heidelberg,
Germany
Background: The aim of this study was to determine feasibility and efficacy
of perioperative chemotherapy in elderly, potentially operable esophagogastric
cancer patients. Methods: Patients aged 65 or older with locally
advanced esophagogastric adenocarcinoma were randomized to perioperative
chemotherapy consisting of four preoperative and four postoperative
cycles of infusional 5-FU, leucovorin, and oxaliplatin (FLO) with or without
docetaxel 50mg/m² (FLOT), every 2 weeks. Results: 44 patients with a
median age of 70 years were randomized to either FLO (22) or FLOT (22)
chemotherapy. In the FLO and FLOT group, 20 and 18 patients completed
four cycles of preoperative chemotherapy and 17(77.3%) and 15(68.2%)
patients proceeded to surgery, with 88.2% and 93.3% R0 resections,
respectively. FLOT was associated with significantly more treatmentrelated
NCI-CTC grade 3/4 adverse events, including neutropenia
(p�.0001), leukopenia (p�.0001), stomatitis (p�0.02) and nausea
(p�0.02) and a higher rate of patients experiencing a �10-points
deterioration of EORTC QoL global health status scores (FLOT, 54%; FLO
23.1%) at 8 weeks. No perioperative mortality was observed, however
postoperative morbidity was nearly doubled with the FLOT regimen (60%
versus 35.3% for FLO), mostly due to wound infections in the FLOT group
(20%). 11 (64.7%) and 9 (60.0%) of patients in the FLO/FLOT group were
able to undergo postoperative chemotherapy. Compared with the FLO
group, the FLOT group had a better response rate (61.9% vs. 18.2%) and a
trend towards an improved median disease free survival (21.1 vs. 12.0
months; p�0.09). Conclusions: Age alone is not a contra-indication for the
selection of patients for three-drug regimens in the multimodal treatment
approach. FLOT seems to be more effective than FLO, but is associated
with an increased toxicity and higher postoperative morbidity. Therefore,
careful patient selection is warranted.
4082 General Poster Session (Board #46A), Mon, 8:00 AM-12:00 PM
A phase II study of tivantinib monotherapy in patients with previously
treated advanced or recurrent gastric cancer. Presenting Author: Kei Muro,
Aichi Cancer Center Hospital, Nagoya, Japan
Background: Tivantinib is a selective, non-ATP competitive, small-molecule
inhibitor of c-MET and is under development in several cancers such as
NSCLC and HCC. Elevated expressions of c-MET and its ligand, hepatocyte
growth factor, have been frequently found in gastric cancer, and are
associated with a more aggressive phenotype. In this single-arm phase II
study, we evaluated the efficacy of tivantinib monotherapy in Asian patients
(pts) with previously treated metastatic gastric cancer (MGC). This is the
first clinical trial evaluating the efficacy of a selective c-MET inhibitor for
MGC. Methods: Eligibility criteria included MGC with at least 1 measurable
lesion per RECIST; 1 or 2 prior chemotherapy regimens; ECOG PS 0 or 1;
and normal CYP2C19 metabolism. Tivantinib was daily administered 360
mg bid orally. The primary endpoint was disease control rate (DCR) defined
as CR, PR or SD after 8 weeks administration. Pretreatment tumor tissue
collection was required to evaluate the relationship between biomarkers
and efficacy. Pharmacokinetic (PK) evaluation was also conducted. Results:
Thirty patients received tivantinib and were eligible for analysis: median
age 62.5 (41-70) years; ECOG PS 0/1 (8/22); 1/2 prior regimen (16/14);
12 pts (40%) with prior gastrectomy. No objective response was observed,
and DCR was 36.7% (11/30 pts). Median progression-free survival was 43
(95% CI: 29.0-92.0) days. Grade 3 or 4 adverse events (AEs) occurred in
13 pts (43.3%), in which neutropenia (n � 4) and anemia (n � 4) were
recognized as drug-related. Only 2 pts discontinued due to AEs. There is no
treatment-related death and novel safety concern. c-MET gene amplification
(� 5 copies/cell) was observed in 4 pts (13.3%). No obvious
relationship of treatment outcome with biomarkers including c-MET gene
amplification, c-MET, p-c-MET and HGF expression in tumor and serum
HGF was identified. Gastrectomy and/or ethnicity (Korean or Japanese) did
not affect PK parameters. Conclusions: Tivantinib as a monotherapy showed
only a modest efficacy in previously treated MGC, and further trial testing in
combination would be warranted in MGC. It would be an important finding
that gastrectomy do not affect PK profile of tivantinib.
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