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

Lung Cancer—Non-small Cell Local-Regional/Small Cell/Other Thoracic Cancers
7030 Poster Discussion Session (Board #22), Sun, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Amatuximab, a chimeric monoclonal antibody to mesothelin, in combination
with pemetrexed and cisplatin in patients with unresectable pleural
mesothelioma: Results of a multicenter phase II clinical trial. Presenting
Author: Raffit Hassan, National Cancer Institute, Bethesda, MD
Background: Amatuximab (MORAb-009) is a chimeric monoclonal antibody
to mesothelin, a cell surface glycoprotein highly expressed in many cancers
including malignant mesothelioma (MM). Based on safety of amatuximab
in phase I clinical trial and pre-clinical studies showing synergy in
combination with chemotherapy, a single arm phase II study of amatuximab
plus pemetrexed (P) and cisplatin (C) was initiated in pts. with MM.
Methods: Eligibility criteria included pts. with unresectable epithelial or
biphasic pleural MM, no prior chemotherapy and KPS � 70%. Pts.
received amatuximab 5 mg/kg on days 1 and 8 with P 500 mg/m2 andC75
mg/m2 (PC) given on day 1, of each 21 day cycle for 6 cycles. Pts. with
objective response or stable disease received amatuximab monotherapy
until disease progression. Primary endpoint was progression-free survival
(PFS) at 6 months. Secondary endpoints were overall survival (OS),
objective response rate and safety of amatuximab with PC. Results: From
2/2009 to 10/2010, 89 pts. were enrolled at 26 sites. Pt. characteristics:
median age 67 yrs. (range 46-80), 78% male, 70% with KPS �90%, 89%
epithelial MM, 11% biphasic MM and 88% had stage III/IV disease.
Median number of PC plus amatuximab cycles was 5 (range 1-6) and 56
(63%) pts. received single agent amatuximab. In addition to the expected
toxicity from PC, hypersensitivity reactions (12.4%; Grade 3/4�4.5%)
from amatuximab were noted. By independent radiological review 30
(39%) pts. had partial response and 39 (51%) had stable disease. PFS at 6
months was 52% (95% CI: 39.5-63.5) with a median PFS of 6.1 months
(95% CI: 5.4-6.5). As of 1/10/12 the median OS was 14.5 months (95%
CI: 12.4-18.5) with 31 pts. still alive and 7 pts. receiving maintenance
amatuximab. Conclusions: Amatuximab in combination with PC was generally
well-tolerated in this study with 90% of pts. having an objective tumor
response or stable disease by independent radiological review. Although
PFS is not significantly different from historical results of PC alone, the
median OS is 14.5 months with 35% of pts. still alive. Updated OS and
biomarker data will be presented at the meeting.
7032 Poster Discussion Session (Board #24), Sun, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Next-generation sequencing of thymic malignancies. Presenting Author:
Milan Radovich, Indiana University School of Medicine, Indianapolis, IN
Background: Thymic malignancies are rare with ~500 cases in the US per
year. Apart from standard chemotherapy, treatment options are limited.
Further, the challenge of histologic subtyping of these tumors along with an
inadequate understanding of the transcriptional biology is a hindrance to
the development of targeted therapies. Methods: Thymic malignancies and
normal tissues were obtained from the Indiana University Simon Cancer
Center. The WHO subtypes of our samples include: (4) type A, (2) A/B, (1)
B2, (5) B3, (1) C, and (3) normal tissues. RNA was sequenced on a Life
Technologies SOLiD sequencer. For gene expression, reads were mapped to
the genome using BioScope and outputs imported into Partek GS. In
Partek, statistical comparison of gene expression as well as PCA &
clustering analyses were performed. Results: Unsupervised hierarchical
clustering of gene expression values revealed 100% concordance between
gene expression clusters and WHO subtype. A subsequent unsupervised
clustering of 705 pre-miRNAs also showed substantial concordance
between clusters and subtype. By analyzing the dendrograms, A&A/B
tumors were significantly different from B type tumors, as well as C and
normal. A substantial differentiator was a large cluster of overexpression in
A&A/B tumors that was nearly absent in the others on chr19q13.42
corresponding to the miR-515 cluster (43 miRNAs). When comparing A &
A/B tumors vs. B type tumors, 1334 genes are differentially expressed (258
downregulated) (FDR�5%). 95/258 genes are predicted to be downregulated
by the miR-515 cluster including several transcription factors and
tumor suppressors. When looking at mutations, we detected no recurrent
gene fusions, though we are detecting several point mutations and small
insertion deletions. These are being followed up by exome sequencing.
Conclusions: Analyses reveal that RNA-seq can be used to accurately
subtype Thymic Malignancies and the development of an expression based
diagnostic is feasible. Further, these data support that the main differentiator
of thymomas may lie in the expression of a single miRNA cluster. In
addition, several mutations in key pathways are implicated. Ongoing
analyses include: alternative splicing, noncoding RNAs, viral analysis and
exome sequencing.
459s
7031 Poster Discussion Session (Board #23), Sun, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Comparison of prognostic impact between metabolic and radiologic response
after induction chemotherapy for resectable malignant pleural
mesothelioma: A multicenter study. Presenting Author: Yasuhiro Tsutani,
Hiroshima University, Hiroshima, Japan
Background: Induction chemotherapy followed by extrapleural pneumonectomy
(EPP) for resectable malignant pleural mesothelioma (MPM) is
controversial. To select optimal candidates for EPP, we evaluates the
usefulness of metabolic response on fluorodeoxyglucose-positron emission
tomography (FDG-PET) compared with radiologic response on highresolution
computed tomography (HRCT) after induction chemotherapy to
predict prognosis for patients with resectable MPM who underwent EPP in
the setting of multicenter study. Methods: We performed HRCT and
FDG-PET before and after induction platinum-based chemotherapy on 50
patients with clinical T1-3 N0-2 M0 MPM who underwent EPP �
postoperative hemithoracic radiation. A decrease of more than 30% in
tumor maximum standardized uptake value (SUVmax) was defined as a
metabolic responder. Radiologic response using modified RECIST or
metabolic response and surgical results were analyzed. Results: In all
cohort patients, median overall survival (OS) from diagnosis was 20.5
month (95% confidence interval [CI], 15.0-26.0 month). Fourteen patients
were classified as metabolic responders (28%) and 36 as nonresponders
(72%). Metabolic responders significantly correlated to OS with
median OS for metabolic responders of not reached (3-year OS of 60.0%)
versus 18.7 month (95% CI, 13.3-24.2 month, 3-year OS of 26.5%) for
non-responders (P � .025). No correlation was observed between OS and
radiologic response with median OS for radiologic responders of 25.7
month (n � 20, 95% CI, 14.5-37.0 month, 3-year OS of 35.8%) versus
17.7 month (n � 30, 95% CI, 12.8-22.6 month, 3-year OS of 35.1%) for
non-responder (p � .216). Based on the multivariate Cox analyses,
decreased SUVmax (%) (p � .010) was a significantly independent factor
for OS as well as epithelioid subtype (p � .044). Conclusions: Metabolic
response on FDG-PET has higher predictive value of prognosis than
radiologic response on HRCT after induction chemotherapy for patients
with resectable MPM. Patients with metabolic responder and/or epithelioid
subtype can be good candidates for EPP after induction chemotherapy.
7033 Poster Discussion Session (Board #25), Sun, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Phase II study of cixutumumab (IMC-A12) in thymic malignancies.
Presenting Author: Arun Rajan, National Cancer Institute, Bethesda, MD
Background: The IGF-1 receptor (IGF-IR) is expressed in thymoma (T) and
thymic carcinoma (TC). Prolonged SD has been seen with anti-IGF-IR
therapy in thymic tumors in phase I trials. Cixutumumab (C) is a fully
human IgG1 monoclonal antibody (ab) that targets IGF-IR. Methods:
Patients (pts) with recurrent T or TC, PS 0-2, measurable disease, and
normal organ function received C at 20 mg/kg IV q3wks until progression or
intolerable toxicity. Primary endpoint was response rate. Correlative studies
included immune cell subset (central memory, effector memory, naïve and
regulatory T cells), circulating endothelial progenitor (CEP) cell, serum
IGF-1 and IGF-IR in PBMCs, anticytokine ab, and tumor mutational
analysis. Results: Forty-five pts enrolled from two centers (20 female,
T�33, med age 52 yrs, range, 26-86). Median number of prior systemic
treatments: 3 (range, 1-11). Median number of cycles of C administered: 6
(range, 1-41). In 30 evaluable T pts there were 4 (13%) PR, 23 (77%) SD,
and 3 (10%) PD. Corresponding numbers in 12 TC pts were 0, 5 (42%) and
7 (58%). Median PFS for T and TC was 40 and 9 wks respectively.
C-related grade 3/4 AEs were hyperglycemia (8%), hyperuricemia, weight
loss, lipase elevation, chest wall pain (5% each) and AST elevation (3%).
Two pts died while on study: one due to respiratory insufficiency related to T
after 5 cycles and one due to worsening myasthenia and an acute coronary
event after 13 cycles. In 8 of 33 T pts autoimmune (AI) symptoms
developed (4 new-onset) due to immune thrombocytopenic purpura,
myositis, myocarditis, colitis, PRCA and food allergy. In the first 13 pts a
trend towards increased numbers of central and effector memory T cells
and a decrease in naïve T cells and CEPs was seen. High-titer anticytokine
abs, including anti-IFNa, anti-IL-12, and anti-IL-17A, were found in 13/27
pts tested. No EGFR, KRAS or BRAF mutation, HER2 amplification or ALK
translocations were detected in 11 tumors analyzed. Conclusions: C
monotherapy is well tolerated and active in T. Accrual will continue until 37
T pts are enrolled. Activity in TC is unworthy of further investigation. CEP
and immune cell subset analysis suggests therapy may impact angiogenesis
and immune response. Development of AI symptoms during treatment
needs further evaluation.
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