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

470s Lung Cancer—Non-small Cell Local-Regional/Small Cell/Other Thoracic Cancers
7076 General Poster Session (Board #39C), Sat, 1:15 PM-5:15 PM
NGR-hTNF as second-line treatment in malignant pleural mesothelioma
(MPM). Presenting Author: Gilda Rossoni, Department of Oncology, Istituto
Scientifico San Raffaele, Milan, Italy
Background: NGR-hTNF exploits the asparagine-glycine-arginine (NGR)
peptide for selectively targeting tumor necrosis factor (TNF) to cancer
endothelial cells. Tumor hypervascularity is an independent predictor of
poor overall survival (OS) in MPM patients (pts). Methods: We report
long-term results of a phase II trial that assessed NGR-hTNF in MPM pts
with performance status (PS) � 2 and radiologic progressive disease (PD)
after a pemetrexed-based regimen. NGR-hTNF was given at 0.8 �g/m2 every 3 weeks (q3w) in 43 pts and weekly (q1w) in 14 pts. Primary endpoint
was progression free survival (PFS), with restaging done q6w by MPMmodified
RECIST criteria, while secondary aims included disease control
(DC) rate and OS. We also tested the impact on outcome of neutrophil to
lymphocyte ratio (NLR) at baseline (median 3; interquartile range 2-5).
Median follow-up was 32.5 months (95% CI 27.5-37.5). Results: Baseline
characteristics were (n�57): median age 57 years; M/F 35/22; PS 0/1-2
31/26; EORTC score good/poor 45/12. Median treatment free interval on
prior therapy was 4.3 months. Only one drug-related grade � 3 adverse
events (AEs) was noted, common grade 1/2 AEs being transient chills
(75%). No higher toxicity was reported using the q1w schedule. Median
PFS was 2.8 months (95% CI 2.2-3.3). DC rate was 46% (95% CI 32-59;
26/57 pts; 1 partial response, 25 stable diseases) and was maintained for a
median time of 4.7 months (95% CI 4.0-5.4). OS rates at 1 and 2 years
were 47% and 16%, respectively. Median OS was longer in pts with DC
than in those with early PD (16.2 and 8.3 months, respectively; p�.02).
According to schedule, 6-month PFS rates were 11% and 36% and 2-year
OS rates were 12% and 29% for q3w and q1w, respectively. In pts with DC,
median PFS were 4.4 and 9.1 months and median OS were 13.3 and 24.8
months for q3w and q1w, respectively. By Cox analyses, a PS of 0 (p�.01)
and a low baseline NLR (p�.004) were the only variables associated with
improved OS. Median OS in pts stratified by NLR � 2,3to4,and�5were 15.7, 10.5, and 4.2 months, respectively (p�.0002 for trend). Conclusions:
NGR-hTNF showed promising PFS and OS in this study. A double-blind
phase III trial is currently testing best investigator choice � NGR-hTNF
q1w in pemetrexed-pretreated MPM pts (NCT01098266).
7078 General Poster Session (Board #39E), Sat, 1:15 PM-5:15 PM
Elevated PDGFRB gene copy number gain as prognostic in resected
malignant pleural mesothelioma. Presenting Author: Anne S. Tsao, University
of Texas M. D. Anderson Cancer Center, Houston, TX
Background: PDGF/PDGFR pathway has been implicated in malignant
pleural mesothelioma (MPM) carcinogenesis. We sought to evaluate the
incidence of PDGFRB gene copy number gain (CNG) and PDGFR pathway
protein expression by immunohistochemistry (IHC) in the tumor cell
cytoplasm, membrane, nucleus, and stroma, and correlate it to patient
clinical outcome. Methods: 88 archived tumor blocks from resected MPM
with full clinical information were used to perform the analyses. IHC
biomarkers for PDGFR�,� and p-PDGFR�, and fluorescence in situ
hybridization were performed for analysis of PDGFRB gene CNG. Spearman’s
rank correlation, Wilcoxon rank-sum test or Kruskal-Wallis test, BLiP
plots, and Kaplan-Meier method were used to assess the biomarkers and
their correlation to clinical outcome. Results: There were several correlations
identified between the IHC biomarkers; however, none associated
with patient demographics or histology subtype, with the exception of high
cytoplasmic PDGFR� occurring in patients with no prior known asbestos
exposure (p�0.029). In the CNG analysis, PDGFRB gene CNG in � 10% of
tumor cells had lower cytoplasmic p-PDGFR� (p�0.029), while PDGFRB
gene CNG in � 40% of tumor cells had a higher cytoplasmic PDGFR�
(p�0.04). PDGFRB gene CNG status did not associate with patient
demographics or tumor characteristics. Patients with PDGFRB CNG �
40% of tumor cells had an improved relapse-free survival (RFS) [HR 0.25
(95% CI 0.09, 0.72), p�0.0096]. In the patients with PDGFRB CNG �
40% of cells, the addition of chemotherapy appeared to also improve RFS
(p�0.017). In the multi-covariate analyses for RFS, there was no association
with any IHC biomarker. In the overall survival (OS) analysis, having
PDGFRB gene CNG � 40% of tumor cells correlated with an improved OS
[HR 0.32 (95% CI 0.11, 0.89), p�0.029] and the addition of perioperative
chemotherapy led to a trend towards improved OS (p�0.089).
Conclusions: PDGFRB CNG � 40% of tumor cells is a potential prognostic
biomarker in surgically resected MPM tumors. Adding chemotherapy to
patients with PDGFRB CNG � 40% of cells improved RFS and led to a
trend towards improved OS. Future validation of this biomarker in prospective
trials is needed.
7077 General Poster Session (Board #39D), Sat, 1:15 PM-5:15 PM
Phase II trial of anti-transforming growth factor-beta (TGFß) monoclonal
antibody GC1008 in relapsed malignant pleural mesothelioma (MPM).
Presenting Author: James Stevenson, University of Pennsylvania, Philadelphia,
PA
Background: TGF� is a pleiotropic cytokine overexpressed by MPM. Based
on preclinical data documenting a key role for TGF� in promoting growth
and progression of MPM, we are conducting a phase II trial of GC1008 in
patients (pts) with progressive MPM. Methods: Pts with progressive MPM by
modified RECIST criteria and PS 0-1 with 1-2 prior systemic therapies (at
least 1 pemetrexed-based) are eligible. Treatment plan: GC1008 3mg/kg
IV over 90 minutes every 21 days. Responses are assessed by modified
RECIST every 6 weeks. The primary endpoint is progression-free survival
(PFS) rate at 3 months; secondary objectives include safety with GC1008,
response rate by modified RECIST, time to progression (TTP), and overall
survival (OS). Results: The modified Gehan stage 1 stopping criterion of
1/13 pts with 3 month PFS has been exceeded. To date, 13 pts (10 PS 0; 3
PS 1) with MPM (median age 69; 2F, 11M; 11 epithelial, 1 sarcomatoid, 1
biphasic) enrolled. Treatment-related toxicities include G1/2 fatigue (3
pts), nausea (1 pt) and xerosis (1 pt). Other adverse events possibly related
to GC1008 were rapid disease progression in 1 pt after 2 cycles, and G2
skin keratoacanthoma in 1 pt after 5 cycles. Three pts met the primary
objective of 3 month PFS at 4.1, 4.2 and 9 months each. Stable disease
(SD) was seen in 3 pts (23%). Median TTP is 1.4 months (95% CI 1.2-�);
median OS is 13 months (95% CI 6-�). Increased serum mesothelin levels
have closely tracked disease progression. Serum from 6/13 pts showed new
antibodies against MPM tumor lysates as measured by immunoblotting.
Two of 3 pts with SD had anti-tumor antibody responses. Mean baseline
plasma level of TGF� was 2447 pg/ml but did not correlate with baseline
plasma TGF� or TTP. Conclusions: GC1008 was well tolerated in pretreated
MPM patients. SD occurred in 3 pts, all with prior disease progression.
Evidence for humoral anti-tumor immunity was seen in nearly half of
enrollees and in 2 of 3 pts with SD. OS compares favorably to prior
single-agent studies in pretreated MPM.
7079^ General Poster Session (Board #39F), Sat, 1:15 PM-5:15 PM
Phase II trial of BNC105P as second-line chemotherapy for advanced
malignant pleural mesothelioma (MPM): Australasian Lung Cancer Trials
Group and NHMRC Clinical Trials Centre Collaboration. Presenting Author:
Anna K. Nowak, School of Medicine and Pharmacology, University of
Western Australia, Perth, Australia
Background: BNC105P is a tubulin polymerization inhibitor that acts as a
Vascular Disrupting Agent (VDA), has direct cytotoxic effects, and had
preclinical and phase I activity in MPM. This aim of this study was to
determine activity and safety of BNC105P as second-line therapy after
pemetrexed and a platin in MPM. Methods: Eligible patients had progressive
MPM, prior pemetrexed and platinum, measurable disease by modified
RECIST, ECOG 0-1, and adequate organ and cardiovascular function.
Important exclusions included recent thromboembolic, cardiovascular or
cerebrovascular disease, or therapeutic anticoagulation. Pts received
BNC105P (16 mg/m2 IV) Day 1 � 8 q21d until progression or toxicity. The
primary endpoint was centrally reviewed objective tumour response rate
(RR); the Simon 2-stage design assumed a RR of interest of 20% and a RR
of no interest of 5%, with � � � � 0.05. Continuation past first stage
accrual required �1 objective response in 24 patients. Results: 30 subjects
were accrued over 10 months (90% male; median age 65 (range 41-83);
77% ECOG PS 1; histology epithelioid (67%), biphasic (10%), sarcomatoid
(7%), other/unspecified (17%)). All pts received at least one dose of
study drug; pts received a median of 2 cycles and median dose intensity
was 100%. No significant haematologic, biochemical, peripheral neurotoxic
or cardiac adverse events (AEs) including hypertension were observed.
Grade 3 or 4 AEs occurred in 10 pts (33%). There were 2 deaths on study: 1
due to stroke, the other due to pneumonia and respiratory failure. We
observed 1 partial response (3%) and 13 pts with SD as their best response
(43%). Median progression free survival was 1.5 mo (95% CI 1.4-2.4);
median overall survival was 8.7 mo (95% CI 3.8-NR). Lung function and
QOL data was collected. Biomarker analyses correlating to pharmacological
changes induced by BNC105P are ongoing and will be presented.
Conclusions: BNC105P was safe and tolerable but its single agent response
rate failed to meet the pre-specified primary endpoint of interest.
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