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

500s Lung Cancer—Non-small Cell Metastatic
7583 General Poster Session (Board #50A), Sat, 1:15 PM-5:15 PM
Correlation between thymidylate synthetase (TS) expression and progressionfree
survival (PFS) in patients receiving pemetrexed (pem) for advanced
NSCLC: A prospective study. Presenting Author: Marianne Nicolson,
Aberdeen Royal Infirmary, Aberdeen, United Kingdom
Background: Pem efficacy in non-squamous (NS) NSCLC is hypothesised to
be associated with TS expression. Our primary objective was to assess the
correlation between TS and PFS, prospectively. Methods: Context: A Phase
II, single-arm, exploratory, multicenter, UK study with appropriate approvals
and consents. Key eligibility criteria: ECOG PS 0-1, NS-NSCLC
histology, stage IIIB/IV. Patients (n�70) received pem/cisplatin induction
x 4. Non-progressive patients continued on maintenance pem until tumor
progression or discontinuation. All patients were followed until death or
study closure. TS by IHC (H-scores) and qPCR (delta CQ values normalized)
were assessed on diagnostic FFPE samples. Kaplan-Meier estimates for
median PFS (mPFS) and Cox regression to determine the statistical
correlation between PFS and TS IHC nuclear score, (continuous variable)
were performed. Maximal Chi-square analysis identified the optimal association
cutpoints between PFS and low vs. high TS scores. Results: Patient
demographics were unremarkable, 32/70 (45.7%) were female. 55 (78.6%)
had adenocarcinoma; 15 were not otherwise specified. Maintenance pem
was started in 43/70 (61.4%) patients. Evaluable patients had at least one
dose of study treatment and a valid TS score (n�60). For the evaluable
population, the mPFS from start of induction was 5.5 months (95% CI
3.9-6.9). A statistically significant correlation between PFS and TS IHC
nuclear scores was observed [p�0.0001, HR� 1.01 (95% CI 1.01,
1.02)], suggesting higher TS values are associated with shorter PFS. When
the population was dichotomized at the identified optimal H-score cutpoint
of 70, the mPFS in the low expression group (n�40) was 7.1 months
(5.7-8.3) compared to 2.6 months (1.3-4.1) in the high expression group
(n�20) [adjusted p�0.0015, HR�0.28 (95% CI 0.16-0.52)]. Similar
trends with cytoplasmic TS IHC (p�0.09) and TS qPCR (p�0.05) levels
were observed. Statistical correlations were seen among the TS levels. Data
is preliminary. Conclusions: Study suggests statistically significant association
between low TS IHC nuclear expression and improved PFS in this
Phase 2 single-arm trial.
7585 General Poster Session (Board #50C), Sat, 1:15 PM-5:15 PM
Expression of folate pathway regulators and pemetrexed (pem) activity in
patients (pts) with advanced non-small cell lung cancer (NSCLC). Presenting
Author: Letizia Gianoncelli, Humanitas Cancer Center, Rozzano, Italy
Background: Thymidylate synthase (TS) expression has been reported to
predict pem activity in pts with advanced NSCLC. Besides TS, pem inhibits
multiple enzymes of the folate pathway including dihydrofolate reductase
(DHFR), glycinamide ribonucleotide formyltransferase (GART) and aminoimidazole
carboxamide ribonucleotide formyltransferase (AICAR). Aim of
present study was to investigate whether these or other biomarkers
influence pem activity in NSCLC pts. Methods: Advanced pretreated NSCLC
pts who received at least two cycles of single agent pem were considered
eligible if they had available tumor tissue to assess at least one of the
proposed biomarkers. TS, DHFR, GART and AICAR protein expression was
assessed by immunohistochemistry (IHC) in FFPE tumor samples. Pts were
grouped as IHC� and IHC– according to staining intensity. Additionally,
presence of EGFR and KRAS mutations was investigated. Results: Ninetysix
pts were included in the study. The majority of subjects was male
(72%), smokers (93%), with adenocarcinoma (72%). Response rate (RR),
disease control rate (DCR), progression-free survival (PFS) and overall
survival (OS) were 12%, 47%, 2.3 and 9.5 months, respectively. Most pts
resulted TS-(72%), AICAR-(82%), DHFR� (68%), GART- (61%). EGFR
and KRAS mutations were identified in 15% and 25% of assessable cases.
None of the biomarkers was significantly associated with pts characteristics
(gender, histology, smoking status), nor with RR or DCR. GART- pts
experienced longer PFS when compared with the GART� group (HR 0.56,
p�.052), while no difference was observed according to TS, DHFR and
AICAR status. A significantly longer OS was observed for TS- (HR 0.52,
p�.012), GART- (HR 0.50, p�.037) and AICAR- (HR 0.40, p�.028) pts.
No significant difference in the distribution of EGFR mutant pts receiving
EGFR TKIs after pem failure was observed between IHC� and IHC- groups.
Conclusions: Low TS, GART and AICAR protein expression predicts significantly
prolonged survival in single agent pem-treated pts with advanced
NSCLC. The lack of PFS difference according to TS and AICAR status
suggests prognostic rather than predictive relevance for these biomarkers.
7584 General Poster Session (Board #50B), Sat, 1:15 PM-5:15 PM
A randomized, double-blinded, phase II study of paclitaxel/carboplatin
(PC) plus CT-322 versus PC plus bevacizumab (Bev) as first-line treatment
for advanced nonsquamous non-small cell lung cancer (NSCLC). Presenting
Author: Eugene Henry Paschold, Piedmont Hematology-Oncology
Associates, Winston-Salem, NC
Background: CT- 322 is a pegylated protein engineered from the tenth type
III human fibronectin domain thatspecifically blocks VEGFR-2 signaling by
all known ligands. This international randomized study assessed the
efficacy and safety of PC � CT-322 compared to PC � Bev as first-line
treatment for advanced non-squamous NSCLC. Methods: In addition to
paclitaxel 200 mg/m2and carboplatin AUC 6 given on day 1 of a 21 day
cycle(maximum 6 cycles), subjects, stratified by ECOG performance
status, disease stage, and site, were randomized 1:1 to receive either
CT-322 2 mg/kg on days 1, 8, and 15 (arm A) or Bev 15 mg/kg on day 1 and
placebo on days 8 and 15 (arm B). CT -322 and Bev/placebo were
continued as maintenance until disease progression, unacceptable toxicity,
or withdrawal of consent. The primary endpoint was progression-free
survival (PFS); secondary endpoints included overall survival (OS), response
rate, and safety. Results: 255 subjects were randomized to arm A
(n�127) or arm B (n�128). Baseline characteristics were wellbalanced.
After a median follow- up of 13.8 months, 9 subjects on arm A and 24 on
arm B remained on study treatment. The median treatment duration was 19
weeks in arm A and 26.3 weeks on arm B. The median PFS in arm A was
5.6 months compared to 6.8 months in arm B (HR 1.51, 1 -sided
p�0.997). In all prespecified subgroups, PFS was favored in arm B. The
response rate was 25.2% in arm A compared to 32.8% in arm B. Median
OS was 12.5 months in arm A compared to 15.2 months in arm B. The
most common grade � 3 adverse events (Arm A vs B) were neutropenia
(47.2% vs 49.2%), thrombocytopenia (11.8% vs 6.3%), and fatigue
(10.2% in both arms). Grade � 3 hypertension was more frequently
reported in arm A (8.7% vs 3.1%). Grade � 3 venous thrombosis (5.5% vs
6.3%), proteinuria (1.6% vs 2.3%), and bleeding events (0.8% vs 1.6%)
were similar. Conclusions: PC � CT-322 failed to improve PFS, OS, or
response rate compared to PC � Bev. However, thesafety profile in the PC
� CT-322 arm was consistent with the anti-angiogenic mechanism of
action, suggesting that CT-322 has biological activity as an inhibitor of
VEGFR-2.
7586 General Poster Session (Board #50D), Sat, 1:15 PM-5:15 PM
Single nucleotide polymorphisms (SNPs) of the platinum pharmacogenetic
and VEGF pathways: Association with survival of platinum-treated stage IV
non-small cell lung cancer (NSCLC) patients. Presenting Author: Sinead
Cuffe, Princess Margaret Hospital, University of Toronto, Toronto, ON,
Canada
Background: Two potentially important host pathways in lung cancer
systemic therapy are: (i) the pharmacogenetic pathway of platinum agents
(DNA repair, metabolism, and multidrug resistance genes); and (ii) the
vascular endothelial growth factor (VEGF) pathway. We investigated the
relationship between SNPs in these two pathways and clinical outcome in
platinum-treated NSCLC patients. Methods: 188 platinum-treated Stage IV
NSCLC patients underwent SNP genotyping for the platinum-related (48
SNPs in 7 genes) and VEGF (64 SNPs in 3 genes) pathways. SNPs were
selected from the literature and through tagging. Association of SNPs and
overall (OS) and progression free survival (PFS) were assessed using
multivariate Cox proportional hazards models. Results: 72% were Caucasian;
73%, adenocarcinoma; 92%, ECOG PS 0-1; median age, 60 years;
54% received � one line of systemic therapy; 10% received anti-VEGF
therapy/placebo; Median OS, 1.3 yrs; median follow up, 2.2 yrs. The top
significant SNPs in the platinum-related pathway were in ABCC2
(rs8187710 and rs2756109, r2�0.68). The G variants of the top SNP,
ABCC2 rs8187710 (4554G�A), were associated with worse OS (adjusted
hazard ratio [aHR], 2.62; 95%CI: 1.5-4.5; p�0.0005) and PFS (aHR,
1.97; 95%CI: 1.2-3.4; p�0.01). Functionally, 4554G�A impairs ATPase
activity and is associated with higher cellular accumulation of ABCC2
substrates [PMID: 22027652]; furthermore, ABCC2 expression is associated
with cisplatin resistance and clinical outcome in other cancers [PMID:
17145840]. Within the VEGF pathway, the top significant SNPs were in
the same haplotype block of VEGFR1/FLT1 (rs1324057, rs7324547,
r2�1.0): for rs1324057, the aHR for OS was 1.59 (95%CI 1.2-2.1);
p�0.001; and the aHR for PFS, 1.48 (95%CI 1.1-1.9); p�0.004.
VEGFR1/FLT1 rs7324547 has been associated with esophageal cancer
risk [PMID: 21751195], but has not been assessed in lung cancer.
Conclusions: SNPS of the VEGFR1 and ABCC2 genes are strongly associated
with OS and PFS in this cohort of platinum-treated advanced NSCLC
patients. Future studies should assess whether these are predictive or
prognostic markers.
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