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

7536 General Poster Session (Board #44B), Sat, 1:15 PM-5:15 PM
A randomized, double-blind, placebo-controlled phase II study of tigatuzumab
(CS-1008) in combination with carboplatin/paclitaxel in patients
with chemotherapy-naive metastatic/unresectable non-small cell lung cancer
(NSCLC). Presenting Author: Joachim Von Pawel, Asklepios Klinikum
Gauting, Munich, Germany
Background: Tigatuzumab (T), a humanized monoclonal antibody that acts
as a DR5 agonist induces apoptosis in human cancer cell lines and has
shown activity in a phase 1 trial; phase 2 trials are ongoing in several tumor
types. In NSCLC cells, single-agent T shows anti-cancer activity. Methods:
Patients (pts) with histologically/cytologically confirmed (TNM ed6) NSCLC
stage IIIB/IV, measurable disease by RECIST (v1.0), and ECOG-PS 0-1
were enrolled at 15 European sites. Pts received T or placebo (PL) IV �
carboplatin/paclitaxel (C/P) every 3 weeks (wks) (1 cycle) for up to 6 cycles.
In the case of complete response (CR)/partial response (PR) or stable
disease, T or PL was given as maintenance therapy. The dosage regimen
was T 10 mg/kg or PL at wk 1/cycle 1 and 8 mg/kg or PL every 3 wks
thereafter; P: 175 mg/m2 every 3 wks; C: AUC 6 every 3 wks. Primary
endpoint: progression-free survival (PFS); secondary endpoints: overall
survival (OS) and objective response rate (ORR) (CR � PR), safety. Efficacy
was assessed in both the full population and a prospectively-defined FCGR
genotype subset. Results: 97/100 pts (9.3% stage IIIB wet; 90.7% stage
IV; 70.1% non-squamous; 29.9% squamous) were eligible for efficacy
analyses (49 to T; 48 to PL). Median PFS (95% CI) was 5.4 months (3.3,
6.6) for T vs 4.3 months (4.1, 5.8) for PL; HR � 0.96; 95% CI: 0.6, 1.6.
Median OS (95% CI) was 8.4 months (6.9, 16.3) for T vs 9.0 months (7.6,
14.5) for PL (HR � 0.95; 95% CI: 0.6, 1.6). 12 pts (24.5%) in the T arm
and 11 pts (22.9%) in the PL arm had PR; no pt had CR. In a subset of pts
(n � 25) with FCGR2A-H131R or FCGR3A-V158F genotypes, there was a
non-significant trend towards increased PFS with T vs PL (HR � 0.47; 95%
CI: 0.16, 1.35) but no difference in OS. T was well tolerated; the only
increased grade 3/4 toxicity was grade 3 neutropenia (16% with T vs 4%
with PL). The number of treatment cycles was similar in both treatment
arms. Conclusions: T does not improve the efficacy of C/P as treatment for
systemic therapy-naïve, unselected advanced NSCLC pts. T was well
tolerated and is being investigated in other settings.
7539 General Poster Session (Board #44E), Sat, 1:15 PM-5:15 PM
A novel targeted oral insulin-like growth factor-1 receptor (IGF-1R) inhibitor
and its implications for patients with non-small cell lung cancer
(NSCLC): A phase I clinical trial. Presenting Author: Simon Ekman,
Department of Oncology, Uppsala University Hospital, Uppsala, Sweden
Background: The small-molecule IGF-1R inhibitor picropodophyllin (PPP)
is the active compound in the oral suspension AXL1717. PPP has shown
extensive preclinical antitumor effects against a wide range of cancers
supporting its use as a single agent treatment. Methods: The clinical phase
Ia/b study on advanced progressive cancer patients with various solid
tumors and without remaining treatment options aimed at establishing the
recommended phase II dose (RPTD) and the maximum tolerated dose
(MTD) of AXL1717. Phase Ia consisted of single day dosing and phase Ib
multiday dosing (to an accumulated total of 28 days of treatment; 2*28
days following amendment) with 3 weeks intermission between treatments.
Non-progressing patients could continue treatment in the extension study
without time limitation (treated 119 weeks). PK samples were obtained at
10 different time-points after the morning dose when appropriate. Results:
Phase Ia included 16 patients treated with 78 BID doses ranging from
5-2900 mg AXL1717 BID without any dose-limiting toxicity. Phase Ib
included 39 patients treated with doses between 290-930 mg BID in
periods between 7-28 days, totally for 147 weeks. Phase Ib showed that
AXL1717 was well tolerated and neutropenia was the only detected
dose-related, reversible, dose-limiting toxicity (DLT). RPTD dose was set at
390 mg BID to minimize neutropenia. Although the study was not designed
for efficacy assessment, some patients, mainly with NSCLC, showed signs
of clinical benefit, including 3 partial responses and 12 patients with stable
disease. The 15 patients with NSCLC and treatment duration of more than
2 weeks with single agent AXL1717 in 3rd or 4th line showed a median
time to progression of 31 weeks and a survival time of 60 weeks with 4
patients being alive at cut-off. Down-regulation of IGF-1R on granulocytes
and increases of serum IGF-1 were seen. The systemic exposure of
AXL1717 was dose-dependent and sufficient for antitumor effects.
Conclusions: AXL1717 has a good safety profile and demonstrated promising
clinical benefits in this severely ill and heavily pretreated patient cohort,
especially in patients with NSCLC.
Lung Cancer—Non-small Cell Metastatic
489s
7537 General Poster Session (Board #44C), Sat, 1:15 PM-5:15 PM
Intratumoral heterogeneity of EGFR mutation and clinical significance in
Chinese patients with advanced non-small cell lung cancer. Presenting
Author: Hua Bai, Peking University School of Oncology, Beijing Cancer
Hospital and Institute, Beijing, China
Background: Whether exist intratumoral heterogeneity of epidermal growth
factor receptor (EGFR) gene mutation remains controversial. This study
aims to evaluate intratumoral heterogeneity of EGFR and its clinical
significance in patients with non-small cell lung cancer (NSCLC). Methods:
Samples were collected from 85 patients with stage IIIa-IV who had
palliative surgery resection. All of the bulk tissues had been routinely
detected EGFR mutation, in which contained 30 wild-type and 55
mutant-type EGFR. 28–34 tumor foci for each sample were microdissected.
EGFR mutation was detected by ARMS. EGFR copy number was
detected by FISH. 23 patients received EGFR-tyrosine kinase inhibitor
(TKIs) therapy. Results: 1740 tumor foci from 55 EGFR mutant-type
(Group-M) and 959 foci from 30 wild-type cases(Group-W) were fractionated.
Mean mutation contents were 73.9%(1285/1740) in Group-M and 0
in Group-W. Accordingly, 28.2%(24/85)consisted of cells with both
wild-type and mutated-type EGFR, with the proportion of EGFR mutant
cells ranging from 1% to 90%, whereas 71.8%(61/85) samples contained
pure mutant-type (n�31) or wild-type EGFR cells(n�30). 31 patients
(36.5%) presented EGFR FISH positive. The patients with mutation
heterogeneity, regardless of high or low mutation contents, presented lower
EGFR copy number than those with pure mutation cases (16.7% vs
71.0%,p�0.05). Among 23 patients who received EGFR-TKIs therapy, the
mean mutation content was higher in partial response (71.1%) and stable
disease group (43.4%) than in progressive disease group (5.0%) (p�0.005).
Conclusions: This study showed that the heterogeneity of EGFR mutation
was found in introtumoral region with different degree. The response to
EGFR-TKIs was correlated with EGFR mutant content.
7540 General Poster Session (Board #44F), Sat, 1:15 PM-5:15 PM
Differential progression-free survival (PFS) to erlotinib according to EGFR
exon 19 deletion type in non-small cell lung cancer (NSCLC) patients (p) in
the EURTAC study. Presenting Author: Enric Carcereny Costa, Catalan
Institute of Oncology, Hospital Germans Trias i Pujol, Barcelona, Spain
Background: Different exon 19 deletion types have shown different in vitro
sensitivity to erlotinib, with the lower IC50 for deletion E746_A750
(ELREA) (Yuza et al. Cancer Biol Ther 2007). This information prompted us
to examine outcome according to type of exon 19 deletion in the EURTAC
study. Methods: The EURTAC trial (clinicaltrials.gov NCT00446225)
randomized 174 p with EGFR exon 19 deletions or L858R mutations to
receive erlotinib or chemotherapy. Progression-free survival (PFS) was 9.7
months (m) vs 5.2 m, respectively (P�0.0001). Exon 19 deletions were
divided into two groups: ELREA vs non-ELREA deletions. Results: Exon 19
deletions were present in 57 p in the erlotinib arm and in 58 p in the
chemotherapy arm. ELREA deletions were found in 41 p (71.9%) in the
erlotinib arm and in 38 p (65.5%) in the chemotherapy arm. Non-ELREA
deletions were found in 16 p in the erlotinib arm and in 20 p in the
chemotherapy arm. There were no differences in p characteristics between
treatment arms according to type of deletion. PFS for p with ELREA
deletions was 9.4 m in the erlotinib arm and 4.6 in the chemotherapy arm
(HR, 0.36; P�0.0004). PFS for p with non-ELREA deletions was not
reached in p in the erlotinib arm and was 5.3 m for p in the chemotherapy
arm (HR, 0.17; P�0.001). The multivariate analysis identified erlotinib
arm (P�0.001) and non-ELREA deletions (P�0.001) as independent
markers of longer PFS. Overall survival (OS) for p with ELREA deletions was
17 m in the erlotinib arm and 18.4 in the chemotherapy arm (P�0.575).
OS for p with non-ELREA deletions was not reached in the erlotinib arm and
19.5 m in the chemotherapy arm (P�0.216). Response rate (RR) for p with
ELREA deletions was 53.6% in the erlotinib arm vs 15.7% in the
chemotherapy arm (P�0.004). RR for p with non-ELREA deletions was
68.7% in the erlotinib arm vs 10% in the chemotherapy arm (P�0.001).
Conclusions: To date, no biological reason has been identified that can
explain the greater sensitivity to erlotinib in p with non-ELREA exon 19
deletions. Our findings indicate the need to define the type of deletion prior
to treatment since this information can be helpful in predicting the
duration of response.
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