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

484s Lung Cancer—Non-small Cell Metastatic
7516 Poster Discussion Session (Board #6), Tue, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Three-arm randomized phase II study of carboplatin (C) and paclitaxel (P)
in combination with cetuximab (CET), IMC-A12, or both for advanced
non-small cell lung cancer (NSCLC) patients who will not receive bevacizumab-based
therapy: An Eastern Cooperative Oncology Group (ECOG)
study (E4508). Presenting Author: Nasser H. Hanna, Indiana University,
Indianapolis, IN
Background: Pre-clinical evidence supports the clinical investigation of
inhibitors to the insulin-like growth factor receptor (IGFR) and the epidermal
growth factor receptor (EGFR) alone and in combination with one
another in patients (pts) with NSCLC. Methods: Pts w/ chemotherapy-naïve,
advanced NSCLC, not eligible for bevacizumab-based therapy, ECOG PS
0/1 were eligible. Pts with uncontrolled or untreated brain mets and/or
severe hyperglycemia were ineligible. Pts were randomized to receive: C
AUC6iv� P 200 mg/m2 iv on day 1 every 3 wks combined with either CET
iv weekly (arm A), IMC-A12 iv every 2 wks (arm B), or both (arm C). Patients
with non-progressive disease (PD) after 12 weeks of therapy were permitted
to continue on maintenance antibody therapy until PD. The primary
objective was PFS. Secondary objectives included OS and toxicity. The
design required 180 eligible patients and had an 88% power to detect a
60% increase in median PFS for either comparison (arm A vs C or arm B vs
C) (1-sided 0.10 level test). Results: Characteristics for arms A (n�39)/B
(n�42)/C (n�48): males were 51%/57%/54%; median age was 60, 62,
60; PS 0 49%/52%/60%; stage IV 87%/83%/94%; adenocarcinoma
44%/26%/42%. The study was closed prematurely due to safety concerns
after 129 eligible pts were treated. 13 patients died during treatment
(A�6; B�2; C�5), including 9 w/in ~1 mo of starting therapy. G3-5
toxicities, all attributions, A/B/C: anemia 16%/7%/13%; neutropenia
27%/29%/42%; febrile neutropenia 7%/5%/4%; thrombocytopenia 7%/
10%/13%; pneumonia 9%/2%/6%; hyperglycemia 2%/10%/15%; rash
5%/2%/8%; hyponatremia 2%/5%/17%; thromboembolic events 2%/10%/
0%; fatigue 16%;22%/13%. The estimated median PFS and OS for arms
A/B/C were 3.4, 4.3, and 4.1 mos and 11.7, 8.6, and 8.4 mos,
respectively. Conclusions: Based upon apparent lack of efficacy and
excessive premature deaths, this study does not support the continued
investigation of C � T � IMC-A12 alone or in combination with CET in pts
with advanced NSCLC not eligible for bevacizumab.
7518 Poster Discussion Session (Board #8), Tue, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Randomized phase II trial of erlotinib (E) plus high-dose celecoxib (HD-C)
or placebo (P) in advanced non-small cell lung cancer. Presenting Author:
Karen L. Reckamp, City of Hope, Duarte, CA
Background: Cyclooxygenase-2 (COX-2)-dependent signalling represents a
potential mechanism of resistance to epidermal growth factor receptor
(EGFR) tyrosine kinase inhibitor (TKI) therapy in NSCLC. This is mediated
in part through an EGFR-independent activation of MAPK/Erk by the COX-2
metabolite PGE2. In addition, PGE2 promotes downregulation of Ecadherin
and epithelial to mesenchymal transition. We hypothesize that
EGFR and COX-2 inhibition with E and HD-C will augment EGFR TKI
efficacy by increasing tumor E-cadherin expression and blocking PGE2mediated
resistance to EGFR inhibition. Methods: Pts with stage IIIB/IV
NSCLC who progressed following at least one line of therapy or refused
standard chemotherapy were randomized to E (150mg/day)/HD-C
(600mg/2x day) vs E/P in a 28-day cycle. Pts were stratified by smoking
status and ECOG PS. The primary endpoint was PFS with 80% power to
detect a 50% improvement; assessments were performed every 2 cycles.
Secondary endpoints included response rate, OS and evaluation of molecular
markers in tissue and serum to assess targeting COX-2-related pathways
and evaluate EGFR TKI-resistance. All pts were required to have pretreatment
tissue available. Results: 107 pts were enrolled with comparable
baseline characteristics in both arms. Disease control rate (DCR) was
similar in both arms, and a trend toward improved PFS was seen in the
E/HD-C arm with HR 0.81 (see Table). Analysis of those with EGFR wild
type revealed a significantly increased PFS while those with EGFR mutation
had similar PFS in both groups. Safety analysis showed similar toxicity in
both arms. Additional biomarker correlations will be presented. Conclusions:
The combination of E/C in metastatic NSCLC with HD-C is well tolerated
and demonstrates significantly improved efficacy in EGFR wt population.
This warrants further study into the COX-2-dependent mechanisms of
primary resistance to EGFR TKI therapy. Supported by NIH 1P50 CA90388,
K12 CA01727 and medical research funds from the Dept of Veterans’
Affairs.
E/HD-C (n�54) E/P (n�53) p value
PFS (mo) 5.4 2.9 0.31
PFS (EGFR mut, mo) 10.8 9.2 0.73
PFS (EGFR wt, mo) 3.6 1.8 0.045
PFS (EGFR na, mo) 2.7 2.7 0.96
DCR (%) 59 55 0.70
7517 Poster Discussion Session (Board #7), Tue, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
SWOG S0635 and S0636: Phase II trials in advanced-stage NSCLC of
erlotinib (OSI-774) and bevacizumab in bronchioloalveolar carcinoma
(BAC) and adenocarcinoma with BAC features (adenoBAC), and in neversmokers
with primary NSCLC adenocarcinoma (adenoCa). Presenting
Author: Howard Jack West, Swedish Cancer Institute, Seattle, WA
Background: Despite recent changes to lung adenoCa pathologic classification,
adv stage BAC remains a definable and clinically applicable entity.
Patients (pts) with BAC, as well as never-smoking (NS) pts with adv lung
adenoCa, have emerged as relevant clinical subpopulations with a high
probability of clinical benefit from epidermal growth factor receptor (EGFR)
tyrosine kinase inhibitors (TKIs), likely related to the high proportion of
activating mutations in the EGFR gene in such pts. Based on these results
and the potential for increased clinical activity conferred by addition of B to
E, SWOG initiated a pair of phase II trials of this combination in pts with
adv BAC (S0635) or NS pts with adv lung adenoCa (S0636). Methods: NS
pts with BAC or adenoBAC were preferentially enrolled on S0636. A total of
78 and 85 eligible pts were enrolled and treated on the S0635 and S0636
trials, respectively. Patients received E 150 mg PO daily and B 15 mg/kg IV
q21 days until progression or prohibitive toxicity. Tumor tissue submission
for pathologic review and assessment of molecular markers was mandated.
Results: Pt demographics of the two trials are as shown in the table below.
RECIST response rate among 61 BAC pts on S0635 with measurable
disease was 18%, and among 53 NS pts on S0636, it was 47%. Median
progression-free survival is 5 and 8 months (mo) on S0635 and S0636,
respectively; median overall survival (OS) is 17 and 26 mo on S0635 and
S0636, respectively. Toxicity consisted primarily of rash, diarrhea, and
hypertension; no treatment-related deaths were reported. Molecular marker
studies will be presented separately. Conclusions: In populations selected
by clinical parameters, E withB is associated with modest toxicity and
encouraging clinical efficacy that exceeded the prespecified OS threshold
of 16 mo in studies of both adv BAC and NS pts, exceeding two years in NS
pts.
Trial Median age (range) Treatment naïve Performance status 0/1 Race
S0635 (BAC) 69.2 (39.1-92.8) 12% 96% 92% White
8% Black
S0636 (NS) 61.3 (31.2-84.8) 13% 97% 66% White
25% Asian
5% Black
4% Other
7519^ Poster Discussion Session (Board #9), Tue, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
A randomized placebo-controlled phase III study of intercalated erlotinib
with gemcitabine/platinum in first-line advanced non-small cell lung
cancer (NSCLC): FASTACT-II. Presenting Author: Tony Mok, The Chinese
University of Hong Kong, Hong Kong, China
Background: FASTACT, a randomized, phase 2 study in advanced NSCLC,
found that intercalated erlotinib with 1st-line platinum-based chemotherapy
(CT) significantly prolongs progression-free survival (PFS) (HR
0.47, p�0.0002) versus CT alone (Mok et al. JCO 2009). FASTACT-II is a
confirmatory, randomized, phase 3, placebo-controlled, double-blind study
in a large patient population Methods: Patients with untreated stage IIIB/IV
NSCLC and ECOG PS 0/1 were randomized (1:1) to receive up to 6 cycles of
gemcitabine (1,250 mg/m2 on d1 and 8) plus platinum (carboplatin
5�AUC or cisplatin 75 mg/m2 on d1) q4w, with either intercalated
erlotinib (150 mg/day on d15–28) or placebo. Non-progressing patients
received maintenance erlotinib or placebo until progression, unacceptable
toxicity or death. Stratification was by disease stage, histology, smoking
status and CT regimen. Primary endpoint was PFS; secondary endpoints
included overall response rate (ORR), overall survival (OS), safety, QoL and
biomarker analyses. Results: From Apr 2009 to Sep 2010, 451 patients
were randomized to receive erlotinib (n�226) or placebo (n�225).
Baseline demographics were well balanced across the arms; overall, 49%
were never smokers, 40% were female and 76% had adenocarcinoma. PFS
was significantly prolonged with erlotinib vs placebo: median 7.6 vs 6.0
months, respectively; HR 0.57 (95% CI 0.46–0.70); p�0.0001. ORR was
significantly improved with erlotinib vs placebo: 42.9% vs 17.8%;
p�0.0001. A non-significant trend towards longer OS was seen with
erlotinib vs placebo (median 18.3 vs 14.9 months; HR 0.78 [95% CI
0.60–1.02]; p�0.069); 73% of placebo patients received a 2nd-line
EGFR TKI. Except for skin rash with erlotinib, there was no clinically
significant difference in toxicity between arms. A total of 283 patients
(62.7%) provided samples for biomarker analyses, including EGFR mutation
status, results of which will be presented. Conclusions: Intercalation of
erlotinib with CT significantly prolonged PFS in 1st-line advanced NSCLC.
Biomarker analysis will determine the significance of this regimen in
patients with or without activating EGFR mutations.
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