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

Lung Cancer—Non-small Cell Local-Regional/Small Cell/Other Thoracic Cancers
7004 Oral Abstract Session, Mon, 8:00 AM-11:00 AM
Phase III trial of concurrent thoracic radiotherapy (TRT) with either the first
cycle or the third cycle of cisplatin and etoposide chemotherapy to
determine the optimal timing of TRT for limited-disease small cell lung
cancer. Presenting Author: Keunchil Park, Department of Medicine,
Samsung Medical Center, Sungkyunkwan University School of Medicine,
Seoul, South Korea
Background: Concurrent thoracic radiotherapy (TRT) with chemotherapy
has been regarded as optimal treatment for limited-disease small cell lung
cancer (SCLC). However, the issue on how early TRT should be commenced
is not yet defined. Methods: A total of 219 patients with limited-disease
SCLC, who were enrolled from July 2003 to June 2010, received four
cycles of cisplatin plus etoposide (cisplatin 70 mg/m2 on day 1 and
etoposide 100 mg/m2 on days 1 to 3 every 3 weeks). We randomly assigned
these patients to receive concurrent TRT, beginning with the first cycle
(initial arm) or the third cycle (delayed arm) of chemotherapy. In both arms,
patients received 2.1 Gy once-daily in 25 fractions over a period of five
weeks, with a total dose of 52.5 Gy. Patients with partial or complete
response were recommended to receive prophylactic cranial irradiation
(PCI). Results: Approximately 82% of patients completed planned four
cycles of chemotherapy with 52.5 Gy TRT (81.1% and 82.4% in the initial
and delayed arm, respectively). After a median follow-up of 4.9 years
(range, 1.2 – 8.1 years), the median overall survivals were 24.1 and 26.8
months (P�0.60) in the initial and delayed arm, respectively. Progressionfree
survival and complete response rates were 12.2 vs. 12.1 months
(P�0.94) and 36.0% vs. 38.0% (P�0.77) in the initial and delayed arms,
respectively. PCI was given to 49.5% and 55.6% of patients in the initial
and delayed arms, respectively (P � 0.37). Febrile neutropenia was
significantly more frequent with the initial arm, occurring in 21.6% of
patients, as compared with 10.2% in the delayed arm (P � 0.02). All grade
esophagitis occurred in 45.0% and 37.0% of the initial and delayed arms,
respectively (p � 0.23). Conclusions: TRT (52.5 Gy, once daily) beginning
with the third cycle of chemotherapy showed comparable survival outcomes
and complete response rates with TRT beginning with the first cycle of
chemotherapy, with a lower frequency of febrile neutropenia.
7006 Oral Abstract Session, Mon, 8:00 AM-11:00 AM
Comprehensive genomic characterization of squamous cell carcinoma of
the lung. Presenting Author: Ramaswamy Govindan, Washington University
School of Medicine, St. Louis, MO
Background: A third of patients with non-small cell lung cancer are
diagnosed with squamous cell carcinoma (SCC) histology. This report
describes findings from the comprehensive genomic analyses of 178 SCC
samples. Methods: The Cancer Genome Atlas (TCGA) is conducting DNA,
RNA, and miRNA sequencing along with DNA copy number profiling,
quantification of mRNA expression and promoter methylation on surgically
resected samples from previously untreated patients with stage I-III SCC of
the lung. Results: The demographics of 178 patients enrolled in the study:
median age 68 years (range: 40-85); female 47 (26%) and history of
tobacco smoking 171 (96%). Over 30 sites of significant somatic copy
number alteration (SCNA) were identified. Exome sequencing of 178 lung
SCC and matched normal samples revealed 13 significantly mutated genes
with a False Discovery Rate (FDR) of �0.01 and high expression levels,
including TP53, CDKN2A, PTEN, KEAP1, and NFE2L2. Apart from the
near universal loss of TP53 and CDKN2A, alterations in the NFE2L2/
KEAP1 and PI3K/AKT pathways were found in 35% and 43% of tumors
analyzed. mRNA expression profiling revealed four distinct expression
subtypes, each one enriched with distinct mutations and SCNAs - classical
(37%): NFE2L2 and KEAP1 mutations, FGFR kinase alterations, increased
global methylation and the highest rate of tobacco use; basal (24%):
alterations in FGFR kinases; secretory (24%): PDGFRA alterations; primitive
(15%): RB1 mutations. Rearrangements involving several known
tumor suppressors were detected by whole genome shotgun sequencing of
20 tumor/normal pairs and confirmed by RNA sequencing including PTEN,
RB1, NOTCH1, NF1 and CDKN2A. CDKN2A loss by one of several
mechanisms (deletion, mutation, rearrangement with loss of function and
methylation) was observed in 72% of specimens. Potential therapeutic
targets for clinical trials with currently available drugs were identified in
127 patients (75%). Conclusions: SCC of the lung is a distinct molecular
subtype of lung cancer potentially amenable to distinct molecularly
targeted therapies.
7005 Oral Abstract Session, Mon, 8:00 AM-11:00 AM
SWOG 0802: A randomized phase II trial of weekly topotecan with and without
AVE0005 (aflibercept) in patients with platinum-treated extensive-stage small
cell lung cancer (E-SCLC). Presenting Author: Jeffrey Warren Allen, University of
Tennessee Health Science Center, Memphis, TN
Background: Topotecan (T) (oral and IV) is the only FDA-approved second-line
chemotherapy for patients with SCLC. Weekly T is associated with less toxicity
than the daily x 5 regimen. AVE0005 (aflibercept) (A) is a novel recombinant
human fusion protein which binds to circulating VEGF, thereby inhibiting its
interaction with cell surface receptors. We sought to evaluate the efficacy and
toxicity of weekly IV T (4 mg/m2) with or without A (6 mg/kg Q21D) in patients
with relapsed SCLC following one line of platinum-based chemotherapy for E or
limited-stage (L) SCLC. Methods: Patients were randomized 1:1 to T or A�T.
Eligible patients had adequate organ function, ECOG PS 0-1, and no recent
bleeding or cardiac events. Patients with brain metastases stable for � 3 months
prior to study entry were allowed. Primary endpoint was 3-month PFS. Patients
were stratified as platinum-sensitive (PS) or platinum-refractory (PR). PR
patients had progressed within 90 days of last chemotherapy for E and 6 months
for L. This report is limited to the PR stratum. Results: 98 patients were
registered. 1 was ineligible and 1 withdrew consent, leaving 96 evaluable for the
primary endpoint (91 for toxicity (see Table for characteristics)). 3-month PFS
was 26% for A�T versus 9% for T (P�0.01). Overall survival was similar in each
arm (4.6 mos (A�T) versus 3.9 mos (T) (P�0.25)). There was 1 partial response
with A�T. Disease control rate (DCR) was 28% with A�T and 12% with T.
Toxicity was mainly hematologic with 14% and 19% of patients experiencing a
Grade 4 event with T and A�T, respectively. There was one treatment-related
death with T (renal failure). Conclusions: This study met its primary endpoint of
improved 3-month PFS with A�T (p�0.01), warranting further study in the PR
setting. Clinical benefit with A�T was achieved primarily through improved DCR.
Toxicity was manageable and less than is seen with standard dose T. Accrual to
the PS cohort is ongoing.
Patient characteristics.
T(n�46) A�T(n�50)
Age (median) 63 60
Gender
Male (%)
Female (%)
Race
Caucasian (%)
Other (%)
PS
0(%)
1(%)
Stage
Extensive (%)
Limited (%)
67
33
83
17
39
61
70
30
7007 Oral Abstract Session, Mon, 8:00 AM-11:00 AM
Prognostic and predictive effects of KRAS mutation subtype in completely
resected non-small cell lung cancer (NSCLC): A LACE-bio study. Presenting
Author: Frances A. Shepherd, Princess Margaret Hospital, University of
Toronto, Toronto, ON, Canada
Background: We reported previously that KRAS is weakly prognostic and not
significantly predictive of benefit from adjuvant chemotherapy (ACT) in
NSCLC (Tsao et al. Proc ESMO 2012, Abst 4217). In colorectal cancer
(CRC), KRAS mutation predicts resistance to EGFR monoclonal antibodies,
but recent reports suggest that this may not be true for all mutation
subtypes (De Roock et al. JAMA 2010). Smoking-related KRAS mutations
in NSCLC differ from those of CRC. To explore the influence of KRAS
mutation subtype, we undertook an analysis of KRAS subtype in LACE-Bio.
Methods: KRAS mutation was determined in blinded fashion in 3 laboratories
by direct sequencing. Exploratory analyses were performed to identify
relationships between mutation status and subtype, overall (OS) and
disease-free survival (DFS) using a Cox model stratified by trial and
adjusted for covariates. Results: KRAS subtype was available in 1,532
patients (756 observation [OBS], 776 ACT). There were 300 mutations
(275 codon 12, 24 codon 13, 1 codon 14). In the OBS arm, there was no
difference in prognosis for OS for codon 12 (Hazard Ratio [HR] mutation v
wild-type [WT] KRAS 1.04, CI .77-1.4) or codon 13 (HR 1.01, CI
0.47-2.17) mutations. A trend for benefit from ACT was observed in WT
(HR ACT v OBS 0.89 CI 0.76-1.04, p�0.15) but not in patients with codon
12 mutations (HR 0.95, CI .67-1.35, p�0.77). In patients with codon 13
mutations, chemotherapy was deleterious (HR 5.78, CI 2.06-16.2,
p�0.001), test for equality among 3 HRs p�0.002. Results were similar
for DFS. Among codon 12 mutations, there was no prognostic effect based
on specific amino acid substitution. Patients with G12A or G12R mutations
appeared to derive greater benefit from ACT (HR 0.66 p�0.48) compared
to those with G12C or G12V (HR 0.94 p�0.77) or G12D or G12S (HR 1.39
p�0.48) or WT, but the differences were not significant (comparison of 4
HRs p�0.76). Conclusions: In this study, patients with KRAS codon 13
mutations had significantly poorer outcomes with ACT. These results
require further confirmation and should be interpreted with caution in view
of the small number of patients with codon 13 mutations. Supported by
unrestricted grants from Sanofi Aventis and LNCC.
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