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

7504 Oral Abstract Session, Mon, 3:00 PM-6:00 PM
Analysis of resistance mechanisms to ALK kinase inhibitors in ALK�
NSCLC patients. Presenting Author: Robert Charles Doebele, University of
Colorado Anschutz Medical Campus, Aurora, CO
Background: Patients with anaplastic lymphoma kinase (ALK) gene fusions
derive significant clinical benefit from crizotinib, an ALK inhibitor; moreover,
next generation ALK kinase inhibitors are in development. Unfortunately,
drug resistance develops after initial benefit (acquired) or occurs in
patients who never derive a benefit (intrinsic). This study aimed to define
molecular mechanisms of resistance to ALK kinase inhibitors in ALK�
non-small cell lung cancer (NSCLC) patients. Methods: 30 ALK� crizotinibtreated
NSCLC patients experienced radiologic disease progression, of
whom 7 progressed only in the CNS. Of the 23 patients with extra-CNS
progression, a biopsy was attempted on 19. One of the patients without
tissue post-crizotinib then proceeded to a second generation ALK inhibitor
and tissue was obtained post progression on this drug. We performed
molecular analysis and initiated cell lines from tumor tissue for these 19
patients. Results: 15 patients had material evaluable for molecular analysis.
Six patients (40%) developed secondary mutations in the kinase
domain of ALK. Two novel mutations were identified in samples from ALK�
NSCLC patients, F1174C and D1203N. Two patients each demonstrated
G1269A or L1196M mutations. Two patients each, one with a resistance
mutation, exhibited new onset ALK copy number gain (CNG). Four patients
demonstrated the presence of another oncogenic driver (1 with EGFR
mutation; 3 with KRAS mutation) with or without a persistent ALK gene
rearrangement. One patient lacked an ALK gene fusion on progression
biopsy, but had no identifiable alternate oncogene alteration. 3 patients
retained ALK positivity with no identifiable resistance mechanism. Data on
additional patients and an in vitro model of copy number gain will be
presented. Conclusions: ALK kinase inhibitor resistance in ALK� NSCLC
occurs through a diverse array of kinase domain mutations, ALK gene
fusion CNG, and emergence of second (same cell) or separate (different
cell) oncogenic drivers. In order to overcome resistance it will be important
to differentiate patients that preserve ALK dominance (secondary mutations
and CNG) versus those that have diminished ALK dominance
(separate or second oncogenic drivers).
7506 Oral Abstract Session, Mon, 3:00 PM-6:00 PM
A randomized phase III trial of single-agent pemetrexed (P) versus
carboplatin and pemetrexed (CP) in patients with advanced non-small cell
lung cancer (NSCLC) and performance status (PS) of 2. Presenting Author:
Rogerio Lilenbaum, Cleveland Clinic Florida, Weston, FL
Background: No standard of care exists for patients with advanced NSCLC
and PS 2 and clinical practice ranges from supportive care to combination
chemotherapy. Methods: In a Brazilian multicenter phase III randomized
trial, advanced NSCLC patients, with any histology at first, amended to
non-squamous only, PS 2, no prior chemotherapy, and adequate organ
function, were randomized to P alone (500 mg/m2) or CP (AUC 5 � same
P) administered every 3 weeks for 4 cycles. Stratification factors included
stage (IIIB vs. IV); age (�70 vs. �70); and weight loss (�5 kgvs.�5kg).
The primary endpoint was overall survival and the study was powered to
demonstrate an improvement in median survival from 2.9 to 4.3 months
based on a prior CALGB trial. Results: A total of 217 patients were enrolled
from 8 centers in Brazil and 1 in the US from April 2008 to July 2011.
Twelve patients were ineligible and excluded. The 2 arms (P�102;
CP�103) were balanced for patient characteristics. 14 patients had
squamous and another 12 had unknown histology. The response rates were
P � 10% and CP � 24% (p�0.019). In the ITT population, the median
PFS was P � 3.0 mo and CP � 5.9 mo (HR�0.46, 95% CI 0.34; 0.63,
p�0.001) and median OS was P � 5.6 mo vs. CP � 9.1 mo (HR�0.57,
95% CI 0.41; 0.79, p�0.001). 1-year survival rates were 22% and 39%
respectively. Similar results were seen when squamous patients were
excluded from the analysis. Grade ¾ anemia (5.5%; 12%) and neutropenia
(2.8%; 5.6%) were more frequent in CP. There were 4 treatment-related
deaths in the CP arm. 30% of patients in each arm received 2nd line therapy
Conclusions: Combination chemotherapy with CP significantly improves
survival, with acceptable safety, in eligible patients with advanced NSCLC
and PS 2, and represents a new standard.
Lung Cancer—Non-small Cell Metastatic
481s
7505 Oral Abstract Session, Mon, 3:00 PM-6:00 PM
Multiplex testing for driver mutations in squamous cell carcinomas of the
lung. Presenting Author: Paul K. Paik, Memorial Sloan-Kettering Cancer
Center, New York, NY
Background: While the majority of lung adenocarcinomas (ADCL) harbor an
identifiable driver mutation, targeted therapies for squamous cell lung
carcinomas (SQCLC) have lagged in development due to a paucity of
druggable oncogenic events. Three targets, which together occur in up to
50% of SQCLC, have been recently identified (FGFR1 amplification, DDR2
mutations, PIK3CA mutations/PTEN loss). Comprehensive molecular analysis
of SQCLC tumors by The Cancer Genome Atlas is ongoing, with new
therapeutic targets on the horizon. Methods: We have instituted prospective,
multiplex testing of SQCLC tumors (Squamous Cell Lung Cancer
Mutation Analysis Program, “SQ-MAP”). Tests include FISH for FGFR1
amplification (defined as FGFR1:CEP8 � 2in�10% of cells), IHC for loss
of PTEN expression, and Sequenom MassARRAY for PIK3CA mutations
(and others, below). We are also incorporating targeted exon sequencing
(Agilent SureSelect/Ion Torrent) of a panel of over 80 lung cancer
oncogenes and tumor suppressors in preparation for future studies. All
tests were performed on formalin-fixed paraffin-embedded samples and
with Institutional Review Board/Biospecimen Utilization Committee approval.
Results: 40 SQCLC patient specimens have been processed through
SQ-MAP over 3 months. 8 samples were excluded (insufficient tissue in 4,
reclassification to ADCL in 4). Data are available for 28 patients. PTEN IHC
was performed on 15 samples to date. Molecular results are summarized in
the table. Events were non-overlapping. Results for the �80 gene sequencing
component will be described. Based on SQ-MAP, accrual to 2 approved
clinical trials (FGFR1 inhibition; PI3K inhibition) has begun, with a third
planned (DDR2 mutations). Conclusions: Actionable defects were detected
in 60% (95% CI: 37-75%) of SQCLC specimens. Mutation data for �80
other oncogenes and tumor suppressors will be available shortly (including
DDR2). SQ-MAP serves as a platform supporting both personalized care
and research.
Test Frequency 95% CI
FGFR1 amplification 25% (7/28) 11-45%
PTEN loss, complete 20% (3/15) 5-49%
PIK3CA mutation 11% (3/28) 2-28%
KRAS mutation 4% (1/28) 0-18%
EGFR mutation 0%
BRAF mutation 0%
HER2 mutation 0%
AKT1 mutation 0%
NRAS mutation 0%
MEK1 mutation 0%
Any 60% 37%-75%
LBA7507 Oral Abstract Session, Mon, 3:00 PM-6:00 PM
PARAMOUNT: Final overall survival (OS) results of the phase III study of
maintenance pemetrexed (pem) plus best supportive care (BSC) versus
placebo (plb) plus BSC immediately following induction treatment with
pem plus cisplatin (cis) for advanced nonsquamous (NS) non-small cell
lung cancer (NSCLC). Presenting Author: Luis Paz-Ares, University Hospital
- Virgen del Rocio, Seville, Spain
The full, final text of this abstract will be available at
abstract.asco.org at 12:01 AM (EDT) on Monday, June 4,
2012, and in the Annual Meeting Proceedings online
supplement to the June 20, 2012, issue of Journal of
Clinical Oncology. Onsite at the Meeting, this abstract will
be printed in the Monday edition of ASCO Daily News.
Visit abstract.asco.org and search by abstract for the full list of abstract authors and their disclosure information.