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

488s Lung Cancer—Non-small Cell Metastatic
7532 Poster Discussion Session (Board #22), Tue, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Characteristics of NSCLCs harboring NRAS mutations. Presenting Author:
Kadoaki Ohashi, Vanderbilt University, Nashville, TN
Background: We sought to determine the frequency and clinical characteristics
of patients with non-small cell lung cancers (NSCLCs) harboring NRAS
mutations. We used preclinical models to identify targeted therapies likely
to be of benefit against NRAS mutant lung cancer cells. Methods: We
reviewed data in the Catalogue of Somatic Mutations in Cancer (COSMIC)
and clinical history from patients with NSCLC whose tumors underwent
systematic screening for driver mutations including NRAS. Patient characteristics
examined included age, gender, race, smoking history, disease
stage, treatment history, and overall survival (OS). 6 NSCLC cell lines with
NRAS mutations were screened for sensitivity against multiple targeted
agents. Gene expression was profiled using Affymetrix U133A arrays in 5
NRAS mutant NSCLC cell lines, 8 with EGFR mutations and 17 with KRAS
mutations. Results: Among 4524 patients with NSCLC tested, NRAS
mutations were present in 29 (0.64%). The types of substitutions found
were Q61H/K/L/R and G12A/C/D/R/S, with NRAS Q61L the most common
(n�14; 48%). One tumor had a concurrent KRAS mutation. 83% had
adenocarcinoma histology, with no significant differences in gender. While
90% of patients were former or current smokers, smoking-related G:C�T:A
transversions were significantly less frequent in NRAS than in KRASmutant
NSCLC (KRAS: 66%, NRAS: 13%, p�0.05). Systemic chemotherapy
showed limited efficacy in 7 patients with metastatic disease
(median OS 7 mos). 5 of 6 NRAS mutant lung cancer cell lines were
sensitive to the MEK inhibitors, AZD6244 and GSK1120212, while other
targeted agents (against EGFR, ALK, MET, IGF-1R, PIK3CA, BRAF) were
minimally effective. Gene expression profiles of NRAS mutant cell lines
were distinct from those with KRAS or EGFR mutations. Conclusions: NRAS
mutations define a distinct subset of NSCLCs (~1%) with potential
sensitivity to MEK inhibitors. While NRAS gene mutations are more
common in current/former smokers, the types of mutations are not those
classically associated with smoking.
7534 Poster Discussion Session (Board #24), Tue, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Native and rearranged ALK copy number and rearranged ALK cell count in
NSCLC: Implications for ALK inhibitor therapy. Presenting Author: D. Ross
Camidge, University of Colorado Cancer Center, Aurora, CO
Background: ALK rearranged NSCLC responds well to ALK inhibitors.
Clinically, �15% cells showing rearrangements by break-apart FISH
classifies tumors as ALK(�). Native ALK copy number gain has also been
reported. We explored the significance of native and rearranged ALK copy
number on crizotinib outcomes and whether �15% reflected a clear
biological distinction in the frequency of ALK(�) cells. Methods: Copy
number and genomic status of ALK assessed by FISH. A total of 1426
NSCLC clinical specimens, 174 ALK(�) and 1252 ALK(-) by standard
criteria, and 26 NSCLC cell lines (2 ALK(�) and 24 ALK(-)) were
investigated. Results: Native ALK gene mean copy number was significantly
higher in ALK(-) than in ALK(�) cases (2.8, SD 0.93, range 1.2-11.4 vs.
1.8, SD 0.79; range 0.6 to 5.2; p�0.01). Frequency of native ALK copy
number gain (�3 copies/cell in �40% cells) was 19% in ALK(�) and 62%
in ALK(-) tumors (p�0.001). In ALK(-) tumors, abundant focal amplification
of native ALK was rare (0.8%); scanty amplification (�10% tumor
cells) occurred in 1.1%, and duplication of the entire native ALK or of the
ALK 3’ end occurred in 3.5%. Among ALK(-) cell lines, mean native ALK
copy number ranged 2.1-6.9 and was not correlated with in vitro crizotinib
sensitivity (IC50s 0.34-2.8 uM). In (�) patients, neither native or rearranged
ALK copy number, nor percentage cell count correlated with
maximal tumor shrinkage or PFS with crizotinib. Clinical specimens with
0-9%, 10-15%, 16-30%, 31-50% and �50% of ALK� cells were found in
79.3%, 8.5%, 1.4%, 2.7% and 8.1% of cases, respectively. Conclusions:
Lower native ALK copy number in ALK(�) NSCLC suggests ALK fusion
occurs early, preceding chromosomal instability. Elevated native ALK copy
number rarely reflects focal amplification and native ALK copy number
increases alone are not associated with sensitivity to ALK inhibition in vitro.
Neither native or rearranged copy number, nor positive cell count within
ALK(�) tumors influences clinical benefit from ALK inhibition. As 8.5% of
ALK(-) cases fall within 5% of the established �15% cell positive
threshold, further investigation of ALK status by other diagnostic techniques
in this subset may be warranted.
7533 Poster Discussion Session (Board #23), Tue, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Results of a global phase II study with crizotinib in advanced ALK-positive
non-small cell lung cancer (NSCLC). Presenting Author: Dong-Wan Kim,
Seoul National University Hospital, Seoul, South Korea
Background: Approximately 3–5% of NSCLC harbors ALK gene rearrangements.
Crizotinib is a first-in-class, oral, small-molecule competitive ALK
inhibitor with anti-MET activity. Methods: PROFILE 1005 is an ongoing
global, multicenter, open-label, single-arm, phase II study evaluating the
safety and efficacy of crizotinib (250 mg BID in 3-week cycles) in patients
with advanced ALK-positive NSCLC who progressed after �1 chemotherapy
for recurrent/advanced/metastatic disease. Tumor response was
evaluated by RECIST 1.1 every 6 weeks. Patient-reported symptoms and
global quality of life (QOL) were assessed using the EORTC QLQ-C30 and
LC-13 at baseline, day 1 each cycle and at end of treatment. Results: As of
June 2011, 439 patients were evaluable for safety and 255 patients for
tumor response. Median age was 53 years. The majority of patients were
female (53%), never smokers (65%), and had adenocarcinoma (92%),
ECOG PS 0–1 (83%) and �2 prior chemotherapy regimens (85%). Among
patients evaluable for efficacy, median treatment duration was 25 weeks
(77% of patients still ongoing). ORR was 53% (95% CI: 47–60), disease
control rate at 12 weeks was 85% (95% CI: 80–89), median duration of
response was 43 weeks (96% CI 36–50) and median PFS was 8.5 months
(95% CI: 6.2–9.9). The most frequent treatment-related AEs were visual
effects (50%), nausea (46%), vomiting (39%), and diarrhea (35%), mostly
grade 1–2. 29 patients (6.6%) had treatment-related SAEs, including
dyspnea and pneumonitis (4 patients each; 0.9%), and febrile neutropenia
and renal cyst (2 patients each; 0.5%). A statistically significant (p�0.05)
and clinically meaningful (� 10 points) improvement from baseline was
observed for patient-reported overall pain, pain in chest, cough, dyspnea,
insomnia, fatigue and global QOL. Conclusions: Crizotinib demonstrated a
high response rate and PFS, favorable tolerability profile and improvement
in patient-reported symptoms. These results provide strong evidence for
crizotinib as a standard of care for advanced ALK-positive NSCLC.
7535 General Poster Session (Board #44A), Sat, 1:15 PM-5:15 PM
Association of epithelial to mesenchymal transition with efficacy of
EGFR-TKIs in non-small cell lung cancer patients with EGFR wild type.
Presenting Author: Shengxiang Ren, Shanghai Pulmonary Hospital, Tongji
University School of Medicine, Shanghai, China
Background: The epithelial to mesenchymal transition (EMT) is a fundamental
biological process during which epithelial cells change to a mesenchymal
phenotype, it has a profound impact on cancer progression and
treatment. The purpose of this study was to investigate the role of EMT to
predict the efficacy of epidermal growth factor receptor tyrosine kinase
inhibitors (EGFR-TKIs) in advanced non-small cell lung cancer (NSCLC)
patients. Methods: We evaluated the correlation between EMT and sensitivity
to EGFR-TKIs in advanced NSCLC patients. Immunohistochemistry was
used to examine the expression of EMT markers, E-cadherin, fibronectin,
N-cadherin and vimentin and ARMs was used to detect the EGFR mutation
in tumor specimens obtained before the treatment. The EMT phenotype
status was determined according to the expression of E-cadherin, fibronectin,
N-cadherin and vimentin. Results: 101 patients enrolled into this study
and 97 had enough tissue to perform the EMT examination. The median
age was 59 years old, male/female:56/45, never smoker/smoker: 71/30,
adenocarcinoma/non-adeno: 73/28, PS 0-1/2-3: 83/18, Stage IIIB/IV:
2/99, 1st /2nd-4th line: 13/88. The response rate and progression free
survival(PFS) in the whole population were 45.5% and 7.6 months
respectively. EMT test revealed that 46(47.4%) samples were epithelial
phenotype, while 51(52.6%) were mesenchymal phenotype. 38 of 79
patients harbour activating EGFR mutation. Among the patients with EGFR
wild type or unknown status, patients with an epithelial phenotype had a
higher response rate(40% Vs 17.6%, P�0.056) and significantly longer
PFS(7.6 m Vs 3.8 m, P�0.045) than these with a mesenchymal phenotype.
However, the response rate(85.7% Vs 64.7%, P�0.249) and
PFS(15.2 m Vs 12.2 m, P�0.420) were similar in the patients with
activated EGFR mutation. Conclusions: Patients with an epithelial phenotype
got more benefit from the treatment of EGFR-TKIs in the advanced
EGFR wild type NSCLC patients, which indicated that the EMT might be a
potential marker to guide the individual therapy of EGFR-TKIs in this
subpopulation.
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