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1191PD CLINICAL ACTIVITY OF CRIZOTINIB IN PATIENTS WITH
ADVANCED NON-SMALL CELL LUNG CANCER (NSCLC)
HARBORING ROS1 GENE REARRANGEMENT
S.I. Ou 1 , D.R. Camidge 2 , J. Engelman 3 , J. Clark 4 ,L.Tye 5 , K. Wilner 6 ,
P. Stephenson 6 , M. Varella-Garcia 7 ,A.Iafrate 4 , A.T. Shaw 4
1 Cancer Centre, Chao Family Centre, Irvine, CA, UNITED STATES OF AMERICA,
2 School of Medicine, University of Colorado, Denver, UNITED STATES OF
AMERICA, 3 Cancer Research, Massachusetts General Hospital, Charlestown,
MA, UNITED STATES OF AMERICA, 4 Cancer Center, Massachusetts General
Hospital, Boston, UNITED STATES OF AMERICA, 5 Oncology, Pfizer, CA,
UNITED STATES OF AMERICA, 6 Chapel Hill, Rho, Inc., NC, UNITED STATES OF
AMERICA, 7 School of Medicine, University of Colorado, CO, UNITED STATES
OF AMERICA
Background: Chromosomal rearrangements in the receptor tyrosine kinase (RTK)
ROS1 define a new molecular subset of NSCLC. ALK inhibitors can inhibit ROS1
kinase activity in cell lines. We examined the efficacy and safety of crizotinib, a small
molecule inhibitor of two other RTKs, MET and ALK, in patients with advanced,
ROS1-rearranged NSCLC.
Methods: Patients with advanced NSCLC harboring ROS1 rearrangement, as
determined using a break-apart FISH assay, were recruited into an expansion cohort
of the original phase 1 study of crizotinib. Patients were treated with crizotinib at the
standard oral dose of 250 mg BID. The objective response rate (ORR) was
determined based on RECIST v1.0. The disease control rate (DCR; stable disease
[SD] + partial response [PR] + complete response [CR]) was evaluated at weeks
8 and 16.
Results: At the time of data cut-off on April 19, 2012, 15 patients with ROS1 NSCLC
had received crizotinib and 14 were evaluable for response. The median age was 54
years (range 31–72). Fourteen patients were never-smokers and all had
adenocarcinoma histology. All patients were confirmed negative for ALK
rearrangement. The median number of prior treatments was 1 (range 0–6). The first
ROS1 patient received crizotinib on October 19, 2010. To date, the ORR is 57%
(8/14; 95% CI 28.9–82.3), with 7 PR and 1 CR. There were 4 SD, one of which was
unconfirmed as PR at the time of data cut-off. The DCR at 8 weeks was 79% (11/14).
Median duration of treatment was 25.7 weeks (range 0.1 + to 65.3 + ), and 12 patients
continue on study. The pharmacokinetics, antitumor activity and safety profile of
crizotinib in this group of patients were similar to those observed in patients with
ALK-positive NSCLC.
Conclusions: Crizotinib is associated with clinically significant antitumor activity in
patients with ROS1 NSCLC. Similar to ALK, ROS1 rearrangement defines another
unique molecular subset of NSCLC patients for whom crizotinib therapy may be
highly effective. Importantly, this study represents the first clinical investigation of
ROS1 as a driver mutation and therapeutic target in cancer.
Disclosure: S.I. Ou: Advisory role: Pfizer, Genentech. Compensated Honoraria:
Pfizer, Genentech, Lilly. Myself Research funding: Pfizer. Myself (institution). D.R.
Camidge: Advisory role: Pfizer. Myself. Honoraria: Pfizer. Myself. L. Tye:
Employment: Pfizer. Clinician. Myself. Stock Ownership; Pfizer. Myself. K. Wilner:
Emplyement: Pfizer. Senior Director. Myself. Compensated. Stock ownership: Pfizer.
Myself. M. Varella-Garcia: Honoraria: Abbott Molecular. Myself. funding for the trial
provided by NIH - yes. A.T. Shaw: Advisory role: Pfizer, Ariad, Chugai, Novartis,
Daiichi-sankyo. Myself. Compensated Research funding: Astra Zeneca, Novartis.
Myself. All other authors have declared no conflicts of interest.
1192PD LACE-BIO POOLED ANALYSIS OF THE PROGNOSTIC AND
PREDICTIVE VALUE OF TP53 MUTATIONS IN COMPLETELY
RESECTED NON SMALL CELL LUNG CANCER (NSCLC)
P. Hainaut 1 ,X.Ma 2 , B. Lacas 3 , M. Tsao 4 , J. Douillard 5 , V. Rousseau 6 ,
A. Dunant 6 , L. Seymour 7 , M. Filipits 8 , S. Graziano 9
1 Research, International Prevention Research Institute, Lyon, FRANCE, 2 Jinan
Central Hospital, Shandong University, Jinan, CHINA, 3 Meta-Analysis Unit,
Institut Gustave-Roussy, Villejuif, FRANCE, 4 Hematology and Oncology, Princess
Margaret Hospital, Toronto, CANADA, 5 Medical Oncology, Centre René
Gauducheau, Saint-Herblain, FRANCE, 6 Biostatistics, Institut Gustave Roussy,
Villejuif, FRANCE, 7 NCIC Clinical Trials Group, Queen’s University, Kingston,
CANADA, 8 Medicine, Medical University of Vienna, Vienna, AUSTRIA,
Annals of Oncology 23 (Supplement 9): ix389–ix399, 2012
doi:10.1093/annonc/mds408
9 Hematology and Internal Medicine, SUNY Upstate Medical University Hospital,
Syracuse, UNITED STATES OF AMERICA, on behalf of the LACE-Bio Study
Group
Background: Mutations in the Tumour Suppressor Gene TP53 occur in about 50%
of Stage II-III NSCLC. However, prognostic and predictive value of survival after
adjuvant therapy not defined. We report here on the pooled analysis of 4
randomized trials of platinum-based Adjuvant ChemoTherapy (ACT) or observation.
Methods: Trials included IALT, JBR10, CALGB-9633 and ANITA. Mutations in
exons 5-8 of TP53 (encompassing hotspots and over 90% of known mutations) were
detected by PCR/sequencing in DNA extracted from formalin-fixed
paraffin-embedded NSCLC. Mutations were classified into 3 structure/function
groups: non-missense; missense outside DNA Binding Notifs (missense non-DBM);
missense DBM. Main endpoint was overall survival (OS). Hazard ratio (HR) and
95% confidence interval (CI) were estimated with a Cox model stratified on trial and
adjusted on gender, age and clinico-pathological variables.
Results: 1209 NSCLC patients (pts) (5.5 years median follow-up) were analysed.
Mutations were detected in 434 pts (36%; IALT: 42%; JBR10: 28%; CALGB-9633:
39%; ANITA: 30%). Mutant TP53 had a borderline significant prognostic effect (HR
for OS, mutation vs. wild-type (WT): 1.19; CI [1.00-1.41]; p = 0.05). Missense
non-DBM mutations, likely to alter p53 protein structure, had a marginally worse
prognostic effect (HR for OS, missense non-DBM vs. WT: 1.38; CI [1.08-1.75]), but
effects in the 3 function groups were not significantly different (p = 0.23). Among pts
with WT TP53, OS was better in the ACT group (HR for OS, ACT vs. no ACT: 0.77;
CI [0.62-0.96]; p = 0.02), whereas ACT had no effect among pts with mutation.
Conversely, in the ACT group, OS was significantly shorter in pts with TP53
mutation than in WT pts (HR for OS, Mutant vs. WT TP53: 1.39; CI [1.09-1.77]; p
= 0.008), whereas TP53 had no prognostic effect in the control group. The ACT effect
in the mutated and WT groups and the prognostic effect in the ACT and control
groups were not different (interaction test p = 0.07).
Conclusion: TP53 mutation status had a borderline prognostic effect and was not
predictive of adjuvant chemotherapy effect on OS in NSCLC. Supported by French
Ligue against Cancer (LNCC) and by unrestricted grant from Sanofi Aventis. XM
was supported by a fellowship from International Agency for Research on Cancer
Disclosure: All authors have declared no conflicts of interest.
1193P ONCOGENIC DRIVER MUTATIONS IN CHINESE NON-SMALL
CELL LUNG CANCER (NSCLC)
J. He 1 , H. Yang 2 , Q. Deng 3 ,P.He 2 , J. Jiang 1 , M. Zhao 2 ,X.Gu 4 , L. Zheng 5 ,
H. Pang 1 , J.X. Zhou 6
1 Thoracic Surgery, The First Affiliated Hospital of Guangzhou Medical University,
Guangzhou, CHINA, 2 Thoracic Oncology, The First Affiliated Hospital of
Guangzhou Medical University, Guangzhou, CHINA, 3 The Center for Translational
Medicine, The First Affiliated Hospital of Guangzhou Medical University,
Guangzhou, CHINA, 4 Pathology, The First Affiliated Hospital of Guangzhou
Medical University, Guangzhou, CHINA, 5 The Center for Translational Medicine,
Xiamen University, Xiamen, CHINA, 6 Pathology, Ningbo University School of
Medicine, Ningbo, CHINA
Background: Oncogenic driver mutations are responsible for both the initiation and
maintenance of cancers including NSCLC. Elucidation of driver mutation occurrence
in NSCLC and its relationship with clinical outcome are imperative to personalized
treatment of NSCLC.
Methods: Tumor tissues from a total of 488 Chinese NSCLC patients at various
stages were enrolled in this retrospective study. Mutations were assessed using
amplification-refractory mutation system (ADx-ARMSTM)-PCR and verified using
direct sequencing. ERCC1 levels were measured using immunohistochemistry
method. The relationship between tumor gene mutation status and patient’s
disease-free survival (DFS) was analyzed.
Results: Of the 488 NSCLC tumors, 28 had EML4-ALK fusions (5.7%). Female
(10.38%), young age (