Journal Thoracic Oncology

Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017
lung cancer adenocarcinoma. Methods: In this retrospective, unicentric
study we assigned 41 patients by convenience with lung adenocarcinoma
in advanced clinical stage of the disease to receive afatinib or gefitinib as
second or third line treatment. The primary end point of our trial is to describe
progression free survival and global survival outcomes in patients that receive
TKIs as second or third line therapy. Secondary end points were time elapsed
from the beginning of TKIs to the time of response by RECIST 1.1, and toxicity
between the two groups. Conflict of interest: Boehringer Ingelheim donated
Afatinib and The National Institute of Respiratory Diseases in Mexico donated
Gefitinib. Results: From 120 patients, 41 of them were selected to receive TKIs
by convenience. The progression free survival with afatinib PFS was 11 months
and 10 months for gefitinib, with no significant difference in both therapeutic
groups (HR 0.79, p=0.173). There is a reduction in 2 years mortality in favor of
afatinib (HR 0.69, p=0.046). There were no significant differences between
afatinib and gefitinib in response rate, also there were no differences by
RECIST 1.1. We observed more incidence of mucositis in the group treated
with afatinib (HR 0.58, p=0.006) and metastasis to CNS at diagnosis observed
in afatinib group (p= 0.029). Conclusion: There was a reduction in 2 years
mortality with afatinib treatment compared with gefitinib. With the data
obtained we can infer that TKIs show similar benefits in second and third line
as if given at the beginning, with a good progression free survival, with no
significant differences between afatinib or gefitinib.
Keywords: TKIS treatment, NSCLC 2nd line treatment, EGFR mutation
treatment
POSTER SESSION 3 – P3.02B: ADVANCED NSCLC & CHEMOTHERAPY/TARGETED THERAPY/
IMMUNOTHERAPY
EGFR RES –
WEDNESDAY, DECEMBER 7, 2016
P3.02B-108 ASSESSMENT OF CLINICAL USABILITY OF A CFDNA-
BASED ASSAY DETECTING EGFR T790M MUTATION IN EGFR-TKI
REFRACTORY NSCLC PATIENTS
Masaki Hanibuchi 1 , Akira Kanoh 2 , Takuya Kuramoto 2 , Hisatsugu Goto 1 ,
Atsuro Saijo 1 , Hirokazu Ogino 1 , Yasuhiko Nishioka 1
1 Department of Respiratory Medicine and Rheumatology, Institute of Biomedical
Sciences, Tokushima University Graduate School, Tokushima/Japan, 2 Biomarker
Research, Taiho Pharmaceutical Co.,ltd., Tsukuba/Japan
Background: Assessment of acquired resistant EGFR mutation T790M
in circulating free DNA (cfDNA) in the plasma of EGFR-TKI treated NSCLC
patients presents several challenges. Furthermore, the feasibility and
required sensitivity of cfDNA-based detection methods in second-line therapy
are not well elucidated. Here, we examined the cfDNA of patients for T790M
and other activating mutations of EGFR to assess the clinical usability of such
data for diagnosis purposes. Methods: cfDNAs were prepared from the plasma
samples of 45 NSCLC patients who were confirmed as harboring activating
EGFR mutations (exon19 deletion, N = 20; L858R, N = 23; and minor mutations,
N = 2). EGFR mutations in cfDNA samples were detected using highly sensitive
methods (NGS-utilizing ultra-deep sequencing, droplet digital PCR) and
originally developed assays (BNA-clamped PCR/F-PHFA combined method,
and BNA-clamped qPCR) and these results were compared to tissue-based
definitive diagnoses. Results: No significant change was observed in amounts
of extracted cfDNA among EGFR-TKI naïve (N = 18) and refractory (N = 27)
groups. There was a positive significant correlation between the amount of
cfDNA and diameter in target regions, suggesting that tumor volume reflects
the amount of cfDNA. Significant negative correlation was observed between
cfDNA amounts and PFS following EGFR-TKI treatment in the TKI-naïve group.
The overall percentage agreement between cfDNA and tissue-based analyses
ranged from 89 to100 % in major activating mutations and was approximately
85% in T790M. Detected fragment number of each mutation in cfDNA
samples by ultra-deep sequencing suggested that it caused the observed
difference in the agreement rates between activating mutations and
T790M. We confirmed the strong agreement between the high performance
assays and definitive diagnosis when the same tissue samples were tested.
Next, cfDNA genotyping results were compared to tissue-based definitive
diagnosis. In the case of BNA-clamped qPCR, the positive percent agreement
was 63% (26/41) in major activating mutations, whereas the negative
percent agreement was 100% (45/45). T790M was detected in 46% (12/26)
cfDNA samples derived from the EGFR-TKI refractory group. We performed
re-biopsies in a proportion of enrolled patients and investigated the tissueplasma
results concordance in matched samples. The observed overall percent
agreement was 63% in case of T790M and 88% regarding exon19 deletions.
Conclusion: Due to heterogeneity or other biological features of drug-treated
tumors, the cfDNA assay feasibility of detecting T790M was more limited
than that of detecting activating mutations. To assess the T790M status in
EGFR-TKI refractory patients, tissue-based assay and cfDNA-based assay
should be performed complementarily.
Keywords: EGFR mutation, non-small cell lung cancer, circulating free DNA
POSTER SESSION 3 – P3.02B: ADVANCED NSCLC & CHEMOTHERAPY/TARGETED THERAPY/
IMMUNOTHERAPY
EGFR RES –
WEDNESDAY, DECEMBER 7, 2016
P3.02B-109 MOLECULAR PROFILING OF EGFR-POSITIVE NSCLC
WITH SECONDARY T790M RESISTANCE MUTATION AND TERTIARY
TRANSFORMATION INTO SMALL-CELL LUNG CANCER
Martin Faehling 1 , Anna-Lena Volckmar 2 , Albrecht Stenzinger 2 , Birgit
Schwenk 1 , Sebastian Kramberg 1 , Jörn Sträter 3
1 Klinik Für Kardiologie Und Pneumologie, Klinikum Esslingen, Esslingen/Germany,
2 Institut Für Pathologie, University Hospital Heidelberg, Heidelberg/Germany,
3 Pathologisches Institut, Esslingen/Germany
Background: In advanced stage NSCLC, activating EGFR-mutations are
prognostic and predictive factors for treatment with an EGFR-tyrosine
kinase inhibitor (TKI). However, invariably, resistance to EGFR-TKI develops.
Resistance is primarily driven by T790M mutations present in approximately
50% of EGFR-mutation positive NSCLC at progression. A different mechanism
of EGFR-TKI-resistance is transformation into SCLC which has been reported
in very rare cases. Methods: Employing Sanger sequencing and targeted
next generation sequencing, we performed full histopathological workup
and molecular profiling of all tumor biopsies obtained during the course of
disease. Both molecular and histopathological data were correlated with
the clinical course. Results: We report the case of a 70 year old patient,
ECOG 1, presenting with dyspnea and fatigue due to a predominantly acinar
adenocarcinoma with extensive metastatic disease. Using Sanger sequencing,
we detected a del Exon19-EGFR mutation. Based on fulfilled response criteria
for EGFR-TKI therapy, erlotinib 150mg was initiated with rapid improvement
of dyspnoe and fatigue. After one month, erlotinib was reduced to 100mg
due to dermatotoxicity. After 5 weeks, CT showed partial remission. After
4½ months, CT revealed mixed response with resolved pleural effusion but
slowly progressive pulmonary metastases. The brain metastases present
at diagnosis had regressed but a new lesion was detected. Due to ongoing
clinical benefit, erlotinib was continued beyond progression. After 7 months,
the patient deteriorated clinically (ECOG 2) with CT showing progression of
all tumor sites including. FNAC of a progressive mediastinal lymph node was
submitted for histopathological and molecular work-up. In parallel one cycle
of systemic chemotherapy with carboplatin/gemcitabine was given, and
cerebral radiation was delivered. Following detection of a T790M mutation,
chemotherapy was stopped and therapy with osimertinib 80mg (CUP) was
started with prompt improvement of the clinical state. CT after 6 weeks
confirmed partial remission. However, 10 weeks later, the patient’s condition
rapidly deteriorated. CT detected complete remission of brain metastasis but
rapid progression of the primary tumor, mediastinal lymphadenopathy, and
hepatic metastases. An endobronchial kryobiopsy revealed small cell lung
cancer as the underlying cause. EGFR analysis revealed the presence of the
original exon19 mutation which had been present in the previous biopsies
showing NSCLC histology. Complementing these preliminary results, a
full molecular workup using next generation sequencing is currently being
performed across all biopsies and will be presented. Conclusion: Integrated
analysis of clinical, histopathological and molecular characteristics reveals
tumor evolution over time and leads to highly individual therapeutic
management benefiting the patient.
Keywords: T790M, SCLC, 3rd generation EGFR-TKI
POSTER SESSION 3 – P3.02B: ADVANCED NSCLC & CHEMOTHERAPY/TARGETED THERAPY/
IMMUNOTHERAPY
EGFR RES –
WEDNESDAY, DECEMBER 7, 2016
P3.02B-110 ROS1 TRANSLOCATION AS A BYSTANDER MUTATION IN
T790M EGFR MUTATED NSCLC
Jan Stratmann 1 , Joerg Kriegsmann 2 , Bernd Sulzbach 3 , Bernd Thöming 4 ,
Hubert Serve 1 , Martin Sebastian 1
1 Med2, Universitätsklinik Frankfurt Am Main, Frankfurt/Germany,
2 Wissenschaftspark Trier, Trier/Germany, 3 Pneumologische Gemeinschaftspraxis
Offenbach, Offenbach/Germany, 4 Ketteler Krankenhaus, Offenbach/Germany
Background: Non small cell lung cancer comprises a number of subtypes that
are defined by genetic alterations in terms of oncogenic driving mechanisms
that constitute groundwork for the development of targeted therapy. EGFR
mutations, as well as ROS1 translocations are two well described genetic
alterations with prognostic and therapeutic implications and almost mutually
exclusive occurance. Activating mutations in the EGF receptor gene are found
in approximately 10% of european patients and large clinical trials with anti
EGFR–kinase inhibitors set EGFR-TKIs as the gold standard of treatment.
However treatment failure obligatory occurs within 8–13months and T790M
gatekeeping mutation is found in approximately 60% as the resistance
mechanism. 3rd generation TKI Osimertinib is a highly active treatment
Copyright © 2016 by the International Association for the Study of Lung Cancer
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