- H. Loong
- E. Smit
414O - Gene mutational profiling of Chinese EGFR-T790M mutation NSCLC patients required resistance to osimertinib by next generation sequencing (ID 953)
- C. Xu
- C. Xu
- W. Wang
- W. Zhuang
- Z. Song
- G. Lin
- X. Chen
- Y. Zhu
- M. Fang
- H. Zhang
- H. Wang
- J. Zhang
- Z. Yu
- R. Chen
- Y. Guan
- X. Yi
- Y. Chen
- G. Chen
- T. Lv
- Y. Song
Abstract
Background
Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), benefits patients with EGFR-T790M mutantion non-small-cell lung cancer (NSCLC) who fail treatment with first-generation EGFR TKIs. Identification of actionable genetic alterations conferring drug-resistance can be helpful for guiding the subsequent treatment decision. One of the major resistant mechanisms is EGFR-C797S mutation. Other mechanisms, such as MET amplifications and BRAF, and PIK3CA mutations, were also reported. In this study, we performed gene mutational profiling in a cohort of 117 EGFR-T790M NSCLC patients and acquired resistance to osimertinib using targeted NGS.
Methods
A total of 117 patients with stage IIIb-IV EGFR-T790M NSCLC were undergoing tumor biopsies, blood or serous effusions withdrawing by the time of acquiring resistance to osimertinib. We used targeted NGS to detect genes status of patients.
Results
In total, we identified 213 genetic alterations with a median of 4 mutations per patient. 58.12% (68/117) of patients still exhibit EGFR-T790M, 71.79% (84/117) of patients still exhibit EGFR sensitive mutations and 23.08% (27/117) of patients acquired EGFR-C797S mutations [Cis structure: 51.85% (14/27); Trans structure: 66.67% (18/27); Cis and trans structure coexistence: 18.52% (5/27)]. Besides other known resistance mechanisms, we identified MET amplification 16.24% (19/117) of patients, PIK3CA mutations in 10.26% (12/117) of patients, and KRAS mutations in 8.55% (10/117) of patients. Interestingly, we also observed TMPRSS2 and KIAA0226 mutations in EGFR-C797S/L718Q/L844V/L792F wild patients, which are restricted to osimertinib treatment resistance.
Conclusions
Our study uncovered mutational profiles of NSCLC patients with osimertinib resistance with potential therapeutic implications, and this study also is first study to depict the genetic landscapes comprehensively in Chinese NSCLC population resistant to osimertinib. Our analysis strongly suggests that MET amplification, PIK3CA mutations and KRAS mutations may serve as bypass resistance mechanisms in patients who are EGFR-C797S/L718Q/L844V/L792F wild type.
Legal entity responsible for the study
Chunwei Xu
Funding
None
Disclosure
All authors have declared no conflicts of interest.
415O - Prevalence of NTRK gene fusions in a large cohort of Japanese patients with lung cancer (ID 1308)
- A. Nakamura
- A. Nakamura
- H. UDAGAWA
- S. Matsumoto
- S. Sugawara
- M. Shingyoji
- A. Horiike
- I. Okamoto
- T. Hida
- S. Saeki
- Y. Ohe
- D. Ogawara
- Y. Kataoka
- Y. Miyata
- H. Mitsufuji
- S. Kuyama
- R. Kanemaru
- T. Kato
- A. Hirata
- K. Yoh
- K. Goto
Abstract
Background
Several actionable gene alterations, such as
Methods
A nationwide lung cancer genomic screening project in Japan (LC-SCRUM-Japan) was initiated from February 2013, and a total of 4118 lung cancer patients have been enrolled as of April 2017. A total of 2668 patients with lung cancer (non-squamous/squamous/small=2088/275/305) were screened by using a next generation sequencing platform, Oncomine™ Focus Assay (OFA) for detecting
Results
Only one patient with
Conclusions
The frequency of
Legal entity responsible for the study
National Cancer Center
Funding
Taiho, Chugai, Ono, Astra Zeneka, Bristol-Myers Squibb, MSD, Astellas, Eisai, DAIICHI SANKYO, Pfizer, Kyowa Hakko Kirin, Novartis, Takeda, Eli Lilly Japan, Merck Serono, Boehringer Ingelheim, Amgen
Disclosure
T. Hida: Ignyta, Y. Ohe: HONORARIA: AstraZeneca, Chugai, Lilly, ONO, BMS, Daiichi-Sankyo, Nipponkayaku, Boehringer Ingelheim, Bayer, Pfizer, MSD, Taiho RESEARCH FUNDING: AstraZeneca, Chugai, Lilly, ONO, BMS, Kyorin, Dainippon- Sumitomo, Pfizer, Taiho, Novartis, Merck Serono, CONSULTING OR ADVISORY ROLE: AstraZeneca, Chugai, Lilly, ONO, Novartis, S. Kuyama: HONORARIA: AstraZeneca, Meiji Seika, Boehringer Ingelheim, Lilly, Chugai, ONO, MSD, K. Yoh: Dr. Yoh has received personal fees as honoraria from Chugai, Eli Lilly, AstraZeneca, Taiho, Boehringer Ingelheim, Bristol-Myers Squibb, and Ono. His institution has received research funding from Pfizer, Taiho, Eli Lilly, AstraZeneca, Bayer and Novartis. K. Goto: Corporate-sponsored research: Taiho, Chugai, Ono, Astra Zeneka, Sumitomo Dainippon, Bristol-Myers Squibb, MSD, Astellas, Eisai, DAIICHI SANKYO, Pfizer, Kyowa Hakko Kirin, Novartis, Takeda, Eli Lilly Japan, Merck Serono, OxOnc, AbbVie Stemcentrx, Ignyta, Boehringer Ingelheim
All other authors have declared no conflicts of interest.
536O - Comprehensive genomic profiling (CGP) of thymic gland carcinomas (ID 1703)
- J. Creeden
- J. Creeden
- J. Ross
- P. Vanden Borre
- N. Almog
- A. Schrock
- J. Chung
- J. Vergilio
- J. Suh
- S. Ramkissoon
- S. Ali
- V. Miller
- P. Stephens
- J. Elvin
- L. Gay
Abstract
Background
Thymic gland carcinomas include a variety of histologic subtypes with variable clinical aggressiveness and response to local and systemic therapies. We queried whether CGP could refine tumor subtypes and uncover new targeted and immunotherapy options for patients with relapsed and metastatic disease (mTC).
Methods
FFPE sections of 174 consecutive cases of mTC was sequenced using hybridization-captured, adaptor ligation-based libraries to a mean coverage depth of > 500X for up to 315 cancer-related genes plus 37 introns from 28 genes frequently rearranged in cancer. Total mutational burden (TMB) was determined on 1.1 Mb. Clinically relevant genomic alterations (CRGA) were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials.
Results
All mTC were clinically advanced and included 4% adenocarcinomas (TAC), 3% basaloid (TBC), 3% lymphoepitheliomatous (TLEC), 17% neuroendocrine (TNEC), 31% non-NE undifferentiated (TNOS), 40% squamous and 2% sarcomatoid (TSRC) carcinomas (Table). mTC were twice as common in men than women, had a peak incidence in late middle age, and featured an average of 4 GA/case and 0.9 CRGA/case. The most common molecular targets were KIT and PIK3CA. Other targets were PDGFRA, FGFR3, PTCH1, FBXW7, BRCA2, IDH1, ERBB2 and ERBB3. The more frequent subtypes (TNEC, TSCC and TNOS) tended to have more GA, with KIT targets in ∼ 10% of cases. Low TMB in mTC was common; only 6% of cases had >10 mut/Mb and 3% had >20 mut/Mb. Examples of mTC with responses to targeted therapies will be presented.
Conclusions
mTC histologic subtypes have varying GA and TMB status. The more common TSCC, TNEC and TNOS feature more GA, and when combined with TAC have more CRGA including KIT mutations and higher TMB. CGP shows promise to guide both targeted and immunotherapy selection for patients with this rare malignancy.
Legal entity responsible for the study
Foundation Medicine, Inc.
Funding
None
Disclosure
J. Creeden: Employee of Roche, J. Ross, P. Vanden Borre, N. Almog, A. Schrock, J. Chung, J-A. Vergilio, J. Suh, S. Ramkissoon, S. Ali, V. Miller, P. Stephens, J. Elvin, L. Gay: Foundation Medicine (employment, equity)TAC TBC TLEC TNEC TNOS TSCC TSRC Patients 7 5 5 30 54 69 4 Median Age (y) 48 58 50 48 57 57 61 Gender 43% F 60% F 20% F 37% F 24% F 34% F 50%F GA/tumor 4.0 2.8 1.0 3.3 4.1 4.1 4.8 CRGA 0.9 0.3 0 0.9 0.8 1.0 1.0 Significant GA TMB >10 mut/Mb 14% 0% 0% 3% 5% 9% 0% TMB >20 mut/Mb 0% 0% 0% 3% 5% 9% 0%
395O - The clinical impact of PD-L1 protein expression in non-small cell lung carcinoma (ID 1977)
- N. Yanagawa
- N. Yanagawa
- S. Shiono
- S. Ogata
Abstract
Background
Programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) are important targets of immunotherapy and its expression has been closely correlated with response and survival benefit from anti-PD-1/PD-L1 immune checkpoint inhibitor therapies in advanced non-small cell lung carcinoma (NSCLC). But it is still unclear whether PD-L1 is prognostic. The aim of this study is to examine the proportion of PD-L1 protein expression in NSCLC and investigate the correlation with clinicopathological backgrounds including patient outcome.
Methods
A total of 899 NSCLC were examined. The male:female ratio was 550:349; the age range was between 32 and 89 years of age and the mean age was 68.9 years. Adenocarcinoma: Squamous cell carcinoma: Others’ ratio was 647:209:43 in histopathology. The follow up duration was from 0.4 months to 168.7 months and the mean duration was 62.2 months. PD-L1 expression was analyzed using immunohistochemistry (VENTANA; clone SP263) in stages I-IV NSCLC using tissue microarray. The PD-L1 staining percentage in tumor cells were scored as follows: 0, 0%; 1, 1-24%; 2, 25-49%; 3, ≥50%. The score of PD-L1 staining was correlated with clinicopathological backgrounds, molecular features and patient outcome.
Results
The score of PD-L1 staining was as follows: 0, 739/899 (82.2%); 1, 47/899 (5.2%); 2, 26/899 (2.9%); 3, 87/899 (9.7%). PD-L1 expression was associated with sex, smoking history, histology, tumor size, stage, pleural invasion, p53 protein expression, MIB-1 labeling index and EGFR mutation. We arranged the value of cut offs at ≥ 1%, ≥25%, ≥50% and investigated the correlation with patient outcome. In adenocarcinoma, the patients with any positive staining of PD-L1 (≥1%) had a trend of worse 5-year overall survival rate than those with negative staining of PD-L1 (73.5% vs. 79%, p = 0.096). In squamous cell carcinoma, PD-L1 expression was not prognostic with these cut offs. In multivariate analysis, PD-L1 expresssion was not independent prognostic factor in adenocarcinoma.
Conclusions
Our study shows PD-L1 protein expression is not a prognostic factor in NSCLC.
Legal entity responsible for the study
Naoki Yanagawa
Funding
None
Disclosure
All authors have declared no conflicts of interest.
416O - Mutation abundance affects the therapeutic efficacy of EGFR-TKI in patients with advanced lung adenocarcinoma: A retrospective analysis (ID 1069)
- H. Wang
- H. Wang
- M. Zhang
- G. Zhang
- J. Ma
- Z. Ma
Abstract
Background
To detect the mutation abundance and sites of epidermal growth factor receptor (EGFR), and to investigate their influence on the therapeutic efficacy of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) in patients with advanced non-small cell lung carcinoma (NSCLC).
Methods
A total of 2,417 NSCLC patients with EGFR gene mutations were retrospectively analyzed using an amplification refractory mutation system (ARMS). Of 861 patients, 407 patients had exon 19 deletions and 454 patients had exon 21 (L858R) site mutations of the EGFR gene. Next we analyzed the mutation abundance of lung adenocarcinoma patients who received EGFR-TKI therapy and complete follow up. 194 patients diagnosed with stage IIIB or stage IV lung adenocarcinoma with an ECOG score of 0-3 were enrolled. The primary endpoint was to determine associations between progression-free survival (PFS) and mutation abundance or mutation sites after EGFR-TKI therapy. The secondary endpoint was to evaluate the objective response rate and effects when EGFR-TKI was administered as the first-line treatment, as well as risk factor analysis for PFS.
Results
Of the 194 enrolled patients, the median PFS was 9.3 months (95% CI, 8.2–10.8 months). The PFS was significantly different with EGFR gene mutation abundance after EGFR-TKI therapy (
Conclusions
The PFS benefits were greater in patients with a higher abundance of exon 19 mutations in the EGFR gene after EGFR-TKI treatment.
Legal entity responsible for the study
Huijuan Wang
Funding
None
Disclosure
All authors have declared no conflicts of interest.
Discussion (ID 2156)
- H. Loong
- E. Smit
- H. Loong
- E. Smit