Journal Thoracic Oncology

Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017
mechanism of which is even more complicated. Recently, by conducting next
generation sequencing (NGS) through peripheral blood samples of patients
treated with AZD9291 and CO1686 in clinical trials, newly drug-resistant
mutations such as C797S and C693I have been found and functionally
verified. This has laid a solid foundation for developing the fourth generation
medicine in future undoubtedly. In the meanwhile, the resistant mechanism
to ALK-TKI is also very complex. Multiple drug-resistant mutations could not
only occur in ALK kinase domain, but also in alternative signal pathways.
Therefore, we should establish a real-time, dynamic and quantitative
detecting system for multiple targetable genes to fulfill detecting and
monitoring the drug resistance during treatment, and on the other hand,
to explore novel drug-resistant mutations through NGS of peripheral blood
samples in future. Checkpoint inhibitors have been studied and utilized
in various cancers, which has changed the perennially stagnant situation
of immunotherapy and opened a new chapter in the treatment of cancers.
Studies have shown an objective response rate of approximately 20%-30%
with a prolonged survival period of 3-6 months to a series of programed death
(PD1)/ programed death-ligand 1(PD-L1) inhibitors immunotherapy in lung
cancer patients, with adenocarcinomas, squamous cell carcinomas and small
cell carcinomas. While the biggest challenge of immunotherapy currently is to
establish a powerful predictive system for efficacy. The existing researches
mostly focus on exploring whether the PD-L1 expression or tumor infiltrating
lymphocytes (TIL) status could predict the efficacy of PD1/PD-L1 inhibitors.
The results varied from different agents of PD1/PD-L1 inhibitors and results
of different trails. For instance, PD-L1 expression was associated with
response to Nivolumab in patients with lung adenocarcinoma, while this kind
of relationship was not observed in squamous cell NSCLC. The inconsistency
between different trails may be attributed to the heterogeneity of PD-L1
expression, the unstandardized sample collecting and storing, and issue in
IHC evaluation system. So the future investigation should lay more emphasis
on overcoming tumor heterogeneity, standardization and optimization of
detection techniques and sample collections, based on which we are looking
forward to more effective predictive biomarkers. Both tumor and host
microenvironment should be equally important as the foundation of precision
medicine for cancer. More and more studies show that mutation loads of
somatic cells contribute to immunogenicity of tumors, so as to be associated
with the efficacy of checkpoint inhibitors. One research showed that different
types of mutations, such as EGFR mutation, ALK fusion gene and PI3KCA
mutation, possess different levels of mutation loads. And another research
indicated that lung adenocarcinoma with higher neoantigen-load responded
better to checkpoint inhibitors than the lower ones. There has been a study
to calculate mutation loads and neoantigens in adenocarcinoma or squamous
carcinoma by whole Exome sequencing based on the Cancer Genome Atlas
(TCGA). The future studies should pay close attention to exploring the
dynamic change patterns of mutation loads and neoantigens prior and during
the treatment strategies, including PD-1/PD-L1 inhibitors immunotherapy,
targeted therapy and traditional chemotherapy, and also to investigate the
relationship between regulatory immune factors in the microenvironment,
to further establish the predictive system for immunotherapy integrating
PD-L1,PD-L2, TIL mutation loads of somatic cells, and neoantigens which are
in great expectations.
Keywords: Immune checkpoint inhibitors, biomarker, dynamic change,
Targeted Therapies
MTE09: BIOMARKERS FOR TARGETED THERAPIES AND IMMUNE CHECKPOINT
INHIBITORS IN ADVANCED NSCLC (TICKETED SESSION)
MONDAY, DECEMBER 5, 2016 - 07:30-08:30
MTE09.02 BIOMARKERS FOR TARGETED THERAPIES AND IMMUNE
CHECKPOINT INHIBITORS IN ADVANCED NSCLC
Sabine Zöchbauer-Müller
Department for Internal Medicine I, Medical University of Vienna, Vienna/Austria
Targeted therapies or immune checkpoint inhibitors may be the adequate
treatment in some patients with advanced non-small cell lung cancer (NSCLC).
So far, certain biomarkers are known which may predict tumor response to
these drugs. Of major importance is the detection of activating epidermal
growth factor receptor (EGFR) mutations. They occur more frequently
in the asian compared to the caucasian population and are usually found
within exon 18-20 of the EGFR gene. Most of them are either a deletion at
exon 19 or the L858R point mutation at exon 21. Activating EGFR mutations
are predominantly detected in female patients with adenocarcinoma
histology and never (or low) smoking history. The efficacy of first (erlotinib,
gefitinib) and second (afatinib) generation EGFR tyrosine kinase inhibitors
(TKI) in patients with advanced NSCLC and an activating EGFR mutation
was demonstrated in several clinical studies. However, at some time during
treatment with a first- or second generation TKI usually resistance to these
drugs occurs which is mediated by the EGFR T790M mutation in about 50%.
Recent trials demonstrated that third generation EGFR TKIs like osimertinib
and olmutinib may be effective in T790M mutation positive patients with
an overall objective tumor response rate of about 60%. Another molecular
aberration which is of importance for treatment decision in patients with
advanced NSCLC is the rearrangement of the anaplastic lymphoma kinase
(ALK) gene. It was demonstrated that patients with an ALK rearrangment do
benefit from therapy with the ALK inhibitor crizotinib. Second generation ALK
inbibitors (e.g. alectinib, brigatinib, ceritinib) can overcome resistance which
may be mediated by secondary ALK mutations. Moreover, third generation
ALK inhibitors (e.g. lorlatinib) were developed and are currently being tested.
Similar to patients with an ALK rearrangement also patients with a ROS1
rearrangement may benefit from treatment with crizotinib. The relevance
of other molecular characteristics like KRAS or BRAF mutations, c-met
amplification and HER2 abnormalities as potential biomarkers for targeted
therapies is currently under investigation. Programmed death 1 (PD-1)
immune checkpoint inhibitor antibodies like nivolumab or pembrolizumab are
used in the clinical routine, however, only about 20% of patients do benefit
from this treatment. To use resources as effective as possible, a biomarker
to predict tumor response to these type of drugs would be enormous helpful
in order to save costs. So far, the impact of expression of the PD ligand 1
(PD-L1) regarding clinical benefit to PD1 and PD-L1 inhibitor therapy was,
besides efficacy of these drugs in comparison to chemotherapy, investigated
in several randomized clinical trials. While in the CheckMate 017 study the
overall survival of squamous cell carcinoma patients treated with nivolumab
was independent from PD-L1 expression on tumor cells, in the CheckMate 057
study there seems to be some association between the PD-L1 expression level
and the overall survival of adenocarcinoma patients treated with nivolumab.
In the KEYNOTE-010 trial especially patients (both squamous cell and
adenocarcinoma histology) with high (≥ 50% score) PD-L1 expression on tumor
cells did benefit from treatment with pembrolizumab. PD-L1 expression on
tumor cells as well as on tumor infiltrating immune cells were investigated in
patients treated with the PD-L1 inhibitor atezolizumab in the POPLAR study.
The overall survival benefit from atezolizumab increased with increasing
PD-L1 expression on tumor cells, tumor infiltrating immune cells or both.
Overall, currently the impact of PD-L1 expression and the use of certain cut-off
levels to predict response to PD-1 and PD-L1 inhibitors is still under discussion.
Different findings may, at least partly, be explainded by the use of variables
regarding tissue fixation and storage as well as by different antibodies for
detection of PD-L1. Alternative biomarker approaches are currently being
investigated. In particular, the mutational load as well as the number of
predicted neoantigens may be of importance. An association between
a higher nonsynonymous mutation burden in tumors and an improved
objective reponse, durable clinical benefit as well as progression-free survival
in patients treated with pembrolizumab was reported and, in addition,
the efficacy was associated with the molecular smoking signature, higher
neoantigen burden and DNA repair pathway mutations. Overall, additional
studies are necessary to definitely define the impact of PD-L1 expression as
biomarker for PD-1 and PD-L1 inhibitors as well as to investigate the value of
alternative biomarkers. In conclusion, strong biomarkers are able to predict
response to certain therapies. Thus, ineffective treatment strategies may
be prevented and resources including costs may be saved. So far, a few
biomarkers are known which are very well established in the clinical routine
and are important for treatment decisions in NSCLC patients. Regarding
immunotherapy, it seems that the expression of PD-L1 may has some impact
to predict response to PD-1 and PD-L1 inhibitors, however, its role needs to
be completely clarified. Several candidate biomarkers exist, however, their
impact needs to be futher investigated.
Keywords: EGFR, ALK, ros1, PD-L1
SESSION MTE10: UNIQUE BIOLOGIC ASPECTS OF TOBAC-
CO-INDUCED LUNG CANCER (TICKETED SESSION)
TUESDAY, DECEMBER 6, 2016 - 07:30-08:30
MTE10.01 UNIQUE BIOLOGIC ASPECTS OF TOBACCO-INDUCED
LUNG CANCER
Mauro Papotti, Giorgio Scagliotti
Oncology, University of Turin, Orbassano Turin/Italy
Lung cancer is the leading cause of cancer death worldwide and cigarette
smoking is a major causative environmental factor. Some unique biologic
profiles are associated to tobacco-induced lung cancer, including clinical,
pathological and genetic features. Lung cancer in never smokers (up to 20%
of cases worldwide) has been suggested to represent a distinct disease,
compared to tobacco-induced lung cancer. Cigarette smoke is a mixture
of more than 5000 chemical compounds, among which more than 60 are
recognized to have a specific carcinogenic potential. Carcinogens and their
metabolites (i.e., N-nitrosamines and polycyclic aromatic hydrocarbons,
among others) can activate multiple pathways, contributing to pulmonary
cell transformation in different ways. Nicotine, originally thought to be
responsible for tobacco addiction, only, is also involved in tumor promotion
Copyright © 2016 by the International Association for the Study of Lung Cancer
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