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latest innovations in nsclc management
81IN PERSONALIZED THERAPY AND BIO-MOLECULAR DRIVEN
TREATMENT IN LUNG CANCER
T. Mitsudomi
Department of Thoracic Surgery, Kinki University Faculty of Medicine,
Osaka-Sayama, JAPAN
Discovery of activating mutation of the EGFR gene in 2004 opened the era of
personalized therapy in thoracic oncology. These tumors are highly dependent on
the EGFR pathway and inhibition of this pathway results in dramatic induction of
apoptosis in vitro, even though cancer cells may have various genetic alterations
(oncogene addiction). These observations were soon translated into clinical trials.
Recent 4 phase III clinical trials for patients with EGFR mutation (NEJ 002,
WJTOG3405, OPTIMAL, EURTAC) reproducibly showed significantly longer
progression free survival for those treated with EGFR-tyrosine kinase inhibitors
(TKI) than those treated with platinum doublet chemotherapy. Although there was
no difference in overall survival probably due to high crossover rate, it was
noteworthy that 40% of patients in EGFR-TKI arm were able to go without
platinum doublet and yet had similar survival outcome in WJTOG3405 In 2007, it
was found that ∼5% of adenocarcinoma of the lung harbors EML4-ALK
translocation and that these tumors are also addicted to the ALK pathway. Clinical
development of the first ALK-TKI, crizotinib, focusing on tumors with ALK
translocation was quick in spite of its rarity. Just 4 years after discovery of
EML4-ALK, crizotinib was approved by FDA for lung cancer with ALK
translocation in 2011 We have learned how effective the targeted therapy is, when
“addicted oncogene” was pharmacologically inhibited. List of addicted oncogenes is
expanding continuously and now it includes HER2, ROS1 or RET in
adenocarcinoma of the lung. Efforts are also being made to identify addicted
oncogenes in squamous cell carcinoma. Variant III of the EGFR gene, mutations of
the DDR2 gene, amplification of the FGFR1 gene seem to be attractive targets of
therapy. However, even in patients with dramatic initial response in these addicted
tumors, resistance almost inevitably develops typically after less than 1 year.
Mechanisms of the resistance include secondary mutation of the targeted gene and
activation of alternative pathways. The future clinical trials should be based on
individual mechanism found in re-biopsy specimens. It is also a challenge how
efficaciously these oncogene alterations are identified in each clinical specimen.
Disclosure: T. Mitsudomi: I received honorarium from AstraZeneca, Chugai,
Elo-Lilly, Pfizer, Daiichi-Sankyo and Taiho. I also served as an advisory board for
Boehringer-Ingelheim, Pfizer, AstraZeneca, Chugai, Eli-Lilly, Merck-Serono.
82IN MOLECULAR MECHANISMS OF ACQUIRED RESISTANCE
TO KINASE INHIBITORS
L.V. Sequist
Cancer Center, Massachusetts General Hospital, Boston, MA, UNITED STATES
OF AMERICA
The discovery of mutations in the epidermal growth factor receptor (EGFR) gene was
been a turning point in clinical lung cancer care. We now know from multiple phase 3
randomized clinical trials that patients with advanced lung cancer should be screened
for EGFR mutations at the time of diagnosis and that first-line genotype-specific
therapy with EGFR tyrosine kinase inhibitors (TKIs) can improve progression-free
survival and quality of life compared to standard chemotherapy. In the last few years
we have seen other examples of successful genotype-directed therapy for lung cancers
with ALK and ROS translocations. However, one significant obstacle that we face in
the clinic today is the development of acquired resistance to therapy. In this lecture, we
will review what is known about acquired resistance to TKI therapies and discuss
possible strategies for treating and/or preventing acquired resistance.
Disclosure: L.V. Sequist: I have done paid consulting for Clovis Oncology and GSK.
I have done pro-bono consulting for Merrimack Pharmaceuticals,
Boehringer-Ingelheim and Daiichi-Sankyo
Annals of Oncology 23 (Supplement 9): ix51–ix52, 2012
doi:10.1093/annonc/mds386
83IN NEW STRATEGIES ON THE HORIZON
T.S.K. Mok
Department of Clinical Oncology, Chinese University of Hong Kong Prince of
Wales Hospital, Shatin, Hong Kong, CHINA
Since the discovery of activating epidermal growth factor receptor (EGFR) mutation
in 2004, personalized therapy for patient with advanced non-small lung cancer
(NSCLC) has become a reality. EGFR TKI and ALK inhibitor are standard treatment
for pt with the target. Mutational status of signalling genes is key to management of
lung cancer. Base on this principles, there are a number of new treatment strategy on
horizon. Clinical application of genome profiling is a strategy that may improve the
outcome of personalized therapy. Population genome profiling has provided
important information on patients with adenocarcinoma. A number of population
based genome profile from patients with adenocarcinoma in USA, France, China and
Japan have been reported. EGFR mutation is more common in Asian population
while KRAS mutation is much less common. Other mutations on ALK, BRAF,
HER-2, PI3K, or MET are less frequent and similar across population. Future
strategy will be personal genome profiling. With the improvement in efficiency and
reduction in cost of second-generation sequencer, it will be feasible and practical to
formulate treatment strategy according to genome profile. However, genome profile
may vary over time and between tumors. Genomic heterogeneity must be addressed
if attempt is comprehensive control of all tumor sites by a single targeted therapy.
Gerlinger et al (NEJM 366:883, 2012) performed extensive exome sequencing from
multiple site of renal cells tumor and its metastasis, and found 63 to 69% of somatic
mutations are not consistently present in all tumor regions. Intra-tumor
heterogeneity included the mTOR gene which is the primary target for approved
therapy such as everolimus. Thus authors concluded that single site needle biopsy
may not be representative of the genomic status of the tumor. Other examples
including pancreatic cancer and breast cancer also review similar heterogeneity.
There is no reason to believe lung cancer to be different. New strategy must be form
to address tumor heterogeneity. In summary, new treatment strategies included
individualized genome profiling and study of tumor heterogeneity. More specifically
there should be upcoming treatment strategy for KRAS mutation and squamous cell
carcinoma.
Disclosure: T.S.K. Mok: Consultancy with Astrazeneca, Roche, Pfizer, Eli Lilly,
Merck Serono, Beigene, Eisai, Jannsen, Taiho Speaker engagment with Astrazeneca,
Roche, Pfizer, Eli Lilly, Merck Serono
84IN BREAKTHROUGHS IN BASIC RESEARCH
P.A. Janne
Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, MA,
UNITED STATES OF AMERICA
Over the last few years several basic research studies have led to new therapeutic
insights into the treatment of patients with advanced non-small cell lung cancer
(NSCLC). These include genomic studies of lung cancers which have revealed
novel potential therapeutic targets. One such target is fibroblast growth factor
receptor (FGFR) 1 which has been found to be amplified in a subset of
squamous cell lung cancers. Preclinical studies have further demonstrated that
inhibition of FGFR1 kinase activity using FGFR tyrosine kinase inhibitors (TKIs)
may be clinically effective in this subset of NSCLC. Clinical trials are now
underway using FGFR TKIs in this subset of NSCLC. A second example is the
identification of novel genomic rearrangements of the RET oncogene in NSCLC.
These rearrangements lead to a fusion gene (KIF5B-RET) which is transforming
in vitro and in vivo. Several already approved kinase inhibitors, including
vandetinib, sorafenib and sunitinib, also inhibit RET and may be effective as
clinical therapies in this subset of NSCLC. In addition, several more potent RET
TKIs are under preclinical development and undergoing validation in model
systems. A second recent basic science advance is the use of mouse models of
lung cancer to mirror ongoing or planned clinical trials. These “co-clinical” trials
aim to use the murine models to determine if they can predict the outcome of
human trials and/or be used to further understand the success and limitations of
the therapeutic approach. A recent example evaluated docetaxel and the MEK
inhibitor selumetinib compared to docetaxel alone in a genetically engineered
© European Society for Medical Oncology 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
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