Journal Thoracic Oncology

Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017
SESSION SC04: EGFR TYROSINE KINASE INHIBITORS:A
MODEL FOR SUCCESSFUL DRUG DEVELOPMENT
MONDAY, DECEMBER 5, 2016
SC04: EGFR TYROSINE KINASE INHIBITORS: A MODEL FOR SUCCESSFUL DRUG
DEVELOPMENT
MONDAY, DECEMBER 5, 2016 - 11:00-12:30
SC04.02 MANAGEMENT OF RESISTANCE TO EGFR TYROSINE
KINASE INHIBITORS
Tetsuya Mitsudomi
Thoracic Surgery, Kindai University Faculty of Medicine, Osaka-Sayama/Japan
Discovery of activating mutations of the EGFR gene in adenocarcinoma of
the lung in 2004 opened the door to a new era for personalized therapy in
thoracic oncology. Lung cancers with EGFR mutation are highly sensitive to
EGFR-tyrosine kinase inhibitors (TKI) such as gefitinib, erlotinib, or afatinib,
resulting in significantly prolonged progression free survival compared with
those treated with platinum doublet chemotherapy. However, acquired
resistance inevitably develops usually after a median of 10~12 months. The
mechanisms for this resistance have been extensively studied and can be
classified into 1) target gene alteration, 2) activation of bypass / accessory
pathway, and 3) histologic transformation (Fig.).
using other mechanisms. Heterogeneities in terms of resistant mechanisms
within a single patient become evident when specific therapeutic pressure
persists. Therefore, we also need to have armamentarium that utilizes
other mechanisms to cure lung cancer. Recent advances of immunotherapy
targeting immune checkpoints appear attractive in this respect. These
mechanism-driven therapeutic approaches will convert this fatal disease into
a more chronic disorder, and eventually into a curable disease with the least
patient burden.
Keywords: Adenocarcinoma, EGFR, Resistance, T790M
SC04: EGFR TYROSINE KINASE INHIBITORS: A MODEL FOR SUCCESSFUL DRUG
DEVELOPMENT
MONDAY, DECEMBER 5, 2016 - 11:00-12:30
SC04.03 SEQUENCING OF EGFR TYROSINE KINASE INHIBITORS
Keunchil Park
Div of HEM/ONC, Samsung Med Ctr, Sungkyunkwan Univ School of Med, Seoul/
Korea, Republic of
Treatment of EGFR-mutant (EGFRm) lung cancer with specific EGFR TKIs,
such as gefitinib, erlotinib or afatinib, has opened the door to the precision
medicine in the management of advanced non-small cell lung cancer with
remarkable tumour shrinkage and improvement in progression-free survival
(PFS) and quality of life compared to standard chemotherapy. Despite such
a remarkable initial clinical response with EGFR TKIs in patients with EGFR+
NSCLC, however, the disease eventually comes back with the emergence of
acquired resistance and median PFS is ~ 1 year. The most common mechanism
of resistance is acquisition of the T790M gatekeeper mutation and the
3rd-generation EGFR TKIs irreversibly inhi bit mutant EGFR, esp. T790M,
with sparing wild-type(WT) EGFR. There are several EGFR mutant specific
inhibitors (EMSIs) under development including AZD9291, CO-1686, BI1482694
/HM61713, ASP8273, etc.
All these 3rd-generation EGFR TKIs have shown a promising early clinical
efficacy in T790M(+) EGFRm NSCLC patients with ORR of ca. 60% and PFS
of 9.6 – 10.3 months and appear to be well tolerated. Based upon these
encouraging early results many confirmatory phase 3 trials(e.g., NCT02151981,
NCT02322281) comparing to the standard chemotherapy in the 2nd-line
setting are underway.
The most common (50~60%) mechanism for acquired resistance to the
EGFR-TKI is a missense mutation at codon 790 of the EGFR gene resulting in
substitution of threonine to methionine (T790M). This amino acid change
reduces affinity between EGFR kinase and EGFR-TKI compared with that
between EGFR-kinase and ATP, leading to reactivation of down-stream
pathways. L747S, D761Y, and T854A are also known as secondary mutations
that cause acquired resistance, but they are very rare. In these cases, cancer
cells are still addicted to or dependent on EGFR pathway. Amplification of
the MET gene which codes for a receptor of hepatocyte growth factor (HGF)
was the first that was identified as a bypass track resistance mechanism
against EGFR-TKI. Following this report, aberrant activation of other receptor
tyrosine kinases such as HER2, HER3, AXL, IGF1R, have been reported. It is
also shown that some ligands for the receptor tyrosine kinases such as HGF,
FGF or IGF cause acquired resistance to EGFR-TKIs. Similarly, alteration of
downstream molecule cause resistance. These molecules include BRAF,
PTEN, JAK2, CRKL, DAPK, NF-kB, or PUMA. The third mechanism of acquired
resistance is histologic transformation that includes small cell lung cancer
transformation and epithelial-mesenchymal transition EMT). Exact
mechanisms of these histologic changes are not fully understood. However,
AXL, Notch-1, TGFb pathway activation as well as down regulation of MED12
((Mediator Complex Subunit 12) have been proposed as mechanisms of EMT.
Then, How are we able to cope with these resistance? For T790M gatekeeper
mutations, the third generation EGFR inhibitors that selectively inhibit
EGFR-T790M while sparing the wild-type EGFR are active. One of these
drugs, osimertinib is already approved and gives a response rate of ~60%
and progression free survival of ~11 months. Therefore, identification of
T790M at the time of disease progression by rebiopsy is important. We
have recently found that three other secondary EGFR mutations implicated
in acquired resistance are also sensitive to osimertinib. Tumor resistance
caused by activation of accessory pathways can be theoretically coped with
by combination of the inhibitor of EGFR and involved molecules. However,
because of rarity of each mechanism, there is no clear evidence whether
these combination therapies will actually improve patient outcome In other
cases, cytotoxic chemotherapy is still an important strategy. According to
the IMPRESS study, median progression free survival for patients without
T790M who received cisplatin plus pemetrexed was 5.4 months. Eeven with
these strategies, cancer cells are smart enough to escape from the therapy
It is very tempting that one might like to move the 3rd-generation EGFR TKI
to 1st-line setting. The development of the 3rd-generation agents as the firstline
therapy for patients with EGFRm disease has already started. Recently
AZD9291 demonstrated an encouraging clinical activity and a manageable
tolerability profile in 1st-line: confirmed objective response rate of 77%
(95% CI 64, 87) and mPFS of 19.3 months (investigator-assessed). Currently
it is being compared with the 1st/2nd-generation EGFR TKI in the 1st-line
setting. The Phase III FLAURA study (NCT02296125), comparing AZD9291 80
mg once daily versus current standard of care EGFR-TKIs for treatment-naïve
patients, is enrolling. Though the preliminary result in the 1L setting is quite
provocative, extreme caution needs to be exerted since the currently available
data are not mature enough to determine which agent is the best in its class
and only from a small subset of patients.
Though it is hoped that the T790M-mediated resistance can be delayed or
prevented by using the EMSIs in the TKI-naïve setting, it is also possible that
other less well known escape mechanisms might emerge. Given that EMSI
works well after failing 1st/2nd-generation EGFR TKI I believe it seems to be
a more reasonable approach to investigate if EMSI in the TKI-naïve setting
is more effective than 1st/2nd-generation EGFR TKI followed by EMSI when
failing 1st/2nd-generation EGFR TKI with acquired resistance.
One of the biggest questions to emerge in the era of next-generation
inhibitors that have activity against the basic driver oncogene is whether
it makes sense to use this approach before the development of acquired
resistance to prevent it from occurring in the first place. Can its use in the 1stline(TKI-naïve)
setting prevent the development of acquired resistance and
lead to a longterm control of the disease?
Considering the well-known genomic heterogeneity with its possible
association with resistance to EGFR TKIs we need better understanding of the
biology and resistance mechanisms to this class of new generation EGFR TKIs
in order to develop better strategies for subsequent therapies to overcome
the resistance including how to best sequence the available EGFR TKIs in the
clinic as well as combination therapies.
It is fair to say that during the past few years we’ve clearly made another
progress in the management of NSCLC patients with EGFRm, including those
who failed previous EGFR TKIs. However, the currently available data are
not mature enough to determine which agent is the best in its class, with
the notable differences primarily related to toxicity and we’re not there yet
and still lots of unanswered questions remain and further researches are
warranted.
S42 Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017