NcXHF

THE BATTLE AGAINST TKI RESISTANCE IN LUNG CANCER
sible? Will blood-based markers, such as circulating
free DNA, become a way for clinicians to adequately
assess resistance mechanisms?
• How do we design and implement novel clinical trials
that take into consideration the rapid pace of scientifıc
discovery and the demand to bring more effective therapies
into the forefront of care? Furthermore, how do we
design these trials to encompass systematic analysis of
biomarkers that are found in increasingly smaller percentages
of patients? Cooperative group trials, such as
the NCI ALK Master Protocol, which is currently being
developed, will certainly assist in achieving this design
goal.
• What other effective combination therapies can be devised
to tackle the problem of TKI resistance? Will cotreatment
with different classes of drugs, such as TKIs
and immune checkpoint inhibitors, be effective in overcoming
resistance? How should these agents be dosed:
simultaneously or sequentially?
• Finally, how can cutting-edge studies of TKI resistance
in NSCLC be translated to other malignancies? Many of
the current and emerging therapeutic targets in NSCLC,
such as ALK, ROS1, and RET, also are found in other
malignancies. To more broadly tackle and surmount the
problem of acquired resistance, studies in NSCLC, we
hope, can be used to inform management in distinct tumor
types that harbor these same targets.
Overall, a thorough understanding of the mechanistic basis
for acquired resistance and the development of innovative
therapeutic strategies to overcome resistance are paramount
to most effectively combat resistance and, therefore, to improve
the care of patients who have lung cancer.
ACKNOWLEDGEMENT
Christine M. Lovly was supported by National Institutes of
Health Awards R01CA121210 and P01CA129243, a Damon
Runyon Clinical Investigator Award, and a LUNGevity
CAreer Development Award.
Disclosures of Potential Conflicts of Interest
Relationships are considered self-held and compensated unless otherwise noted. Relationships marked “L” indicate leadership positions. Relationships marked “I” are those held by an immediate
family member; those marked “B” are held by the author and an immediate family member. Institutional relationships are marked “Inst.” Relationships marked “U” are uncompensated.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: Christine M. Lovly, Harrison and Star. Consulting
or Advisory Role: Christine M. Lovly, Novartis, Pfizer. Speakers’ Bureau: Christine M. Lovly, Abbot Molecular, Qiagen. Research Funding: Christine M. Lovly,
Astra Zeneca, Novartis. Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: None.
Other Relationships: None.
References
1. Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are
common in lung cancers from “never smokers” and are associated with
sensitivity of tumors to gefıtinib and erlotinib. Proc Natl Acad SciUSA.
2004;101:13306-13311.
2. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal
growth factor receptor underlying responsiveness of non-small cell
lung cancer to gefıtinib. N Engl J Med. 2004;350:2129-2139.
3. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation
with clinical response to gefıtinib therapy. Science. 2004;304:
1497-1500.
4. Mok TS, Wu YL, Thongprasert S, et al. Gefıtinib or carboplatinpaclitaxel
in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947-
957.
5. Maemondo M, Inoue A, Kobayashi K, et al. Gefıtinib or chemotherapy
for non-small cell lung cancer with mutated EGFR. N Engl J Med. 2010;
362:2380-2388.
6. Mitsudomi T, Morita S, Yatabe Y, et al. Gefıtinib versus cisplatin plus
docetaxel in patients with non-small-cell lung cancer harbouring
mutations of the epidermal growth factor receptor (WJTOG3405):
an open label, randomised phase 3 trial. Lancet Oncol. 2010;11:121-
128.
7. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy
as fırst-line treatment for European patients with advanced
EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre,
open-label, randomised phase 3 trial. Lancet Oncol. 2012;13:
239-246.
8. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or
cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma
with EGFR mutations. J Clin Oncol. 2013;31:3327-3334.
9. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy
in advanced ALK-positive lung cancer. N Engl J Med. 2013;368:2385-
2394.
10. Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy
in ALK-positive lung cancer. N Engl J Med. 2014;371:
2167-2177.
11. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase
inhibition in non-small cell lung cancer. N Engl J Med. 2010;363:1693-
1703.
12. Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in
patients with ALK-positive non-small cell lung cancer: updated results
from a phase 1 study. Lancet Oncol. 2012;13:1011-1019.
13. Ladanyi M, Pao W. Lung adenocarcinoma: guiding EGFR-targeted
therapy and beyond. Mod Pathol. 2008;21(suppl 2):S16-S22.
14. Fukuoka M, Wu YL, Thongprasert S, et al. Biomarker analyses and fınal
overall survival results from a phase III, randomized, open-label, fırstline
study of gefıtinib versus carboplatin/paclitaxel in clinically selected
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e171