TARGETED THERAPY FOR THE TREATMENT OF METASTATIC LUNG ADENOCARCINOMA
A CASE STUDY
Bohdan KADLEC, Jana SKŘIČKOVÁ
Klinika nemocí plic a tuberkulózy LF MU a FN Brno
MUDr. Bohdan Kadlec, Ph.D.
Department of pulmonary diseases and TB LF MU a FN Brno

1.png
NSCLC classification is evolving from histological to molecular subtyping of the tumor
•EGFR mutation shows approximately 10% NSCLC in the "western" population and 30% - 40% of tumors in
the Asian population
2
Li T, King H-J, Mack DC, et al. J Clin Oncol. 2013;31:1039-1049.
Histological subtypes of NSCLC
AKT, protein kinase B; ALK, anaplastic lymphoma kinase; Amp, amplification; BRAF, serine-threonine
kinase type B; DDR2, type 2 receptor tyrosine kinase; FGFR, fibroblast growth factor receptor;
HER2, type 2 human epidermal growth factor receptor; KRAS, plasma tyrosine kinase;
MAP2K1mitogen-activated protein kinase type1; NRAS, plasma tyrosine kinase; PIK3CA,
alpha-4,5-diphosphate 3-kinase catalytic subunit; RET, receptor tyrosine kinase; ROS1, receptor
tyrosine kinase
ALK
HER2
BRAF
PIK3CA
AKT1
MAP2K1
NRAS
ROS1
RET
EGFR
KRAS
Unknown
EGFR
EGFR
Adenokarcinoma
Squamous carcinoma
EGFRvIII
PIK3CA
EGFR
DDR2
FGFR1 Amp
Unknown
Adenocarcinoma
55%
Jiné
11%
Squamous
carcinoma
34%

Traditional histological subtyping of NSCLC gives way to molecular profile determination
> 50% of adenocarcinomas show the presence of control mutations, some of which can be specifically
targeted
EGFR mutations are among the most common and are also the most common targets of specifically
targeted therapies
squamous
Reference
Li T, Kung HJ, Mack PC, Gandara DR. Genotyping and genomic profiling of non-small-cell lung cancer:
implications for current and future therapies. J Clin Oncol. 2013;31(8):1039-1049.

Resistance due to an acquired mutation is the most common cause of disease progression1
3
Lung carcinoma cell with EGFR sensitive mutation
1.png 1.png
Initial answer
  to TKI
The appearance of an acquired mutation, for example
T790M
Progression
during TKI treatment
End of TKI
treatment due to tumor progression
Lung cancer cell
with aquired resistant mutation
Metastatic
EGFRm NSCLC
Most patients with metastatic EGFRm NSCLC progress within 8–14 months during first-line TKI
treatment2
1. Diagram adapted from Sacher AG, Jӓnne PA, Oxnard GR. Cancer. 2014;120:2289-2298. 2. Langer CJ. J
Clin Oncol. 2013;31:3303-3306.

Most patients develop 1.2 after the initial response to TKI treatment
Targeted treatment creates selection pressure on the tumor cell population, thereby enabling the
proliferation and growth of other mutated cell types. This results in an increase in the treatment
of refractory tumor cells and tumor progression 2
Clinically, progression occurs when a critical amount of refractory cells 3.4 has been reached
References
1.Sacher AG, Jänne PA, Oxnard GR. Management of acquired resistance to epidermal growth factor
receptor kinase inhibitors in patients with advanced non-small cell lung cancer. Cancer.
2014;120(15):2289-2298.
2.Kosaka T, Yamaki E, Mogi A, Kuwano H. Mechanisms of resistance to EGFR TKIs and development of a
new generation of drugs in non-small-cell lung cancer. J Biomed Biotechnol. 2011;2011:165214.
3.Kwak EL, Sordella R, Bell DW, et al. Irreversible inhibitors of the EGF receptor may circumvent
acquired resistance to gefitinib. Proc Natl Acad Sci U S A. 2005;102(21):7665-7670.
4.Landi L, Cappuzzo F. Irreversible EGFR-TKIs: dreaming perfection. Transl Lung Cancer Res.
2013;2(1):40-49.

EGFR T790M mutations are among the most common causes of acquired resistance to EGFR TKI treatment
•Nearly two-thirds of patients with metastatic EGFRm NSCLC who progressed to EGFR TKI treatment had
the presence of an acquired EGFR T790M mutation
4
Yu HA, Arcila ME, Rekhtman N, et al. Clin Cancer Res. 2013;19:2240-2247.
Frequencies of different mechanisms of acquired resistance.

524/5000
In a study of 155 patients with EGFRm NSCLC and radiographic progression after initial response or
disease stabilization in first-generation EGFR-TKI therapy, the EGFR T790M mutation was the most
common cause of acquired TKI resistance, observed in approximately 2/3 of treated patients (95 % CI
55% -70%) 1
Other causes of resistance were, among others, amplification of HER2 and MET1
Rare mechanisms leading to the development of resistance are mutations PIK3CA, BRAF, FGFR, and
transformation of tumor cells to small cell type2
References
1.Yu HA, Arcila MA, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired
resistance to EGFR TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res.
2013;19(8):2240-2247.
2.Gerber D, Gandhi L, Costa DB. Management and Future Directions in Non-Small-Cell Lung Cancer with
Known Activating Mutations. ASCO Educational Book. 2014; e353-e365.

Acquired resistance to EGFR TKI treatment
•1st and 2nd generation TKI inhibits EGFR signaling
5
First line
EGFR TKI
Acquired  EGFR mutationT790M
TAGRISSO
EGFRm
TKI
TKI
TAGRISSO
•The T790M mutation leads to the development of acquired resistance
•TAGRISSO inhibits both the EGFR-sensitive mutation and the EGFR T790M mutation responsible for
resistance to TKI 1./2. generation
SPC Tagrisso.

TAGRISSO is an EGFR kinase inhibitor that binds irreversibly to specific mutated forms of EGFR
(T790M, L858R, deletion of exon 19) at concentrations approximately 9x lower than those required to
bind to wild-type EGFR 1.
In both cell cultures and animal models with implanted tumors, TAGRISSO showed antitumor activity
in NSCLC cells carrying specific EGFR mutations (T790M / L858R, L858R, T790M / exon 19 deletion or
exon 19 deletion). To a lesser extent, EGFR 1 was also active in cells with WT amplification
TAGRISSO was prepared to have minimal activity against IR or IGFR2
Reference
1.TAGRISSO [Package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2015.
2.Cross DA, Ashton SE, Ghiorghiu S, et al. AZD9291, an irreversible EGFR TKI, overcomes
T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014;4(9):1046-1061

TAGRISSO® (osimertinib): Therapeutic indications
•Indication
•TAGRISSO is indicated for the treatment of adult patients with locally advanced or metastatic
non-small cell lung cancer with a proven mutation in the T790M epidermal growth factor receptor
(EGFR).
6
Therapeutic scheme
Localy advanced or metastatic EGFRm NSCLC
EGFR T790M mutation test in case of tumor progression
(blood or tissue)
Alternative treatment
gefitinib
afatinib
erlotinib

Case study
•woman, 46 years old
•english teacher
•never smoker still healthy
•3/2016 dg. adenocarcinoma of the upper lobe of the left lung, wedge. st. IV with malignant pleural
effusion and skeletal metastases
•EGFR M + deletion in exon 19
•symptoms: pain, shortness of breath,
•in April 2016 there is a pathological subcapital fracture of the femur on the left, which was
resolved by a total endoprosthesis
•ECOG - PS 1-2
Výsledek obrázku pro metastasis proximal femur Výsledek obrázku pro francouzské berle

She is a young, still completely healthy woman with a university degree employed as an English
teacher, living in a complete family with two minor children, a non-smoker. At the time of
diagnosis, this woman was 46 years old. The disease manifested itself in skeletal pain, especially
in the upper right femur, and has been examined since February 2016. A general examination revealed
an X-ray lesion in the upper lobe of the left lung and a CT examination of the chest including the
skeleton confirmed a malignant lesion in the lung parenchyma in segment 3 left subpleurally. size
about 17 mm, described as a large soft tissue pathological formation of markedly pinched contours
with adhesion to the chest wall, postcontrast it is clearly saturated (Fig. 5 + 6). The CT also
showed the destruction of the pedicle and the left side of the L2 vertebra, a small deposit was in
the scapula of the hip bone on the left, irregular contours were sacrally bilaterally on the left
neck of the hip bone to the left. Skeletal scintigraphy confirmed pathologically increased activity
in the head, neck and diaphyseal part of the left femur, in the left scapula of the hip bone and in
L2. On bronchoscopic examination, no signs of pathology were found macroscopically, 5
transbronchial biopsies were performed from the bronchial region for segment 3 of the left lung,
and tumor cells of low-differentiated non-small cell carcinoma, most likely adenocarcinoma, were
captured histologically. In the meantime, we have already consulted the findings on CT whether it
would be possible to perform a lung biopsy under CT due to a larger supply of material, including
the possibility of genetic testing for EGFR mutation status. This biopsy was performed without
complications, although the original material from bronchoscopy, the pathologist sent the tumor
material to the Center for Molecular Biology and Gene Therapy (CMBGT) in FDN, but the material was
not suitable for mutation analysis, and it was not safe to examine the ALK gene (anaplastic
lymphoma kinases), however, biopsy material from transthoracic puncture under CT was already on the
way, where primary lung adenocarcinoma was confirmed to be moderately differentiated and EGFR
positive mutations were found from this material, again a common type of exon 19 deletion mutation.
The progression of cancer with metastatic skeletal involvement was according to the TNM
classification determined as T2N0M1b - stage IV, the indication for initiating biologically
targeted treatment with afatinib from the end of March 2016 was met at the same time as regular
administration of denosumab in the prevention of complications of metastatic skeletal involvement.
The patient has a complication at the beginning of treatment in April 2016, namely a pathological
subcapital fracture of the femur on the left at the site of metastatic involvement, which was
resolved by total endoprosthesis at the orthopedic clinic of the University Hospital at St. Anny.
The patient continued treatment with afatinib and denosumab with improvements in control chest CT
and anterior anterior skiagrams, first relieving the limb with the crutches for the first months,
then fully loading. Her health improved so much during treatment with afatinib and denosumab that
she required a return to work, that is, back to school with the pupils, which enabled her to
improve her quality of life and satisfaction. The treatment response of partial regression in the
lungs lasted until July 2017 (16 months in total), a small thoracic pleural effusion was found in
the anterior and lateral skiagram of the chest (Fig. 7), at the same time on regular CT
examinations of the chest after 3 months throughout the treatment in addition to effusion, nodules
with up to small saturating deposits on the pleura are described, otherwise a stationary image of
the regression of a pathological lesion in the upper lobe of the left lung (Fig. 8). Continue on CT
without pathological lymphadenopathy of the mediastinum and hils, without fresh lesions on the
skeleton, without expansion of the adrenal glands or in the liver parenchyma. This time we were
satisfied with probatory pleural puncture and sending the material for cytology and again the
required mutational analysis to determine the mutational status of EGFR. Adenocarcinoma tumor cells
were confirmed in the collected effusion and retested in CMBGT - in addition to the already present
deletion of exon 19, a resistant T790M mutation was detected. Again, we responded quickly with a
request for reimbursement for osimertinib for a sick woman who clinically felt the left hemitorax
area as more sensitive, painful, and mildly impaired dyspnea. Again, we were not successful with
the application for the insurance company, chemotherapy was recommended, which would not be
suitable for a woman practicing the profession due to a higher risk of infection, greater fatigue
and the need to interrupt this work activity. Again, we gratefully used the osimertinib samples
provided by the company, and after use on another chest X-ray, the left-hand finding completely
regressed, which was also confirmed on CT in the next month. The current regular use of denosumab
for skeletal disorders, which is not clinically worsening, continues. Since August 2017, the
patient has been taking Tagrisso with a long-term treatment

Initiation of afatinib and denosumab treatment



 Discovery of a resistant mutation
•7/2017 clinical deterioration, pleural pain, left pleural effusion detected •performed a probatory
puncture of pleural effusion from which the T790M mutation was proved
ctDNA

Targeted therapy - osimertinib
•started at a dose of 80 mg once a day from 8/2017 •pleural effusion regressed during treatment
•pain and shortness of breath improved

Targeted therapy
F:\Grycová_Spacil_tagrisso\RTG 8_2017_PD.jpg F:\Grycová_Spacil_tagrisso\RTG 1_2018_CR.jpg

Regression of lung tumor, pleural nodularities and effusion.

Conclusion
•
•
•This case report demonstrates the treatment options of targeted therapy - osimertinib in
metastatic lung cancer with the occurrence of the T790M mutation, shows significantly higher
survival with comfortable oral administration and significantly lower toxicity compared to
conventional chemotherapy treatment.

A case study of a Vietnamese girl
•
•Female, 22 years old, Vietnamese
•Anamnestic - in the family without the occurrence of more serious diseases, non-smoking, allergies
to grass pollens and mites.
•
•For more than a month, he has difficulty breathing, coughs, wheezes, catches his breath with less
exertion, it gets worse overnight, he observes pressure on his chest, he does not give pain.
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Clinical and imaging examination
•Clinically numerous wheezing and wheezing on both sides. •CRP 21, KP without respiratory
insufficiency, other laboratory tests in the norm. •Deployed ATB treatment, given bronchodilator
infusions including corticoids, bronchodilator therapy and inhaled corticoids •Accepted within a
week for non-improving problems
14
•

Suggestion for further examination?
•A) spirometry and bronchodilation test
•B) bronchoscopy
•C) CT of the chest
•D) PET-CT
•E) PET-MR
15

>

Spirometry
•
16

Hospitalization
•Laboratory:
•IgE  233 (0-90)
•hCG  less then 2 ( 0 - 5 ) SCCA  0.7  ( 0 - 1.5 )
•AFP  1.08   ( 0.74 - 7.29 )
•CYFRA  7.99 ( 0 - 3.3 )
•NSE  25.5   ( 0 - 16.3 )
•Bronchoscopy
•the trachea is normal
•the main carina is not identifiable, it is taken in a bumpy touch of slightly bleeding
infiltration, which spreads to both main bronchi so that they are obturated from 2/3 and a slit
remains dorsally, which allows ventilation
17

Initial chest CT
•
•
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Differential diagnostics?
•A) Lymfoma
•B) Germininal tumor (teratoma)
•C) Lung cancer(NSCLC/SCLC)
•D) Carcinoid
•E) Another primary lung tumor
19

B- lymfoma
20


Intrapulmonary teratoma
•Rare germ cell tumor.
•Causes pain, cough and haemoptysis.
•Main treatment is surgical
21

Lung carcinoid
—They make up about 1% of lung tumors, incidence 0.5-1.5 / 105.
—It belongs to malignant lung tumors.
—Typical carcinoids occur more in the younger, atypical in the older.
—Central location predominates (> 80%), remaining peripherally, may metastasize to liver, bone,
brain, adrenal glands and ovaries
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https://c1.staticflickr.com/9/8074/8268010336_91690be44f_b.jpg pic_pulmonary_carcinoid_bronchi

Biopsy
•necrotic tumor formed by dominantly merging squamous tumor pins precisely with monocellular
keratinization. The tumor sparsely scattered light cells with smaller dark nuclei corresponding to
mucinous cells, which are positive for mucus staining. •Immuno: p63 +, CK5 / 6 +, TTF1-, CD5-,
CD117-, CK7 +, CK20 fok. +, Chromogranin-, synaptophysin-
•
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•
•
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•
•
•Conclusion: mucoepidermoid carcinoma (high grade)
23

Mukoepidermoid carcinoma
•Rare malignant tumor of the salivary glands (<1%), occurs in the small salivary glands of the
bronchi.
It occurs in young people and is not associated with smoking.
Symptoms include cough, hemoptysis, bronchitis, wheezing, fever, chest pain and are therefore often
diagnosed as asthma, COPD or pneumonia.
Histologically, it is divided into low-grade and high-grade.
Treatment - similar to NSCLC, preferably surgery.
Prognosis: 95% of low-grade patients survive 5 years, high-grade patients survive <10%.
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CT regression after chemoradiotherapy
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Spirometry before and after treatment
•Before
•After
26

Conclusion
•
•This case report shows a case of malignant cancer of the airways, which is clinically reminiscent
of an obstructive disease - bronchial asthma. It shows the need to think about this disease and
perform examinations to exclude it in the initial differential diagnosis, especially in the case of
persistent problems with bronchodilator therapy.