lung cancer part i
TRANSCRIPT
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LUNG CANCER
PART IBY DR. KHRONGKAMOL SIHABAN
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TOPICOverview of lung cancer
Treatment of the early stage non small cell lung cancer
Chemotherapy
EGFR TKI
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RISK FACTORSSmoking tobacco
Radon gas
Asbestos
Recurring lung inflammation
Lung scarring secondary to TB
Family history
Other carcinogens
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Clinical Manifestations of Lung CancerPulmonary symptoms
◦ Chronic cough
◦ Hemoptysis
◦ Dyspnea
◦ Pleural effusion
◦ Cardiac tamponade
◦ SVC syndrome
Extra-pulmonary symptoms
◦ Hoarseness voice
◦ Horner’s syndrome (Pancoast tumor)
◦ Brachial plexus involvement (Pancoast tumor)
◦ Weakness, seizure (brain mets)
◦ Bone pain (bone mets, HOA)
◦ Cord compression
◦ Lambert-Eaton myasthenia syndrome (LEMS)
◦ Hyponatremia (SIADH)◦ Ectopic ACTH
◦ Hypercalcemia
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USPSTF to "recommend annual screening for lung cancer with low-dose computed
tomography in adults aged 55 to 80 years
who have a 30 pack-year smoking history
and currently smoke or have quit within the past 15 years."
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SUBTYPE OF LUNG CANCERSmall cell lung cancer
Non small cell lung cancer◦Squamous cell carcinoma
◦Non squamous cell carcinoma : adenocarcinoma, large cell carcinoma, other cell types
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LUNG CANCER
Small cell lung cancer
SCLC
Non-small cell lung cancer
NSCLC
• 15% of Lung cancer
• usually widespread
when it firsts presents
• 85% of Lung cancer
• when presentation is by
symptoms >50% have distant
metastases and only 25% are
potentially resectable for cure
Aberle DR, J Thorac Imaging. 2001; 16(1): 65
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IMMUNOHISTOCHEMICAL STAINING
Squamous cell carcinoma : TTF1 -, p63 +
Adenocarcinoma : + TTF1, B72.3, Ber-EP4, MOC-31
(- in mesothelioma : + WT1, calretinin, D2-40 [podoplaninantibody], CK5/6)
Pulmonary adenocarcinoma : CK7 +, CK20 -, CDX2 –
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12
Li, Mack, Gandara et al. JCO. 2013 (adapted from Pao et al).
Evolution of NSCLC Subtyping From Histologic to Molecular-Based
NSCLC
as one
diseaseALK
EGFR
First
Targeted
Therapies
in NSCLC
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APPROACH IN PATIENTS SUSPECTED LUNG CANCER
First : obtain tissue for histology/cytology
Second : defined extent of lesion
work up for clinical staging
Treatment planning
1. Tumor factor : staging
2. Host factor : PS (ECOG)
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STAGING INVESTIGATIONS
Careful PE supraclav, liver etc
CXR mass, effusion, chest wall
CT chest, abd size, mediastinal LN, DM
Chemistry lab LFT, alk phos, ca
PET scan evaluate LN, DM
Mediastinoscope sampling mediastinal LNs
Miscellaneous depend on S/S - bone scan
PET scan : SPN,mediastinal LNFalse + : infection ,inflamation
False- : Bronchoalveolar cell carcinoma
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STAGING OF NSCLC
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AJCC 8 th
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TREATMENTStage I lung cancer (T1-2 N0 M0)◦ Lobectomy or Pneumonectomy
Stage II lung cancer (T1-2 N1 M0 or T3 N0 M0)◦ Lobectomy or Pneumonectomy ◦ Adjuvant chemotherapy
Stage IIIA lung cancer (T3 N1 M0 or Any T N2 M0)◦ Concurrent chemoradiation Surgery◦ Adjuvant chemotherapy + adjuvant radiation
Stage IIIB lung cancer (T4 N1-2 M0 or Any T N3 M0)◦ Concurrent chemoradiation + Surgery
Stage IV lung cancer (Any T Any N M1)◦ Palliative chemotherapy + Targeted therapy or immunotherapy
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การตดเฉพาะสวน การตดกลบปอดทงกลบ การตดปอดทงขาง
SUGERY
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CHEMOTHERAPY
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SYSTEMIC CHEMOTHERAPY Adjuvant chemotherapy
- Treatment that is given after primary curative treatment for that particular cancer (which is usually after surgery).
- Aim to treat microscopically residual disease in the systemic circulation in an attempt to prevent or delay recurrence.
Palliative chemotherapy
- Most of the time this will not significantly change the patients’ survival.
- But may help to improve symptoms that are related to the tumor (improve quality of life).
- Side effects must be tolerable (risk-benefit ratio).
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1995 Meta-Analysis Adjuvant Cisplatin Trials (n=1,934)
Non-small Cell Lung Cancer Collaborative Group, BMJ 1995;311:899-909.
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The International Adjuvant Lung Cancer Trial Collaborative Group (IALT)
The International Adjuvant Lung Cancer Trial Collaborative Group (IALT), NEJM 2004;350:351-360.
Overall Survival Disease-Free Survival
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ADJUVANT CHEMOTHERAPY
The NCIC, CALGB and Anita studies confirmed the positive IALT findings of a benefit of post-operative platinum-based chemotherapy in completely resected NSCLC.
Consistent reductions in the risk of death have been observed in recent adjuvant platinum-based trials and the 1995 meta-analysis.
Adjuvant platinum-based chemotherapy should be recommended to completely resected NSCLC stage II & IIIA and T size > 4 cm with good performance status.
Cisplatin-based doublets chemotherapy should be the best regimen (LACE Meta-analysis).
Cisplatin/Vinorelbine is the most effective regimen.
No adjuvant targeted therapy
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PALLIATIVE CHEMOTHERAPY
Chemotherapy improves survival and quality of life vs. best supportive care
Combination chemotherapy is the gold standard
Duration of treatment is 4–6 cycles
Traditional approach: platinum-based doublets (ECOG 1594)
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กลมท 1 ปกต ไมมอาการ ECOG 0 (PS 100%)
กลมท 2 มอาการบาง ท ากจวตรไดปกตECOG 1 (PS 90-70 %)
กลมท 3ท ากจวตรพอได เรมมคนชวย ตองพกบาง ECOG 2 (PS 60-70%)
กลมท 4 ตองมคนชวย นอนพกบางECOG 3 (PS 40-60%)
กลมท 5 นอนพกบนเตยงตลอดมคนชวยตลอด ECOG 4
สภาพความแขงแรงของรางกาย
เคมบ าบด
ประคบประคองตามอาการ
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9 Randomized Trials in Stage IV NSCLC
Best Supportive Care Best Supportive Care+
Chemotherapy*
*Cisplatin + Vinblastine (3 trials)
Cisplatin + Vindesine (2 trials)
Cisplatin + Etoposide (1 trial)
Carboplatin + Etoposide (1 trial)
Mitomycin + Ifosfamide + Cisplatin (1 trial)
Mitomycin + Vinblastine + Cisplatin (1 trial)
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Supportive Care versusSupportive Care + Chemotherapy
Patient Survival
0
20
40
60
80
100
6 12 18 24
Supportive Care +Chemotherapy
Supportive Care
P e
r c
e n
t
S u
r v
i v
a l
S u r v i v a l T i m e (mos)
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ECOG 1594: Kaplan-Meier Estimates of Overall Survival
Month
100
80
60
40
20
0
0 10 20 30 40
Cisplatin and paclitaxel
Cisplatin and gemcitabine
Cisplatin and docetaxel
Carboplatin and paclitaxel
Su
rviv
al
(%)
Reprinted with permission: Schiller JH, et al. N Engl J Med. 2002;346:92-98.
Copyright © 2002 Massachusetts Medical Society. All rights reserved.
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Kelly K, et al. J Clin Oncol 2001;19:3210–3218
1st line Platinum-based Chemotherapy:
Efficacy Plateau
Study
arm
OS
(mo)
1 year
(%)
PCb 8.6 38
CV 8.1 36
Study
arm
OS
(mo)
1 year
(%)
PC 7.8 31
GC 8.1 36
DC 7.4 31
PCb 8.1 34
Study
arm
OS
(mo)1 year (%)
PCb 9.9 43
GC 9.8 37
CV 9.5 37
Schiller JH, et al. N Engl J Med 2002;346:92–98 Scagliotti GV, et al. J Clin Oncol 2002;20:4285–4291
Pacli + carbo (PCb)Cis + vin (CV)
Months MonthsO
vera
ll s
urv
ival
Pacli + cis (PC)
Gem + cis (GC)
Doc + cis (DC)
Pacli + carbo (PCb)
5 10 15 20 25
Pacli + carbo (PCb)Gem + cis (GC) Cis + vin (CV)
Months
1.0
0.9
0.6
0.5
0.4
0.3
0.8
0.7
0.2
0.1
0
305 10 15 20 250305 10 15 20 25
Overa
ll s
urv
ival%
100
80
60
40
20
0
0 30 0
Overa
ll s
urv
ival
1.0
0.9
0.6
0.5
0.4
0.3
0.8
0.7
0.2
0.1
0
Response Rate 15-30%
Median Survival 8-9 Months
No Survival Different Among
Histological Subtypes
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Palliative Chemotherapy
in Advanced NSCLC
First-line chemotherapy– Platinum doublets chemotherapy
– Single agent chemotherapy (in elderly or poor PS patient)
• Gemcitabine, Vinorelbine
– EGFR-TKIs
Second-line chemotherapy– Single agent chemotherapy
• Docetaxel, Pemetrexed
– EGFR-TKIs
Maintenance chemotherapy– Pemetrexed
– EGFR-TKIs
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PALLIATIVE CHEMOTHERAPY First line chemotherapy Platinum doublets chemotherapy Single agent chemotherapy ( in elderly or poor PS patients) :
Gemcitabine, Vinorelbine
Second line chemotherapy Single agent chemotherapy : Docetaxel, Pemetrexed
Third line chemotherapy
Maintenance chemotherapy : Pemetrexed
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TARGETED
THERAPY
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MOLECULAR PATHWAYS
Cell growth & proliferation pathways
Angiogenesis pathways
Apoptosis pathways
Metastasis pathways
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Growth factor
Extracellular domain
Cytoplasmicdomain
Catalytic domain
Cell membrane
Growth & Proliferation Pathways
Signal transduction
pathways
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TKTK
Survival
(anti-apoptosis)
PI3-K
STAT3
AKTPTEN
MEK
Gene TranscriptionMAPK
Proliferation/maturation
Chemotherapy /
radiotherapy
resistanceAngiogenesis
Metastasis
pY
pY
RAS RAF
SOSGRB2pY
G1
SM
G2
Signal Transduction in Cancer Cells
Cancer Cell
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Categories of Targeted Therapy
● Humanized monoclonal antibodies
– Block upstream pathways
(block ligand or receptor)
● Small molecules
– Block downstream pathways
(Tyrosine kinase inhibitors)
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Shc
PI3-K
RafMEKK-1
MEKMKK-7
JNK
ERK
Ras
mTOR
Grb2
AKT
Sos-1
Monoclonal Antibodies (xxx-mab)Extracellular
Intracellular
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Shc
PI3-K
RafMEKK-1
MEKMKK-7
JNK
ERK
Ras
mTOR
Grb2
AKT
Sos-1
Tyrosine Kinase Inhibitors (xxx-tinib)
Extracellular
Intracellular
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● Humanized monoclonal antibodies (-mab)
– Rituximab (anti-CD20)
– Trastuzumab (anti-HER2 receptor)
– Cetuximab (anti-EGF receptor)
– Bevacizumab (anti-VEGF)
● Tyrosine kinase inhibitors (TKIs, -tinib)– Imatinib (Glivec), Nilotinib (Tasigna), Dasatinib (Sprycel)
– Gefitinib (Iressa), Erlotinib (Tarceva)
– Sunitinib (Sutent), Pazopanib (Votrient)
– Sorafenib (Nexavar)
– Lapatinib (Tykerb)
– Vemurafenib (Zelboraf)
Categories of Targeted Therapy
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50
Li, Mack, Gandara et al. JCO. 2013 (adapted from Pao et al).
Evolution of NSCLC Subtyping From Histologic to Molecular-Based
NSCLC
as one
diseaseALK
EGFR
First
Targeted
Therapies
in NSCLC
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EGFR TKI
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BIOMARKERS IN NSCLC
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Incidence of driver mutations in
adenocarcinoma of the lung
Japan (NCC)(N=319)(Kohno et al., Nature med, 2012)
US(N=1000)(Kris et al., ASCO 2011)
Courtesy of Dr. Mitsudomi
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EGFR activating mutations tend to cluster at exons 18 through 21 in NSCLC
*Literature review as reported in COSMIC (Catalogue Of Somatic Mutations In Cancer) database; may vary depending on study and population factors. †Sensitizing mutations that confer sensitivity to first- and second-generation TKIsEGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor.
1. Shigematsu H, et al. J Natl Cancer Inst. 2005;97(5):339-346. 2. Lynch TJ, et al. N Engl J Med. 2004;350(21):2129-2139. 3. Paez JG, et al. Science. 2004;304(5676):1497-1500. 4. Siegelin MD, et al. Lab Invest. 2014;94(2):129-137.
Distribution of mutation types4,*
Mutation type Percent
Exon 18 G719A/C
1.03%
Exon 19 deletion†
46%
Exon 20T790M de novo
Other exon 20 mutations
4.1%
2.3%
Exon 21 point mutation L858R† 37.5%
L861Q 1.12%
EGFR gene1-4
extracellular
Exons
19
intracellular
20
18
21
A-loop
C helix
P-loop
LIGAND
BINDING
DOMAIN
CYSTEINE-RICH DOMAIN
LIGAND
BINDING
DOMAIN
CYSTEINE-RICH DOMAIN
TRANS-MEMBRANE
REGION
TYROSINE KINASE
DOMAIN
REGULATORY DOMAIN
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Gefitinib 250 mg/day1–4 Erlotinib 150 mg/day1,2,5 Afatinib 40 mg/day6–9
Binding to EGFR Reversible Reversible Irreversible
Bioavailability 59% 60%Absolute bioavailability
in humans is unknown
Major routes
of metabolismLiver primarily by CYP3A4
Liver primarily by CYP3A4
and less by CYP1A2
Minimal metabolism detected in
healthy volunteers,‡ absence of
detectable CYP-mediated
metabolism9
Cmax, ng/mL 307–420† 2384 29–83
T½, terminal hours 41 (mean) 36 (median) 34–40 (mean)
AUCss, µg.h/mL 5.0–5.7† 15.2 (10.4–22.1) 498–1,240 ng.h/mL
Vdss (L), mean 1,400 131–233 1,880–3,150§
MTD 800–1,000 mg/day 150 mg/day 40–50 mg /day
Gefitinib, erlotinib and afatinib have
different pharmacokinetic profiles*
AUC, area under curve; Cmax, maximum plasma concentration; CYP, cytochrome P450; MTD, maximum tolerated dose; T½, terminal half-life; Vdss, volume of distribution at steady state
*Descriptive not comparative pharmacokinetic profiles; †At doses of 225 and 300 mg/day; ‡At dose of 15 mg/day; §Data refer to apparent Vd during the terminal phase after an extravascular dose
1. Yun, et al. Cancer Cell 2007;11:217–227; 2. Rukazenkov, et al. Anticancer Drugs 2009;20:856–866; 3. Ranson, et al. J Clin Oncol 2002;20:2240–2250; 4. Baselga, et al. J Clin Oncol
2002;20:4292–4302; 5. Yamamoto, et al. Cancer Chemother Pharmacol 2008;61:489–496; 6. Yap, et al. J Clin Oncol 2010;28:3965–3972; 7. Gordon, et al. Invest New Drugs 2013;31:409–416;
8. Murakami, et al. Cancer Chemother Pharmacol 2012;69:891–899; 9. Stopfer, et al. Cancer Chemother Pharmacol 2012;69:1051–1061
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ORR, PFS and OS from PIII RCTs
EGFR-TKI ORR, %Median PFS, months
(HR [95% CI])
Median OS, months
(HR [95% CI])
Gefitinib
IPASS1,2
(vs carboplatin/paclitaxel) n=261*71.2 vs 47.3 (p<0.001)
9.5 vs 6.3
(0.48 [0.36, 0.64]; p<0.001)
21.6 vs 21.9
(1.00 [0.76, 1.33]; p=0.990)
NEJ0023,4
(vs carboplatin/paclitaxel) N=22873.7 vs 30.7 (p<0.001)
10.8 vs 5.4
(0.32 [0.24, 0.44]; p<0.001)
27.7 vs 26.6
(0.89 [0.63, 1.24]; p=0.483)
WJTOG34055,6
(vs cisplatin/docetaxel) N=17262.1 vs 32.2 (p<0.0001)
9.6 vs 6.6
(0.56 [0.41, 0.77]; p<0.001)
34.8 vs 37.3
(1.25 [0.88, 1.78]; p=0.206)
Erlotinib
EURTAC7–9 (vs platinum-based
chemotherapy) N=17364 vs 18 (p<0.0001)
10.4 vs 5.1
(0.33 [0.23, 0.49]; p<0.0001)
22.9 vs 22.1
(p=0.97)
OPTIMAL10−12
(vs carboplatin/gemcitabine) N=15483 vs 36 (p<0.0001)
13.7 vs 4.6
(0.16 [0.11, 0.26]; p<0.0001)
22.8 vs 27.2
(1.19 [0.83, 1.71]; p=0.2663)
ENSURE13
(vs cisplatin/gemcitabine) N=21762.7 vs 33.6
11.0 vs 5.5 months
(0.34 [0.22, 0.51]; p<0.0001)
26.3 vs 25.5
(0.91 [0.63, 1.31]; p=0.6073)
Afatinib
LUX-Lung 314,15
(vs cisplatin/pemetrexed) N=34556 vs 23 (p=0.001)
11.1 vs 6.9
(0.58 [0.43, 0.78]; p=0.001)
28.2 vs 28.2
(0.88 [0.66, 1.17]; p=0.39)
LUX-Lung 615,16
(vs cisplatin/gemcitabine) N=36466.9 vs 23.0 (p<0.0001)
11.0 vs 5.6
(0.28 [0.20, 0.39]; p<0.0001)
23.1 vs 23.5
(0.93 [0.72, 1.22]; p=0.61)
LUX-Lung 3 and 6 combined15 NR NR25.8 vs 24.5
(0.91 [0.75, 1.11]; p=0.37)
HR, hazard ratio; CI, confidence interval; NR, not recorded
*Data relate to the subset of EGFRm patients in IPASS
1. Mok, et al. N Engl J Med 2009;361:947–957; 2. Fukuoka, et al. J Clin Oncol 2011;29:2866–2874; 3. Maemondo, et al. N Engl J Med 2010;362:2380–2388; 4. Inoue, et al. Ann Oncol 2013;24:54–59; 5.
Mitsudomi, et al. Lancet Oncol 2010;11:121–128; 6. Yoshioka, et al. J Clin Oncol 2014;32(suppl):abstr 8117; 7. Rosell, et al. Lancet Oncol 2012;13:239–246; 8. Costa, et al. Clin Cancer Res 2014;20:2001–
2010; 9. Karachaliou, et al. JAMA Oncol 2015;1:149–157; 10. Zhou, et al. Lancet Oncol 2011;12:735–742; 11. Chen, et al. Ann Oncol 2013;24:1615–1622; 12. Zhou, et al. Ann Oncol 2015 [Epub ahead of
print]; 13. Wu, et al. Ann Oncol 2015 [Epub ahead of print]; 14. Sequist, et al. J Clin Oncol 2013;31:3327–3334; 15. Yang, et al. Lancet Oncol 2015;16:141–151; 16. Wu, et al. Lancet Oncol 2014;15:213–222
• The PIII RCTs listed below are the key trials supporting gefitinib, erlotinib and afatinib
in the first-line EGFRm aNSCLC setting.
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Selected AEs: gefitinib, erlotinib and afatinibThe data listed below are from the key trials supporting gefitinib, erlotinib and afatinib in the
first-line aNSCLC setting. IPASS and IFUM were the main regulatory trials in the EU and US.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; ILD, interstitial lung diseaseagrouped term; bnail changes; cdata reported as adverse reactions from US FDA PI; dtreatment-related AEs
1. Mok, et al. N Engl J Med 2009;361:947–957; 2. Douillard, et al. Br J Cancer 2014;110:55–62; 3. Maemondo, et al. N Engl J Med 2010;362:2380–2388; 4. Mitsudomi, et al. Lancet Oncol 2010;11:121–128; 5. Rosell, et al. Lancet Oncol
2012;13:239–246; 6. TARCEVA US FDA Full Prescribing Information, accessed 20 July 2015; 7. Zhou, et al. Lancet Oncol 2011;12:735–742; 8. Wu, et al. Ann Oncol 2015 [Epub ahead of print]; 9. Yang, et al. Lancet Oncol 2015;16:141–151;
10. Wu, et al. Lancet Oncol 2014;15:213–222
%
Rash Diarrhoea Nausea/vomiting Stomatitis Paronychia
Elevated liver
transaminases or
ALT/AST
FatigueILD
events,
n, (%)All (%)
Grade
≥3 (%)
All
(%)
Grade
≥3 (%)All (%)
Grade
≥3 (%)All (%)
Grade
≥3 (%)All (%)
Grade
≥3 (%)
All
(%)
Grade
≥3 (%)
All
(%)
Grade
≥3 (%)
Gefitinib
(range)
45–85 0–5 31–54 1–4 10–17/
6–13
0–1/
0–1
10–22 0–0.2 10–32 0–3 8–70/
6–70
1–28/
0–26
11–39 2–3 1–5
IPASS1 66.2a 3.1a 46.6 3.8 16.6/
12.9
0.3/
0.2
17.0a 0.2a 13.5 0.3 NR 9.4a NR NR 16 (2.6)
IFUM2 44.9 0 30.8 3.7 10.3/
13.1
0/0 NR NR NR NR 8.4/5.6 0.9/0 NR NR 1 (0.9)
NEJ0023 71.1 5.3 34.2 0.9 NR/
6.1
NR/
0.9
9.6 0 9.6b 2.6b 55.3a 26.3a 10.5 2.6 6 (5.3)
WJTOG34054 85.1 2.3 54.0 1.1 17.2/
NR
1.1/
NR
21.8 0 32.2 1.1 70.1/
70.1
27.6/
16.1
39.0 2.3 2 (2.3)
Erlotinib
(range)
70–80 2–13 25–57 1–5 1–5/
1–6
0 0-13 0–1 4–16 0 6–37/
0–6
2–4/
2–2
6–51 0–6 0–1
EURTAC5 79.8 13.1 57.1 4.8 NR NR NR NR 14c 0c 6.0a 2.4a 51.2 6.0 1 (1.2)
OPTIMAL6,7 73.5 2.4 25.3 1.2 1.2a 0a 13.3 1.2 3.6 0 37.3/
NR
3.6/
NR
4.8 0 0
ENSURE8 70.9 6.4 45.5 1.8 4.5/6.4 NR/NR NR NR 15.5 NR 11.8/
NR
NR/NR 5.5 NR 0
Afatinib
(range)
81–89 15–16 90–95 6–14 12–18/
13–17
0–1/
1–3
52–72 5–9 33–57 0–11 11–23/
8–18
2–2/
0–2
17–18 1–2 0–1
LUX-Lung 39,10,d 89.1a 16.2a 95.2 14.4 17.9/
17.0
0.9/
3.1
72.1a 8.7a 56.8 11.4 11/8c 2/2c 17.5 1.3 3 (1.3)
LUX-Lung 610 80.8a 14.6a 89.5 5.9 11.7/
13.4
0.4/
1.3
52.3a 5.4a 32.6a 0a 23/18 2.1/0.4 17.2a 2.1a 1 (0.4)
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Resistance Via Acquired Mutation Is the Most Common Mechanism of Disease Progression1
67
Lung cancer cell
with sensitising
EGFR mutation
Initialresponse
to TKI
Emergence of an acquired
resistance mutation, such
as T790M
Progression on TKI
TKIdiscontinued—further tumour
growth
Lung cancer cell
with an acquired
resistance mutation
Metastatic EGFRm NSCLC
Most patients with metastatic EGFRm NSCLC
will progress on a first-line TKI within 8–14 months2
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.
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The EGFR T790M Mutation Is the Most Common Mechanism of Acquired Resistance to EGFR TKI Therapy
Nearly two-thirds of patients with metastatic EGFRm NSCLC who have progressed on an EGFR TKI have an acquired EGFR T790M mutation
68
Yu HA, Arcila ME, Rekhtman N, et al. Clin Cancer Res. 2013;19:2240-2247.
The relative frequencies of the various mechanisms of acquired resistance. Composite pie chart with percentages compiled from tests with varying denominators.
MET + T790M3% HER2 + T790M
4%
Small cell + T790M
2%
T790M60%
HER28%
Small cell1%
Small cell + MET1%
METamplification
3%
Unknown18%
0
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Osimertinib Is a Third-Generation EGFR TKI Designed to Target Both EGFR-Sensitisingand EGFR T790M-Resistance Mutations1
69
1. AstraZeneca Pharmaceuticals. Osimertinib™ (osimertinib). Summary of Product Characteristics, 2017. 2. Cross DA, Ashton SE, Ghiorghiu S, et al. Cancer Discov. 2014;4:1046-1061.
In preclinical in vitro studies:
• Osimertinib is a third-generation irreversible EGFR
TKI with activity against both EGFR-sensitising and
EGFR T790M-resistance mutations, and with
activity in the CNS1
• Wild-type EGFR effects of TKIs currently approved in the first-line setting have been associated with high rates of adverse events such as rash and diarrhoea2
Selectively targets bothEGFRm and EGFR T790M1
Minimal activity against WT EGFR1,2
EGFRm EGFR T790M WT EGFR
Osimertinib Osimertinib
Osimertinib
EGFRm, EGFR mutant; WT, wild type.
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Acquired Resistance to EGFR TKI Therapy
• 1st-/2nd-generation TKIs inhibit EGFR signaling
70
First-line EGFR TKI therapy
Acquired EGFR T790Mmutation resistance
Osimertinib
EGFRm
TKI
TKI
Osimertinib
• T790M results in acquired resistance
• Osimertinib is designed to inhibit both EGFR-sensitising mutations and the EGFR T790M resistance mutation
AstraZeneca Pharmaceuticals. Osimertinib™ (osimertinib). Summary of Product Characteristics, 2017.
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Osimertinib Was Studied in AURA3, a Phase IllRandomised Trial vs. Platinum-Pemetrexed1,2
AURA3 was a Phase Ill, randomised, international, open-label study comparing Osimertinib with platinum-pemetrexed in 419 patients with EGFR T790M mutation-positive NSCLC who had progressed on first-line TKI therapy.1
72
* cobas® EGFR Mutation Test v2 (Roche Molecular Systems).
†Platinum-pemetrexed (every 3 weeks for up to 6 cycles of pemetrexed 500 mg/m2 plus either carboplatin AUC5 or cisplatin 75 mg/m2). Patients whose disease had not progressed after 4 cycles of platinum-pemetrexed could continue maintenance pemetrexed according to the approved label.
‡Patients could receive study treatment beyond RECIST-defined progression as long as they experienced clinical benefit, as judged by the investigator.
§ In the platinum-pemetrexed group, 60% (n=82) of patients crossed over to receive Osimertinib. Patients on platinum-pemetrexed could cross over to Osimertinib after BICR-confirmed progression.2
Primary endpoint: PFS (by investigator assessment)
Secondary endpoints: ORR, DoR, OS, DCR, tumour shrinkage, HRQoL, and safety
1. Mok TS, Wu YL, Ahn MJ, et al. N Engl J Med. 2017;376:629-640.
Disease progression following 1st-line treatment
with an EGFR TKI in patients with documented
EGFRm NSCLC
Central confirmation of tumourEGFR T790M mutation*
RECIST v1.1 assessments every 6 weeks until objective progressionǂ
Follow-upoverall survival
(OS) every 6 weeks
CROSSOVER§
Optional: patients on platinum-
pemetrexed could begin post-
progression open-label Osimertinib
Platinum-pemetrexed
every 3 weeks for up to 6
cycles†
N=419
R 2:1
80 mg
+
Osimertinib
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Osimertinib Demonstrated Significantly Longer Progression-Free Survival vs. Platinum-Pemetrexedin AURA3
75
Median PFS was more than twice as long as with platinum-pemetrexed
(by investigator assessment)
Overall Survival (OS) data were not mature at the time of this initial analysis (25% mature for Osimertinib; 29% mature for platinum-pemetrexed [HR=0.72; 95% CI: 0.48, 1.09; P=0.121]).
Osimertinib
Mok TS, Wu YL, Ahn MJ, et al. N Engl J Med. 2017;376:629-640.
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PFS Was Significantly Longer for Osimertinib Across All Pre-Defined Subgroups
77
Mok TS, Wu YL, Ahn MJ, et al. N Engl J Med. 2017;376:629-640.
PFS was significantly longer than with platinum-pemetrexed,
with a hazard ratio <0.5 across all pre-defined subgroups*
* Size of circle is proportional to the number of events.
†NC=non-calculable. If there were <20 events in a subgroup, the analysis was not performed.
Osimertinib
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ORR Was Over Twice That of Platinum-Pemetrexed
78
1. Mok TS, Wu YL, Ahn MJ, et al. N Engl J Med. 2017;376:629-640.
Objective Response Rate (ORR)1 Disease Control Rate (DCR)1
Osimertinib(n=279)
(95% Cl: 65%, 76%)
Platinum-pemetrexed
(n=140)
(95% Cl: 24%, 40%)
Osimertinib(n=279)
(95% Cl: 90%, 96%)
Platinum-pemetrexed
(n=140)
(95% Cl: 66%, 81%)
(P<0.001) (P<0.001)
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Rapid and Durable Responses Were Seen With Osimertinib vs. Platinum-Pemetrexed
79
1. Mok TS, Wu YL, Ahn MJ, et al. N Engl J Med. 2017;376:629-640.
* One-week window was allowed at approximately 6 weeks.
†At data cutoff, 59% (n=166) of patients receiving Osimertinib and 12% (n=16) of those receiving platinum-pemetrexed were still receiving randomised study treatment.1
Percent of responders demonstrating response at ≤6 weeks (first scan)*1
Median Duration of Response (DoR)†1
Osimertinib (n=197)
Osimertinib (n=297) (95% CI: 8.3, 11.6)
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Osimertinib Significantly Improved Patient-Reported Outcomes vs. Platinum-Pemetrexed*
80
AstraZeneca Pharmaceuticals. Osimertinib Summary of Product Characteristics, 2017.
* PROs were assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 items (EORTC QLQ-C30) and EORTC QLQ–Lung Cancer 13 items Questionnaire.
†Based on a mixed model for repeated measures analysis of patient-reported outcomes across 5 prespecified symptoms during the overall time period from randomisation until 6 months.
Mean change in baseline lung cancer symptoms†
Osimertinib (n=279)
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In Patients With CNS Metastases, Median PFS Was Twice as Long With Osimertinib vs. Platinum-Pemetrexed*1
81
Median PFS of Osimertinib vs. platinum-pemetrexed in patients with CNS metastases (investigator assessment)
* Median PFS in patients without CNS metastases was 10.8 months (n=186; 95% Cl: 8.3, 12.5) with Osimertinib vs. 5.6 months (n=89; 95% Cl: 4.2, 6.8) with platinum-pemetrexed.2
1. Mok TS, Wu YL, Ahn MJ, et al. N Engl J Med. 2017;376:629-640.
Osimertinib
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CNS Efficacy in Patients With CNS Metastases at Baseline in AURA3 (BICR)*†
82
AstraZeneca Pharmaceuticals. Osimertinib Summary of Product Characteristics, 2017.
* Blinded Independent Central Review assessment of CNS efficacy in the subgroup of 116/419 (28%) patients identified to have CNS metastases on a baseline brain scan.
†CNS ORR and CNS DoR evaluated in the population with CNS measurable lesions at baseline; CNS PFS evaluated in the full analysis set population (CNSmeasurable and non-measurable lesions at baseline by BICR).
CNS Objective Response Rate
Osimertinib (n=30)
Platinum-pemetrexed(n=16)
70%(95% CI: 51%, 85%)
31%(95% CI: 11%, 59%)
Odds Ratio=5.1 (95% CI: 1.4, 2.1); P=0.015
CNS Duration of Response
Osimertinib (n=30)
Platinum-pemetrexed(n=16)
8.9 months (95% CI: 4.3, NC)
5.7 months(95% CI: NC, NC)
CNS Disease Control Rate
Osimertinib (n=75)
Platinum-pemetrexed(n=41)
87%(95% CI: 77%, 93%)
68%(95% CI: 52%, 82%)
Odds Ratio=3 (95% CI: 1.2, 7.9); P=0.021
CNS Median Progression-Free Survival
Osimertinib (n=75)
Platinum-pemetrexed(n=41)
11.7 months(95% CI: 10, NC)
5.6 months(95% CI: 4.2, 9.7)
Hazard Ratio=0.32 (95% CI: 0.15, 0.69); P=0.004
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Osimertinib overall frequency (n=279)Platinum-pemetrexed
overall frequency (n=136)
All causality adverse events Any grade (%) Grade ≥3 (%) Any grade (%) Grade ≥3 (%)
Respiratory, thoracic and mediastinal disorders
Interstitial Lung Disease*† 3.6 0.4 0.7 0.7
Eye disorders
Keratitis* 1.1 0 0.7 0
Gastrointestinal disorders
Diarrhoea 41 1.1 11 1.5
Stomatitis 15 0 15 1.5
Skin and subcutaneous tissue disorders
Rash* 34 0.7 5.9 0
Dry skin* 23 0 4.4 0
Paronychia* 22 0 1.5 0
Pruritus* 13 0 5.1 0
Investigations
QTc interval prolongation‡ 1.4 0 0.7 0
Findings based on test results presented as CTCAE grade shifts
Platelet count decreased 46 0.7 48 7.4
Leukocytes decreased 61 1.1 75 5.3
Neutrophils decreased 27 2.2 49 12
In AURA3, Osimertinib Was Well Tolerated With Low Levels of Grade ≥3 Adverse Events
83
AstraZeneca Pharmaceuticals. Osimertinib Summary of Product Characteristics, 2017.
* Grouped term. If a patient has multiple preferred-term level events within a specific grouped term adverse event, then the maximum CTCAE grade across those events is counted.
†One fatal ILD event was reported that was deemed to be possibly causally related to Osimertinib.
‡No QTc-related arrhythmias were reported in the AURA studies.
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Recommended Dosing
AstraZeneca Pharmaceuticals. Osimertinib Summary of Product Characteristics, 2017.84
• The recommended dose is 80 mg once a day until disease progression or unacceptable toxicity
• If a dose of Osimertinib is missed, the dose should be made up unless the next dose is due within 12 hours
• The tablet should be swallowed whole with water and it should not be crushed, split, or chewed
In patients treated with Osimertinib 80 mg once daily, 2.3% had a
dose reduction and 6.5% discontinued treatment due to adverse reactions
or abnormal laboratory parameters
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Some Adverse Reactions May Require Dose Interruption or Discontinuation
86
TargetOrgan
Adverse Reaction Recommended Dose Modification
Pulmonary ILD/Pneumonitis Permanently discontinue Osimertinib
Cardiac
QTc interval greater than 500 msecon at least 2 separate ECGs
Withhold Osimertinib until QTc interval is less than 481 msec or recovery to baseline if baseline QTc is greater than or equal to 481 msec, then restart at a reduced dose (40 mg)
QTc interval prolongation with signs/symptoms of serious arrhythmia
Permanently discontinue Osimertinib
Other
Grade 3 or higher adverse reaction Withhold Osimertinib for up to 3 weeks
If Grade 3 or higher adverse reaction improves to Grade 0–2 after withholding of Osimertinib for up to 3 weeks
Osimertinib may be restarted at the same dose (80 mg) or a lower dose (40 mg)
Grade 3 or higher adverse reaction that does not improve to Grade 0–2 after withholding for up to 3 weeks
Permanently discontinue Osimertinib
AstraZeneca Pharmaceuticals. Osimertinib Summary of Product Characteristics, 2017.
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Testing for the EGFR T790M Mutation
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Test for EGFR T790M at the First Signs of Progression
• Initiate testing at the first signs of progression1
• A positive tissue or plasma EGFR T790M mutation test indicates eligibility for Osimertinib2
88
1. Diaz LA Jr, Bardelli A. J Clin Oncol. 2014;32:579-586. 2. AstraZeneca Pharmaceuticals. Osimertinib Summary of Product Characteristics, 2017.
ELIGIBLE
TISSUE TEST
PLASMA TEST
Ensure your lab is prepared to test for
EGFR T790M using both plasma and tissue
Osimertinib
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Plasma and Tissue Tests Are Complementary Approaches
Key considerations
89
1. Schwaederle M, Husain H, Fanta PT, et al. Oncotarget. 2016;7:9707-9717. 2. Thress KS, Brant R, Carr TH, et al. Lung Cancer. 2015;90:509-515.
3. cobas® EGFR Mutation Test v2 [package insert]. Indianapolis, IN: Roche Molecular Systems, Inc.; 2016. 4. Oxnard GR, Thress KS, Alden RS, et
al. J Clin Oncol. 2016;34:3375-3382. 5. Karlovich C, Goldman JW, Sun JM, et al. Clin Cancer Res. 2016;22:2386-2395. 6. Redig AJ, Jänne PA. J Clin
Oncol. 2015;33:975-978.
Plasma (ctDNA) testing Tissue testing
• Not all tumours shed enough DNA to be detected in plasma1
• Sensitivity for T790M varies significantly by technology2
• T790M can be more difficult to detect in plasma than ex19del or L858R*3
• More invasive, and some patients may be ineligible for biopsy at progression4-6
• Due to heterogeneity, some mutations may appear in only certain metastases or certain parts of the tumour4-6
30%–40%+ chance of a
false negative depending
on test used2-4
Tumour heterogeneity
can impact T790M
identification
* Using cobas® EGFR Mutation Test v2.
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Plasma and Tissue Testing Concordance for EGFR T790M
Of 334 patients with paired, valid results from tissue and plasma samples tested for EGFR T790M at progression with the cobas® EGFR Test:
90
T790M negative
in both plasma and
tissue: 89 (27%)
131
(39%)
T790M+ in tissue
T790M+ in plasma
92
(28%)
22
(7%)
cobas® EGFR Mutation Test v2 [package insert]. Indianapolis, IN: Roche Molecular Systems, Inc.; 2016.
131
(39%)
92
(28%)
22
(7%)
• Plasma and tissue testing concordance was lower for EGFR T790M than for ex19del and L858R
Of 334 patients total:
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Incorporating Both Tests Into Your Practice May Identify More Patients With the EGFR T790M Mutation
Example testing sequence:
91
Diaz LA Jr, Bardelli A. J Clin Oncol. 2014;32:579-586.
If plasma results are negative, follow up with a tissue test
wherever possible due to the potential for false-negative plasma results
Osimertinib
Osimertinib
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SUMMARY
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Summary of NSCLC treatment in
Stages I–III disease
NCCN Treatment Guidelines. NSCLC Version 1.2015.
http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
*Patients with Stage IIIB disease are not candidates for
surgical resection
Operable Medically inoperable
Surgical exploration and resection and
mediastinal lymph node dissection or
systematic lymph node sampling*Definitive radiotherapy
Adjuvant treatment• Reresection
• Radiotherapy
• Chemotherapy
• Resection ± chemotherapy
• Radiotherapy ± chemotherapy
• Chemoradiation
• Concurrent chemoradiation
• Sequential chemotherapy
Consider adjuvant treatment for high-risk
Stages IB–IIIB• Radiotherapy
• Chemotherapy
• Radiotherapy ± chemotherapy
• Chemoradiation
• Concurrent chemoradiation
• Sequential chemotherapy
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The choice of chemotherapeutic agent is complex and treatment decisions will be
based on multiple factors
Chemotherapy options for Stage I–III
disease
Chemotherapy options for neoadjuvant or adjuvant
therapy
Chemotherapy regimens used with radiation therapy
Cisplatin + vinorelbine Concurrent chemotherapy/radiotherapy
Cisplatin + etoposide Cisplatin + etoposide; concurrent thoracic radiotherapy
Cisplatin + vinblastine Cisplatin + vinblastine; concurrent thoracic radiotherapy
Cisplatin + gemcitabine Carboplatin + pemetrexed; concurrent radiotherapy
Cisplatin + docetaxel Cisplatin + pemetrexed; concurrent radiotherapy
Cisplatin + pemetrexed Sequential chemotherapy/radiotherapy regimens
Paclitaxel + carboplatin (for patients with comorbidities or
unable to tolerate cisplatin)
Cisplatin + vinblastine; followed by radiotherapy
Paclitaxel + carboplatin; followed by radiotherapy
Concurrent chemotherapy/radiotherapy, followed by
chemotherapy
Paclitaxel + carboplatin; concurrent thoracic
radiotherapy, followed by paclitaxel + carboplatin
Cisplatin + etoposide; concurrent thoracic radiotherapy,
followed by cisplatin + etosposideNCCN Treatment Guidelines. NSCLC Version 1.2015.
http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
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Summary of NSCLC treatment in
Stage IV (metastatic) disease
NCCN Treatment Guidelines. NSCLC Version 1.2015.
http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
Metastatic disease
Limited metastases Distant metastases
Local therapy if necessary
For patients with brain metastases:• Surgical resection then whole brain
radiotherapy OR
• Stereotactic radiosurgery + whole brain
radiotherapy
Patients with multiple metastases:• Surgical resection of lung lesion OR
• Stereotactic ablative radiotherapy of lung
lesion OR
• Chemotherapy
Systematic Treatment
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96
Li, Mack, Gandara et al. JCO. 2013 (adapted from Pao et al).
Evolution of NSCLC Subtyping From Histologic to Molecular-Based
NSCLC
as one
diseaseALK
EGFR
First
Targeted
Therapies
in NSCLC
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Erlotinib
Gefitinib
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Incorporating Both Tests Into Your Practice May Identify More Patients With the EGFR T790M Mutation
Example testing sequence:
103
Diaz LA Jr, Bardelli A. J Clin Oncol. 2014;32:579-586.
If plasma results are negative, follow up with a tissue test
wherever possible due to the potential for false-negative plasma results
Osimertinib
Osimertinib
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Powerful Efficacy and Consistent Tolerability in AURA3 and Phase II Clinical Trials
105
1. Mok TS, Wu YL, Ahn MJ, et al. N Engl J Med. 2017;376:629-640. 2. AstraZeneca Pharmaceuticals. Osimertinib™ (osimertinib). Summary of Product Characteristics, 2017. 3. Yang J, Ramalingam SS, Janne PA, Cantarini M, Mitsudomi T. J Thorac Oncol. 2016;11:S152-S153. 4. Data on File, 986,561.001, AstraZeneca Pharmaceuticals. 5. Data on File, REF-4791, AstraZeneca Pharmaceuticals LP. 6. Yang J, Ramalingam S, Janne P, et al. Presented at: The European Lung Cancer Conference; April 2016; Geneva, Switzerland.
• In AURA3, Osimertinib was well tolerated with no single Grade 3 or higher adverse event occurring in ≥3% of patients
• The overall safety and tolerability profile of Osimertinib in AURA3 was consistent with that observed in the Phase II studies
• At progression on or after an EGFR TKI, test for the EGFR T790M mutation
• 10.1 months median PFS for Osimertinib vs. 4.4 months for platinum-pemetrexed (HR=0.30; 95% Cl: 0.23, 0.41; P<0.001)
• 71% ORR for Osimertinib vs. 31% for platinum-pemetrexed
• 93% DCR for Osimertinib vs. 74% for platinum-pemetrexed
• 70% CNS ORR for Osimertinib vs. 31% for platinum-pemetrexed
• 11.0 months median PFS (95% Cl: 9.6, 12.4)
• 91% DCR
• 66% ORR
Phase II3-6Phase III1,2
Test for EGFR T790MConsistent Tolerability1,2
Eff
icacy
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