lung cancer part i

LUNG CANCER

PART IBY DR. KHRONGKAMOL SIHABAN

TOPICOverview of lung cancer

Treatment of the early stage non small cell lung cancer

Chemotherapy

EGFR TKI

RISK FACTORSSmoking tobacco

Radon gas

Asbestos

Recurring lung inflammation

Lung scarring secondary to TB

Family history

Other carcinogens

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

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."

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

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

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 –

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

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)

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

STAGING OF NSCLC

AJCC 8 th

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

การตดเฉพาะสวน การตดกลบปอดทงกลบ การตดปอดทงขาง

SUGERY

CHEMOTHERAPY

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).

1995 Meta-Analysis Adjuvant Cisplatin Trials (n=1,934)

Non-small Cell Lung Cancer Collaborative Group, BMJ 1995;311:899-909.

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

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

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)

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

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)

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)

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.

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

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

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

TARGETED

THERAPY

MOLECULAR PATHWAYS

Cell growth & proliferation pathways

Angiogenesis pathways

Apoptosis pathways

Metastasis pathways

Growth factor

Extracellular domain

Cytoplasmicdomain

Catalytic domain

Cell membrane

Growth & Proliferation Pathways

Signal transduction

pathways

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

Categories of Targeted Therapy

● Humanized monoclonal antibodies

– Block upstream pathways

(block ligand or receptor)

● Small molecules

– Block downstream pathways

(Tyrosine kinase inhibitors)

Shc

PI3-K

RafMEKK-1

MEKMKK-7

JNK

ERK

Ras

mTOR

Grb2

AKT

Sos-1

Monoclonal Antibodies (xxx-mab)Extracellular

Intracellular

Shc

PI3-K

RafMEKK-1

MEKMKK-7

JNK

ERK

Ras

mTOR

Grb2

AKT

Sos-1

Tyrosine Kinase Inhibitors (xxx-tinib)

Extracellular

Intracellular

● 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

50



NSCLC

as one

diseaseALK

EGFR

First

Targeted

Therapies

in NSCLC

EGFR TKI

BIOMARKERS IN NSCLC

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

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

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

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.

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)

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.

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

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.

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.

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

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.

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

ORR Was Over Twice That of Platinum-Pemetrexed

78


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)

Rapid and Durable Responses Were Seen With Osimertinib vs. Platinum-Pemetrexed

79


* 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)

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)

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


Osimertinib

CNS Efficacy in Patients With CNS Metastases at Baseline in AURA3 (BICR)*†

82


* 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)


8.9 months (95% CI: 4.3, NC)

5.7 months(95% CI: NC, NC)

CNS Disease Control Rate

Osimertinib (n=75)


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)


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

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


* 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.

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

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


Testing for the EGFR T790M Mutation

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

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.

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:

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

SUMMARY

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

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.


Summary of NSCLC treatment in

Stage IV (metastatic) disease

NCCN Treatment Guidelines. NSCLC Version 1.2015.


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

96



NSCLC

as one

diseaseALK

EGFR

First

Targeted

Therapies

in NSCLC

Erlotinib

Gefitinib

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

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

lung cancer part i

Documents