Overview of Lung Cancer NB... · 2017-10-23 · Causes and Risk factors of Lung Cancer. These slides have been provided, on request by AstraZeneca Diagnostics. AstraZeneca does not,

Proprietary and Confidential ©AstraZeneca 2016 • FOR INTERNAL USE ONLY

Overview of Lung Cancer

Mahmoud Abdelsalam MD/PHD

Chief of Oncology / Hematology, The Moncton Hospital

Professor, Dalhousie University

These slides have been provided, on request by AstraZeneca Diagnostics. AstraZeneca does not, under any circumstances, promote its products for off-label or unapproved uses.

• The magnitude of problem.

• Risk Factors.

• Screening and early detection.

• Pathology and types of lung cancer.

• How to manage Lung cancer.

• What is new in advanced NSCLC and future direction.

• Take home messages.

What to Learn

1



• Risk Factors.






What to Learn

2


• Most frequently diagnosed cancer worldwide

– About 1.35 million new cases diagnosed worldwide each year

• Leading cause of cancer deaths in the United States and

Canada

• 73 new cases daily diagnosed with lung cancer in Canada

(too many)


Incidence


Cancer Death


Canadian Cancer Statistics 2017

6



7



8


5 Years survival

9



• Risk Factors.






What to Learn

10


Causes and Risk factors of Lung Cancer


• Tobacco smoking.

• Contact with second-hand smoke.

• Contact with Radon (decay of uranium found in Rocks and soil).

• Contact with Asbestos or other carcinogens (Coal smoke, diesel fumes, metallic..).

• History of other cancer (smoking related, use of radiotherapy or alkylating Cth.).

• History of lung disease (COPD, Pulmonary Fibrosis).

• Dietary factors and Alcohol consumption.

• Family history of lung cancer (Genes or shared environment).

-Metabolic Polymorphism (detoxicants)

-DNA repair deficiency

Risk Factors

12


Cigarette smoking is the most important risk factor for lung cancer

› Causes approximately 90% of male and 75-80% of female lung cancer deaths

By the early 1950s, case control studies in the US and Great Britain clearly showed an association between smoking and lung cancer

In 1964, the US Surgeon General released a report on the causal relationship



• More than 80 carcinogens in cigarette smoke according to

the International Agency for Research on Cancer (IARC)

– Polycyclic aromatic hydrocarbons (PAHs) are a well

documented lung carcinogen

– Nicotine-derived nitrosamine ketone (NNK), has been shown

to induce lung carcinoma


Prevent smoking

Screening

› Early detection improves resectability and survival

› Methods

Low-dose spiral CT

Combination of chest X-rays and sputum cytology

› May only be cost-effective in high-risk populations


• First high Risk

-55-74 years old

-> 30 Pack years of smoking

-Quit smoking < 15 years

• Second high risk

-> 50 years old

-> 20 pack years smoking or contact with second hand smoke

-Other risk factors

• Moderate risk

-> 50 years old

-> 20 pack years smoking or contact with second hand smoke

-No other risk factors.

• Low risk

-<50 years old

-< 20 pack year smoking

Risk Groups

17



• Risk Factors.






What to Learn

18


Types of Lung Cancer

Two main Types of Lung Cancer:

Small Cell Lung Cancer (20-25% of all lung cancers)

Non Small Cell Lung Cancer (most common ~80%)

20

Features of SCLC

NSCLC (~85%)

“Small blue round-cell

tumor”

SCLC (~15%)

Lung Cancer[1,2]

Squamous cell

carcinomaAdenocarcinoma Large cell carcinoma

• Undifferentiated neoplasm[2]

• Small cells with limited cytoplasm; also referred to as “oat cell carcinoma”[3]

• Distinguishable from NSCLC by smaller cell size, rapid doubling time, high growth fraction, and early

development of metastases[3].

• IHC positive for CD56, Cytokeratin, TTF1, Synaptophysin

1. El-Deiry WS (ed). Impact of Genetic Targets on Cancer Therapy. Adv Exp Med Biol. 2013.DOI:10.10071978-1-46146176-0_18. 2. He L et al. Comput Methods Programs Biomed. 2012;107(3):538-556. 3. Elias AD. Chest.

1997;112(4 suppl):251S-258S.

Abbreviations can be found in the speaker notes.

PERMISSION NOT OBTAINED He et al, Comput Methods Programs Biomed, 20122


Lung Cancer Re-cap

Small Cell Lung Cancer Non-Small-Cell Lung Cancer

Squamous cell Adenocarinoma

ADC39.5%

LCC10.1%

Sq31.7%

Other carcinoma

1.4%

Other

morphologies

0.2%SCLC

17.0%

ADC47.8%

LCC9.9%

Sq21.2%

Other carcinoma

2.3%

Other

morphologies

0.1% SCLC18.6%

Note: graph depicts Canadian data (Alberta, British Columbia, Manitoba, New Brunswick, Newfoundland, Nova Scotia, Ontario and Saskatchewan) from 1998-2002.1

ADC: adenocarcinoma; LCC: large cell cancer; NOS: not otherwise specified; NSCLC: non-small cell lung cancer; SCLC: small cell lung cancer;Sq: squamous cell carcinoma.1. Lortet-Tieulent et al. Lung Cancer. 2014;84:13-22; 2. NCCN clinical practice guidelines in oncology. Non-small cell lung cancer. Available from: nccn.org.

Histological classification: basis for prognosis and treatment

Lung Cancer Histology1

(% of total population)Men Women


Localized Signs and Symptoms

Cough

Breathing Problems, SOB, stridor

Change in phlegm

Lung infection, hemoptysis

Hoarseness, Hiccups

Wt loss

Chest Pain and tightness

Pancoats Syndrome

Horner’s Syndrome

Pleural Effusion

Superior Vena Cava Syndrome

Fatigue


TMN Staging system for Lung Cancer

T= Tumors : tumor size, (local invasion)

N= Node : node involvement (size and

type)

M= Metastasis : general involvement in

organs and tissues




Lung Cancer Staging Continued

• T: Tx, T0, Tis, T1-T4 (T3-tumors

greater than 7cm, T4 is a tumor of

any size)

• N: N0, N1, N2, N3

• M: M0, M1a, M1b

28

Staging of SCLC: VALSG and TNM

• TNM staging system[1-3]

– More descriptive than VALSG

– The IASLC recommends the TNM staging system

• TNM staging system demonstrates more prognostic value than the VALSG system, but treatment choices are still

governed by the 2-class system[1]

• In clinical trial settings TNM stage may be an important stratification factor[3]

Limited Stage (confined to ipsilateral hemithorax

within a single radiation port)

Extensive Stage (metastatic disease outside of

ipsilateral hemithorax)

Stage I-III (T any, N any, M0) safely treated

with radiation doses

Stage IV (T any, N any, M1a/b)

TNM4

1. van Meerbeeck JP et al. Lancet. 2011;378(9804):1741-1755. 2. Kalemkerian GP et al. J Natl Compr Netw. 2013; 11(1): 99-104. 3. Shepherd FA et al. J Thorac Oncol. 2007;2(12):1067-1077. 4. Amin MB et al. AJCC

Cancer Staging Manual. 8th edition. Springer International Publishing. 2016.

Abbreviations can be found in the speaker notes.

VALSG3 AJCC4

Limited Stage(T any, N any, M0; can be safely

treated with definitive radiation)

Extensive Stage(T any, N any, M 1a/b), or T3-4*

* T3–4 due to multiple lung nodules or a tumor/nodal volume that does not fit in tolerable radiation plan.



• Risk Factors.






What to Learn

29

30

mOS: 15–20 months

5-yr OS: 10%–13%

5-yr OS for resectable LD (~5% of all SCLC):

~50%

mOS: <10 months

5-yr OS: 1%–2%

Goals of Therapy in LD- and ED-SCLC

LD-SCLC*[1-3] ED-SCLC*[1-3]

Curative intent with chemoradiotherapy (CRT)

• CRT duration† of <30 days is significantly

associated with improved 5-yr survival rate

(HR: 0.62; P = 0.0003)

Treatment Goal[1,3]

Extend OS, palliative

• Chemotherapy and radiotherapy aim to

extend survival and provide symptom relief

Treatment Goal[1,4]

* Efficacies indicated are regardless of treatment.† CRT duration defined as first day of CT and last day of RT.

1. Früh M et al. Ann Oncol. 2013;24(suppl 6):vi99-vi105. 2. Lally BE et al. The Oncologist. 2007;12(9):1096-1104. 3. Alvarado-Luna G, Morales-Espinosa D. Transl Lung Cancer Res. 2016;5(1):26-38. 4. Parsons HM et al.

Cancer J. 2014;20(2):97-104.

Abbreviations can be found in the speaker notes

31

Treatment of Limited/Localized SCLC

• Clinical trial enrollment is encouraged by NCCN[1]

• ESMO guidelines are endorsed by JSMO[2]

N+: Concurrent

systemic therapy:

• Chemotherapy ± RT

• Nivo ± ipiChemotherapy

+ concurrent RT

T1–2, N0: Systemic therapy:

• Chemotherapy ± RT

• Nivo ± ipi

Limited

excess of

T1–2, N0

OR mediastinal

positive, or

inoperable[1-2]

PCI†

If responsive to

therapy‡

III,C

V,C

NCCN* ESMO Both

* NCCN recommendations are Category 2A unless otherwise indicated. † NCCN does not recommend PCI for patients with poor PS or impaired neurocognitive function.‡ For patients with poor condition, chest irradiation may be postponed until the start of the third cycle of chemotherapy (II,B ESMO).

1I,A

Initial Treatment Subsequent Treatment

Good PS

(0–2)

Poor PS

(3–4)

Poor PS

(3–4) not due to

SCLC

See slide notes for references and abbreviations.

1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Small Cell Lung Cancer V.2.2017. © National Comprehensive Cancer Network, Inc 2016. All rights reserved. Accessed September 26,

2016. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National

Comprehensive Cancer Network, Inc.

2. Früh M et al. Ann Oncol. 2013;24(suppl 6):vi99-vi105.

NCCN permission granted for internal & external use within the US. NCCN permission for use ex-US is pending. Cannot be used ex-US with external customers without NCCN permission.

Limited, T1–2, N0, no

mediastinal LN

involvement[1-2]

Surgery

Individualized treatment,

including SC

Chemotherapy

± RT

II,B

I,A1

V,C

Nivo ± Ipi (NCCN)

Nivo ± Ipi (NCCN)

ORAL10.06: Long-Term Survival after Surgery for Pathologic N1 and N2 Small Cell Lung Cancer: A Comparison with Nonoperative Management

– Yang C-F et al

• Key results

• Conclusions

– Surgery + adjuvant CT ± RT was associated with better survival vs. non-operative management in patients with node-positive SCLC

– Results support the re-evaluation of the role of surgery for selected patients

Yang et al. J Thorac Oncol 2015; 10 (suppl 2): ORAL10.06

mOS, months Surgery No surgery p-value

pN1 36.2 17.1 <0.01

pN2 22.6 13.3 <0.01

OS

OS

(P

rob

ab

ility

)

1.00

0.75

0.50

0.25

0.00

Time (months)

0 12 24 36 48 60

Log-rank p-value <0.01

Median survival 5-year survival

Surgery 26.3 months 28.5%

No surgery 17.1 months 16.7%

A meta-analysis of thoracic RT in LD-SCLC

12 phase III studies

Pignon et al NEJM 1992

34

Treatment of Extensive/Metastatic Disease

Systemic therapies

Regimen NCCN ESMO Comments

EP 2A I,B

EC 2A I,B

IP 2A II,C • If E not indicated

• Preferred regimen in Japan

IC 2A

GC II,C Poor PS + E not indicated

IV/PO TP II,C If E not indicated

Nivo ± Ipi 2A

• Routine use of thoracic RT is not recommended by ESMO[2]

• Systemic therapy for localized symptomatic sites or brain metastases recommended by NCCN*[1]

• Clinical trial participation encouraged by NCCN[1]

• ESMO guidelines are endorsed by JSMO[2]

PCI if responsive to therapy and good PS

NCCN ESMO

NCCN

ESMO

Both

Extensive[1]

(T3,4; Stage IV; no

localized

symptomatic sites or

brain metastases)

Metastatic[2]

(Stage IV)

* RT for localized symptomatic sites; WBRT for brain metastases; radiation can precede chemotherapy for patients with spinal cord compression or symptomatic brain

metastases unless immediate systemic therapy is required.

Initial Treatment

1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Small Cell Lung Cancer V.2.2017. © National Comprehensive Cancer Network, Inc 2016. All rights reserved. Accessed September 26, 2016.

To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National

Comprehensive Cancer Network, Inc.

2. Früh M et al. Ann Oncol. 2013;24(suppl 6):vi99-vi105.

NCCN permission granted for internal & external use within the US. NCCN permission for use ex-US is pending. Cannot be used ex-US with external customers without NCCN permission.

See slide notes for references and abbreviations.

35

IP vs EP in SCLC ED – US experience

Hanna et al. Proc. ASCO 2005, #1094

36

• SCLC represents 15-20% of all lung cancer cases.

• Sensitive to treatment with very high rate of recurrence

• No major breakthrough for long time.

• Thorough molecular profiling of SCLC/LCNEC with possible druggable

target identified.

• Promising novel agents for relapsed disease (immune check-point

inhibitors, DLL3 Rovalpituzumab…).

• Many areas of unmet needs.

• Limited current phase III trials.

• Area for research.

Take home message SCLC


Treatment Algorithm

Non Metastatic Non-small cell lung cancer

N Engl J Med 2004;350:351-60

New Engl J Med 2004;350:351-60

4%

935 775 619 520 447 372 282 208 125

932 780 650 550 487 399 300 208 133

0%

20%

40%

60%

80%

100%

0 1 2 3 4 5 6 7 8 years

chemotherapy: 578 deaths

- 495 deaths before 5 years

- 83 deaths after 5 years

control 590 deaths

- 534 deaths before 5 years

- 56 deaths after 5 years

HR: 0.91 (0.81-1.02, P = 0.10)

Le Chevalier T, et al. J Clin Oncol. 2008(May 20 suppl). Abstract 7507.

"Fading" Benefit ?IALT: 7.5-Year Median Follow-Up

Adjuvant Platinum-Based Chemotherapy

Study Design Stage N Chemo

ALPI RCT I-III 1209 Cis / Mito / Vindesine

IALT RCT I-III 1867 Cis / Vinca or Etoposide

BLT RCT I-IIIA 488* Cis regimen (1 of 4)

JBR.10 RCT IB-II 482 Cis / Vinorelbine

CALGB RCT IB 344* Carbo / Paclitaxel

ANITA RCT I-IIIA 840 Cis / Vinorelbine

*Failed to complete goal enrollment.Negative trial result

Positive trial result

Initial positive result, later follow-up negative

Perception or Reality???

Adjuvant Chemotherapy for NSCLC

Lung Adjuvant Cisplatin Evaluation (LACE)

• Meta-analysis of adjuvant cisplatin trials performed since

1995

• BLT, ALPI, IALT, JBR.10, ANITA

• Pooled individual patient data

• 4584 resected patients, 5 randomized trials– 7% Stage IA

– 30% Stage IB

– 36% Stage II

– 27% Stage III

Pignon JP, et al. J Clin Oncol. 2008;26:3552-3559.


LACE: Pooled Data Overall Survival

5.4% survival advantage at 5 years

HR = 0.89

95% CI 0.82-0.96

P = 0.005

Su

rviv

al

(%)

0

20

40

60

80

100

Time from Randomization (Years)

0 1 2 3 4 5

61.0

48.857.1

43.5

Chemotherapy

No chemotherapy

Su

rviv

al

(%)

0

20

40

60

80

100

0 1 2 3 4 5 ≥ 6

61.0

48.857.1

43.5



LACE Analysis by Stage

Adjuvant chemo has greatest benefit for stage II

and III and may be detrimental for stage IA

Stage IA 104 / 347 1.41 [0.96;2.09]

Stage IB 515 / 1371 0.92 [0.78;1.10]

Stage II 893 / 1616 0.83 [0.73;0.95]

Stage III 878 / 1247 0.83 [0.73;0.95]

CategoryNo. Deaths

/ No. Entered

Hazard Ratio(Chemotherapy / Control) HR [95% CI]

0.5 1.0 1.5 2.0 2.5

Stage IA 1.41 [0.96;2.09]

Stage IB 0.92 [0.78;1.10]

Stage II 0.83 [0.73;0.95]

Stage III 0.83 [0.73;0.95]

CategoryNo Deaths

/ No Entered

Hazard(Chemotherapy / Control) HR [95% CI]

Test for trend: P = 0.051Chemotherapy better Control better

0.5 1.0 1.5 2.0 2.5


SBRT and Early Lung Cancer

Interesting SBRT data from

Japan in operable pts who declined surgery

(Onishi et al)

5 year survivals for stage IA and IB comparable to surgery

Stage IA=77%

Stage IB=68%

Unresectable Tumors

• Definitive radiation therapy: 40% of patients have loco-regional advanced lung cancer (stage lIlA or IIIB)

• Medically inoperable patients with early-stage non-small cell lung cancer

• Locally recurrent: confined to chest

• 5-yrs S.V 5-15% ( R/T alone )

Chemoradiation Vs. R/T alone

for unresectable NSCLC

• RTOG 88-08

• Sequentially chemoradiation therapy

• C/T regimens: CDDP 100 D1, 29

VBL D1,8,15,22,29

• R/T 60Gy since D50

Sequentially R/T alone P-value

Median S.V(M) 13.2 11.4 0.04

5-yrs S.V 8% 5% 0.04

PFS by BICR (Primary Endpoint; ITT)P

FS

pro

babili

ty

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 3 6 9 12 15 18 21 24 27

Time from randomization (months)

Placebo

Durvalumab

476 377 301 264 159 86 44 21 4237 163 106 87 52 28 15 4 3

10

No. at riskDurvalumab

Placebo

Durvalumab

(N=476)

Placebo

(N=237)

Median PFS (95% CI), months 16.8 (13.0–18.1) 5.6 (4.6–7.8)

12-month PFS rate (95% CI) 55.9% (51.0–60.4) 35.3% (29.0–41.7)

18-month PFS rate (95% CI) 44.2% (37.7–50.5) 27.0% (19.9–34.5)

BICR, blinded independent central review; CI, confidence interval; ITT, intention-to-treat; PFS, progression-free survival

Stratified hazard ratio, 0.52 (95% CI, 0.42–0.65)Two-sided P<0.0001

Durvalumab is an investigational drug and is not currently approved for use in this indication in any country

Time to Distant Metastasis or Death by BICR (ITT)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

1 3 6 9 12 15 18 21 24 27 30

Pro

babili

ty o

f death

or

dis

tant

meta

sta

sis

Time from randomization (months)

Placebo

Durvalumab

No. at riskDurvalumab

Placebo476 407 336 288 173 91 46 22 4 1 0237 184 129 106 63 32 16 5 4 0 0

Durvalumab Placebo14.6 (10.6–18.6)23.2 (23.2–NR)Median time (95% CI),

months

BICR, blinded independent central review; ITT, intention-to-treat

Stratified hazard ratio, 0.52 (95% CI, 0.39–0.69)Two-sided P<0.0001

Durvalumab is an investigational drug and is not currently approved for use in this indication in any country


Molecular characterization of lung cancer1

1. Li T, et al. J Clin Oncol. 2013;31(8):1039-1049. 2. Pao W, et al. Proc Natl Acad Sci U S A. 2004;101(36):13306-13311. 3. Shigematsu H, et al. J Natl Cancer

Inst. 2005;97(5):339-346. 4. Sequist LV, et al. Ann Oncol. 2011;22(12):2616-2624. 5. Kris MG, et al. JAMA. 2014;311(19):1998-2006. 6. D’Angelo SP, et al. J

Clin Oncol. 2011;29(15):2066-2070. 7. Keedy VL, et al. J Clin Oncol. 2011;29(15):2121-2127. 8. American Cancer Society. Cancer Facts & Figures 2015.

Atlanta, GA: American Cancer Society; 2015.

Adenocarcinoma

Squamous

cell

carcinomaAll

NSCLC

Other

KRAS

EGFR

ALK

HER2

BRAF

PIK3CA

AKT1

MAP2K1

NRAS

ROS1

RET

KRAS

EGFR

Unknown

FGFR 1 Amp

EGFRvlll

PI3KCA

EGFR

DDR2

Unknown

Squamous

Cell Cancer

Adenocarcinoma

ECOG 1594: OS

Schiller JH, et al. N Engl J Med. 2002;346:92-98.

1.0

0.8

0.6

0.4

0.2

0Pro

po

rtio

n o

f p

ati

en

ts

Mos

0 5 10 15 20 25 30

Survival by Treatment Group

All Randomized Cases

Cisplatin/paclitaxel

Cisplatin/gemcitabine

Cisplatin/docetaxel

Carboplatin/paclitaxel

1st-line treatment of Met NSCLC: No molecular target

Diagnosis

No specific molecular target

Squamous2

cis/pem or other CT doublet*‡48,52,56

(cis/pem has slight advantage over

cis/gem)14

cis/G, other CT doublet,‡14,48,52,56

PS 0-1 PS 2

Non-Squamous2

55

*For patients with private insurance carboplatin/paclitaxel + bevacizumab is an option;48,53

‡Approved CT doublets include, but are not limited to: cis/pem (only for non-squamous),48 cis/gem,48,52 or cis or carbo/vinorelbine.48,58

ll Approved single CT agents include: gem48,52 or vinorelbine48,58

ALK: analplastic lymphoma kinase; BSC: best supportive care; cis: cisplatin; CT: chemotherapy; EGFR: epidermal growth factor receptor; G: gemcitabine; M+: positive for genetic alteration; pem: pemetrexed; PS: performance status. 2. NCCN Clinical Practice Guidelines in Oncology. Non-small cell lung cancer. Available from: nccn.org; 14. Scagliotti et al. J Clin Oncol. 2008;26:3543-51; 28. Tarceva Product Monograph. Hoffmann-La Roche Limited; 30. Giotrif Product Monograph. Boehringer Ingelheim (Canada) Ltd. 45. Serquist et al. J Clin Oncol. 2013;31:3327-34; 46. Rossell et al. Lancet

Oncol. 2012;13:239-46; 47. Mok et al. N Engl J Med. 2009;361:947-57; 48. Régie de l’assurance maladie du Québec. Liste des médicaments – Établissements. Available from: https://www.prod.ramq.gouv.qc.ca/DPI/PO/Commun/PDF/Liste_Med/Liste_Med_Etab/liste_med_etab_2014_06_02_fr.pdf; 49. Drug products undergoing evaluation and evaluated June 2014 [last modified 2014; cited 2014 June 9]. Available from: http://www.inesss.qc.ca/en/activites/drug-products/drug-products-undergoing-evaluation-and-evaluated.html; 50. Shaw et al. N Engl J Med. 2013;368:2385-94; 51. Djalalov et al. J Clin Oncol. 2014;32:1012-9; 42; 52. Gemzar Product Monograph. Eli Lilly Canada Inc.; 53. Avastin Product Monograph. Hoffman-La Roche Limited; 56. Cancer du poumon - Algorithmes d'investigation, de traitement et de suivi [last modified2014 Aug 8; cited 2014 Aug 15]. Available from: http://www.inesss.qc.ca/; 58. Vinorelbine PM. Hospira.

Palliative Care56

PS 0-1 PS 2

cis/G, other CT doublet,‡14,48,52,56 or single-

agent CT

cis/pem or other CT doublet*‡48,52,56 or single-agent CT2

BSC2Erlotinib 56

PS 3 PS 4

Reimbursed in NB

Enrollment in clinical trials is encouraged.2

BSC2Erlotinib 56

PS 3 PS 4

C/P vs C/G in Advanced NSCLC: OS by Histology

Mos

Su

rviv

al

Pro

ba

bil

ity

SquamousNonsquamous

Mos

Su

rviv

al

Pro

ba

bil

ity

Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551.

C/PC/G

C/P vs C/G

Median Survival

11.8 mos10.4 mosAdjusted HR: 0.81

(95% CI: 0.70-0.94)

C/PC/G

C/P vs C/G

Median Survival

9.4 mos10.8 mosAdjusted HR: 1.23

(95% CI: 1.00-1.51)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0300 6 12 18 24

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0300 6 12 18 24

PARAMOUNT Study of Maintenance Pemetrexed vs BSC in NSCLC: PFS

Paz-Ares LG, et al. J Clin Oncol. 2013;31:2895-2902.

1.0

0.8

0.6

0.4

0.2

00 3 6 9 12 15 18 21 24 27 30 33 36 39

PF

S (

%)

MosPts at Risk, nPemetrexed + BSCPlacebo + BSC

359180

21575

13933

9716

679

477

326

224

162

100

50

00

Pemetrexed + BSCPlacebo + BSC

Pemetrexed: median 4.4 mos (range: 4.1-5.7 mos)Placebo: median 2.8 mos (range: 2.6-3.0 mos)Log-rank P < .001Unadjusted HR: 0.60 (95% CI: 0.50-0.73)

PARAMOUNT Study of Maintenance Pemetrexed vs BSC in NSCLC: OS

Paz-Ares LG, et al. J Clin Oncol. 2013;31:2895-2902.

Pemetrexed Placebo

Median OS, mos

(95% CI)

13.9

(12.8-16.0)

11.0

(10.0-12.5)

HR: 0.78 (95% CI: 0.64-0.96; P = .0195)

OS, % (95% CI)

1 yr 58 (53-63) 45 (38-53)

2 yrs 32 (27-37) 21 (15-28)

1.0

0.8

0.6

0.4

0.2

00 3 6 9 12 15 18 21 24 27 30 33 36 39

Overa

ll S

urv

ival

(%)

Mos From Random AssignmentPts at Risk, nPemetrexed + BSCPlacebo + BSC

359180

333169

272131

235103

20078

16665

13849

10535

7923

4312

158

23

00

Pemetrexed + BSCPlacebo + BSC

Treatment Algorithm for Advanced NSCLC:

Molecular Biomarker Positive

ALK positive

Progression

Firs

t line

Se

co

nd

lin

e a

nd

b

eyo

nd

EGFR mutation positive

Advanced NSCLC (Molecular Biomarker Positive)

ROS1 positive PD-L1 positive

Crizotinib

Follow treatment options for adenocarcinoma or squamous cell carcinoma without actionable biomarker

Pembrolizumab

Osimertinib

EGFR T790M mutation negative

Alectinib, brigatinib, or

ceritinib dependent on

previous therapy

Alectinib, ceritinib, or crizotinib

Erlotinib, afatinib, or gefitinib

EGFR T790M mutation positive

BRAF V600Epositive

Dabrafenib/trametinib

A-NSCLC: Algorithm Scaffold

Non-Squamous

EGFR M+ ALK+ WT/WT UNKNOWN

1L

1LM

2L

3L

Squamous

NOS Adenoca Large

IPASS: PFS by EGFR Mutation Status

• Randomized phase III trial; previously untreated pts with advanced NSCLC (N = 1217)

• PFS: Gefitinib superior to carboplatin/paclitaxel in ITT population

• EGFR mutations strongly predicted PFS (and tumor response) to first-line gefitinib vs carboplatin/paclitaxel

Mok TS, et al. N Engl J Med. 2009;361:947-957.

EGFR Mutation–Positive

HR: 0.48 (95% CI: 0.36-0.64; P < .001)

Pro

ba

bil

ity o

f P

FS

Mos Since Randomization

1.0

0.8

0.6

0.4

0.2

00 4 8 12 16 20 24

EGFR Mutation–Negative

HR: 2.85 (95% CI: 2.05-3.98; P < .001)

Pro

ba

bil

ity o

f P

FS

Mos Since Randomization

1.0

0.8

0.6

0.4

0.2

00 4 8 12 16 20 24

GefitinibPac/carbo

GefitinibPac/carbo

EURTAC: PFS in ITT Population

Erlotinib (n = 86)

Chemotherapy (n = 87)

HR: 0.37 (95% CI: 0.25-0.54; log-

rank P < .0001)

PF

S P

rob

ab

ilit

y

1.0

0.8

0.6

0.4

0.2

00 3 6 9 12 15 18 21 24 27 30 33

Mos

5.2 9.7

Rosell R, et al. ASCO 2011. Abstract 7503.

Lee CK, et al. J Natl Cancer Inst. 2013;105:595-605

Favors EGFR TKI Favors Chemo

Meta-analysis of Randomized First-line EGFR TKI Studies: Improved PFS

StudyHR

(95% CI)

HR

(95% CI)

EGFRmut (first-line therapy)

EURTAC

First-SIGNAL

GTOWG

INTACT1-2

IPASS

LUX LUNG3

NEJ002

OPTIMAL

TALENT

TOPICAL

TRIBUTE

WJTOG3405

Subtotal

0.37 (0.25-0.54)

0.54 (0.27-1.10)

1.08 (0.24-4.90)

0.55 (0.19-1.60)

0.48 (0.36-0.64)

0.58 (0.43-0.78)

0.32 (0.24-0.44)

0.16 (0.11-0.26)

0.59 (0.21-1.67)

0.90 (0.39-2.06)

0.49 (0.20-1.20)

0.52 (0.38-0.72)

0.43 (0.38-0.49)

TAGRISSO® (osimertinib) Tablets

© AstraZeneca 2017


Proprietary and Confidential ©AstraZeneca 2017 – any content used externally must be approved locally by local Nominated Signatory prior to use

Median PFS, months (95% CI)

18.9 (15.2, 21.4)

10.2 (9.6, 11.1)

1.0

Pro

ba

bilit

y o

f p

rog

res

sio

n-f

ree

su

rviv

al

0.2

0.4

0.6

0.8

0.0

0 3 6 9 12 15 18 21 24 27Time from randomisation (months)

279

277

262

239

233

197

210

152

178

107

139

78

71

37

26

10

4

2

0

0

No. at risk

Osimertinib

SoC

Osimertinib

SoC

Primary endpoint: PFS by investigator assessment

FLAURA data cut-off: 12 June 2017

Tick marks indicate censored data;

CI, confidence interval; DCO, data cut-off; HR, hazard ratio; SoC, standard-of-care; PFS, progression-free survival. Ramalingam et al. Presented at :ESMO Congress Sep 8-12,, 2017; Madrid, Spain.

342 events in 556 patients at DCO: 62% maturity; osimertinib: 136 events (49%), SoC: 206 events (74%)

HR 0.46

(95% CI 0.37, 0.57)

p<0.0001

64


© AstraZeneca 2017


Proprietary and Confidential ©AstraZeneca 2017 – any content used externally must be approved locally by local Nominated Signatory prior to use

Overall survival interim analysis

FLAURA data cut-off: 12 June 2017; Tick marks indicate censored data ǂFor statistical significance, a p-value of less than 0.0015, determined by O’Brien-Fleming approach, was required

CI, confidence interval; DCO, data cut-off; HR, hazard ratio; NS, not significant; SoC, standard-of-care. Ramalingam et al. Presented at :ESMO Congress Sep 8-12,, 2017; Madrid, Spain.

Pro

ba

bilit

y o

f o

ve

rall

su

rviv

al

0.2

0.4

0.6

0.8

1.0

0.0

0 3 6 9 12 15 18 21 27Time from randomisation (months)

279

277

276

263

269

252

253

237

243

218

232

200

154

126

87

64

4

1

No. at risk

Osimertinib

SoC

3024

0

0

29

24

Osimertinib

SoC

HR 0.63

(95% CI 0.45, 0.88)

p=0.0068 (NS)ǂ

Median overall survival

Not reached

Not reached

141 deaths in 556 patients at DCO: 25% maturity; osimertinib: 58 deaths (21%), SoC: 83 deaths (30%)

65

A-NSCLC: Algorithm Scaffold

Non-Squamous

EGFR M+ ALK+ WT/WT UNKNOWN

1L

1LM

2L

3L

Squamous

NOS Adenoca Large

67 Prepared by Pfizer in response to an unsolicited request – Not for further distribution67

PROFILE 1014 Primary Endpoint: PFS by Independent Radiologic Review (ITT

Population)

Solomon BJ, et al. N Engl J Med 2014;371:2167−77a2-sided stratified log-rank test

Crizotinib

(n=172)

Chemotherapy

(n=171)

Events, n (%) 100 (58) 137 (80)

Median, mo 10.9 7.0

HR (95% CI) 0.45 (0.35−0.60)

Pa <0.001

Crizotinib

Chemotherapy

No. at risk:

Crizotinib 172 120 65 38 19 7 1 0

Chemotherapy 171 105 36 12 2 1 0 0

Time (months)

0 35

PF

S p

rob

ab

ilit

y (

%)

100

80

60

40

20

0

2015105 25 30

Distributed upon unsolicited request from HCP

Primary endpoint: PFS, investigator-assessed

Presented By Alice Shaw at 2017 ASCO Annual Meeting

Distributed upon unsolicited request from HCP

Secondary endpoint: OS

Presented By Alice Shaw at 2017 ASCO Annual Meeting


Evolving targeted therapies now include immuno-therapies

70

PD-L1

Metastatic Lung

Cancer

Molecular Genotyping

BRAFCMETROS1ALKEGFR

Erolotinib

Gefitinib

AfatinibCeritinib

Alectinib

Brigatinib

Dabrafenib

+Trametinib

NTRK1

Entrectinib

Larotrectinib

CrizotinibCrizotinibCrizotinib

Osimertinib

TARGET

1st Line

2nd Line Pembrolizumab ≥ 50%

Nivolumab

Alice Shaw, ASCO 2017


PD-1/PD-L1 antibodies block PD-L1/PD-1 interactions, inducing antitumour responses

• TCs and tumour-infiltrating ICs express PD-L1, which binds to PD-1 on the surface of T cells, inhibiting T-cell signalling and blocking antitumour immune responses1–3

• Durvalumab, a monoclonal PD-L1 antibody, prevents PD-L1 binding to PD-1 and CD80, inducingantitumour immune responses1–5

Tumour

cell

Immune

cell

T cell

PD-L1

PD-1PD-L1 PD-1

CD8

0

CD80

TCRMHC

PD-L1

Tumour

antigen

CD80

Activation

CD28Activation

TCRMHCActivation

Activation

Inhibition

Inhibition

InhibitionInhibition

Inhibition

Durvalumab

Durvalumab blocks PD-L1 binding to PD-1 and

CD80

–

Durvalumab

–

–

Figure adapted from Antonia SJ et al. ESMO 2016. Reproduced with kind permission of SJ Antonia. 1. Pardoll DM. Nat

Rev Cancer 2012;12(4):252–64 2. Borczuk AC, Allen TC. Arch Pathol Lab Med 2016;140(4):351–4. 3.Antonia SJ, et al.

Poster presented at ESMO 2016 (Abstract 1216). 4. Postow MA, et al. J Clin Oncol 2015;33(17):1974–82 5. Stewart, R,

et al. Cancer Immunol Res 2015;3(9):1052–62


Higher PD-L1 expression is associated with higher ORR across tumour types

Direct comparisons cannot be made between agents due to different trial designs, patient populations, treatment line, PD-L1 assays and PD-L1

expression cut-off used

Associated PD-L1 expression cut-offs separating high vs low expression: durvalumab: nivolumab: ≥1% vs <1%; pembrolizumab: ≥50% vs 1-49%, <1%;

atezolizumab, ≥ 5% vs <1%; avelumab, ≥ 5% vs <5%

Monotherapy is

associated with higher

ORRs in patients with

PD-L1 high tumours

Higher responses to

combination regimens

are observed in patients

with high or low/no PD-

L1 expression compared

with monotherapy in

similar patients

Nivolumab + ipilimumab (CheckMate 012) 1L

Pembrolizumab (KEYNOTE-001) 1L

Pembrolizumab (KEYNOTE-052) 1L

Durvalumab (Study 1108: NSCLC cohort) 1L, 2L, ≥3L

Durvalumab + tremelimumab (Study 006) 1L

Pembrolizumab (KEYNOTE-012) 1L– ≥5L

Nivolumab (CheckMate 141) 1L, 2L, ≥3L

Pembrolizumab (KEYNOTE-012: UC cohort) ≥3L

Nivolumab (CheckMate-032) 2L

Atezolizumab (IMvigor 210) 2L

Nivolumab (CheckMate 057) ≥2L

Avelumab (JAVELIN) 2L

NS

CLC

HN

SC

CU

C

Higher ORR in

PD-L1 high

Higher ORR in

PD-L1 low/negative

57–100% 0–30%

34–45% 9–17%

17%–29% 20%

25% 6%

22% 29–40%

18–21% 6–19%

17–28% 10–12%

29–33% 0–9%

24% 26%

18–50% 8–18%

54% 4%

31% 9%

Pembrolizumab (KEYNOTE-055) 2L 17% 8%

Durvalumab (Study 1108: UC cohort) 1L, 2L, ≥3L 46% 0%

Durvalumab (Study 1108: HNSCC cohort) 1L, 2L, ≥3L 18% 8%

Nivolumab (CheckMate 275) 2L 23.8–28.5% 15.4%

Pembrolizumab + ipilimumab (KEYNOTE-021) 1L– ≥5L

15%–37% 18%


PD-L1 testing and treatment regimen decisions

References are provided in the slide notes

PD-1/PD-L1

pathway

inhibition

CTLA-4

pathway

inhibition

High and low/no

PD-L1 expression

Single-agent

PD-1/PD-L1

pathway

inhibition

High

PD-L1 expression

Testing for PD-L1 expression status will help guide

combination treatment decisions to identify and confirm

patients with high and low PD-L1 expression

Testing for PD-L1 expression status is important for

monotherapy treatment decisions to identify and confirm

patients with high PD-L1 expression

1.Garon EB, et al. N Engl J Med 2015;372:2018–28. 2. Antonia SJ, et al. Poster presented at ESMO 2016 (Abstract 1216). 3.Segal NH, et al.

Poster presented at ESMO 2016 (Abstract 949). 4.Massard C, et al. J Clin Oncol 2016;34(26):3119–25. 5. Antonia SJ, et al. Lancet Oncol

2016;17(3):299–308. 6.Hellmann et al. Lancet Oncol 2016; epub ahead of print

KEYNOTE-024 Study Design (NCT02142738)

Presented By Julie Brahmer at 2017 ASCO Annual Meeting

12

KEYNOTE-024: Survival Outcomes

Reck M, et al. N Engl J Med. 2016;375:1823-1833. Brahmer JR, et al. ASCO 2017. Abstract 9000.

PFS OS

PF

S (

%)

100

80

60

40

20

0

Mos

180 3 6 9 12 15

Mos

OS

(%

)

100

80

60

40

20

0240 3 6 9 15 18 21

Pembro

(n = 154)

CT

(n = 151)

Median PFS, mos 10.3 6.0

HR (95% CI) 0.50 (0.37-0.68); P <

.001

Pembro

(n = 154)

CT

(n = 151)

Median OS,

mos

NR 14.5

HR (95% CI) 0.63 (0.46-0.88); P = .003

Slide credit: clinicaloptions.com

http://www.clinicaloptions.com/

KEYNOTE-021g: First-line CT + Pembrolizumab

vs CT Only

Papadimitrakopoulou V, et al. ASCO 2017. Abstract 9094.

Pembro + CT

CT Alone

Median PFS, mos

NR 8.9

HR (95% CI) 0.50 (0.29-0.84)

P value .0038

100

80

60

40

20

0

PF

S (

%)

0 3 6 9 12

Pts at Risk, n

60

63

51

41

Mos

OS

(%

)

Mos

Pembro + CT

CT Alone

Median OS, mos NR NR

HR (95% CI) 0.69 (0.36-1.31)

P value .13

PFS OS

Slide credit: clinicaloptions.com

15 18 21

Pembro + CT

CT42

34

31

23

21

13

13

8

6

3

0

1

100

80

60

40

20

00 3 6 9 12

Pts at Risk, n

60

63

56

57

15 18 21

Pembro + CT

CT53

57

49

51

43

39

28

26

15

14

3

3

http://www.clinicaloptions.com/


PD-L1 testing: A dynamic landscape for patients and providers

77

Nonsquamous cell Squamous cell

ROS1 +

fusion

ALK

fusion

EGFR

mutation+

≥50% PD-L1

expression

0 to 49% PD-

L1 expression≥50% PD-L1

expression

0 to 49% PD-

L1 expression

Pembrolizuma

bChemo ±

Bevacizumab

Carbo/Pemetrexe

d/Pembrolizumab

Bevacizumab (if

eligible)

Pembrolizumab

Nivolumab,

Pembrolizumab, or

Atezolizumab

Chemo

Pemetrexed (if

eligible)

Chemo

Nivolumab,

Pembrolizumab, or

AtezolizumabChemo

1st or 2nd

generation

EGFR-TKI

T790M+

OsimertinibT790M-

Chemo

Crizotinib

,

Ceritinib,

or

(Alectinib

)

Crizotinib

or

Ceritinib

Chemo

Alectinib, Brgatinib,

or Ceritinib

1st line

Maintenance

(responders

only)

2nd/3rd

line

Adapted from Tsao MS et al. in IASLC Atlas of PD-L1 IHC Testing in Lung Cancer (Tsao, Kerr, Dacic, Yatabe, Hrsch, eds) (IASLC 2017)



• Risk Factors.






What to Learn

78


• Lung Cancer is third common cancer

• It is main cause of cancer death

• Smoking is the main risk factor

• Screening is considered for high risk population

• SCLC, sensitive to treatment, potential recurrence, poor outcome, area of research

• Early cases NSCLC, options of treatment, research to improve recurrence rate

• LA NSCLC, recently improved using immunotherapy

• Met NSCLC, fractionated based on pathology, molecular, genetic, improve

outcome

• Ongoing research

Take home messages

79


THANK YOU

80

Documents

Overview of Lung Cancer NB... · 2017-10-23 · Causes and Risk factors of Lung Cancer. These slides have been provided, on request by AstraZeneca Diagnostics. AstraZeneca does not,