James R. Jett, MD

National Jewish Health

Denver, Colorado

Lung Cancer: 2015

James Jett MD

I have no potential conflicts of interest related to this lecture.

Cancer Statistics 2015Lung Cancer

New

Cases

Deaths

(no.)

Cancer

Deaths (%)

Men 115,610 86,380 28

Women 105,590

(48%)

71,660 28

Total 221,200 158,050

American Cancer Society, Cancer Statistics; 2015

Cancer Statistics 2015

kk k

k

k

Cancer Statistics 2015

Primary

Site

New

Cases

(no.)

Deaths

(no.)

1975-

1977

2004-

2010

Lung 221,200 158,040 12 18

Colorectal 132,700 49,700 51 65

Breast 234,190 40,730 75 91

Pancreas 48,960 40,560 3 7

Prostate 220,800 27,540 68 >99

American Cancer Society, Cancer Statistics; 2015

5-Year Survival

Deaths Due to Cigarette Smoking (2011)for 12 Smoking-Related Cancers in USA

Total

Deaths

Smoking

Attributed Percent

Larynx 3,728 2,856 77%

Lung 156,855 125,799 80%

Oral Cavity & Pharynx 8,576 4,032 47%

Esophagus 14,404 7,307 51%

Urinary Bladder 14,997 6,724 45%

Total (all 12 cancers) 345,962 167,805 48%

Amer Can Society JAMA, pub online June 15, 2015

Stage groups according to TNM descriptor and subgroups.

Chest;2009;136:260-271

©2009 by American College of Chest Physicians

Focus of this Lecture

• Current Status of Innovative Treatments of Lung Cancer

• Impact on Survival

• Update on Lung Cancer Screening

• Solitary Pulmonary Nodule followupand risk of cancer.

Survival With Stage IV NSCLC:First Line Therapies

1980 No Treatment 4-5 Months

1990 Platinum Doublets 9 Months

2000 Platinum Doublets ±Bevacizumab 12 Months

2010 EGFR Sensitizing Mutations 24 Months

13

ECOG 1594: Time to Progression

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

1.0

0.8

0.6

0.4

0.2

0

10 15 25

Months

0 5 20 30

Cisplatin/Paclitaxel

Cisplatin/Gemcitabine

Cisplatin/Docetaxel

Carboplatin/Paclitaxel

Traditional

Molecular Testing for NSCLC - 2012

Adenocarcinoma

Squamous

Large Cell

Unknown

FGFR1

Amp

EGFRvIII

PI3KCA

EGFR TK

DDR2

BRAF

AKT

VEGFRHER2

EPHA/B

PDGFR

FGFR

INSR

PI3K

MAPK

KRAS

EGFR

ALK

Unknown

Adenocarcinoma

Squamous Cell Ca

RET

Adapted from W. Pao and N Girard, Lancet Oncol, 2011

Driver Mutations

• “Driver mutations” confer growth advantage and are causal to cancer development versus “passenger” mutation which are biologically neutral with no growth advantage

• These mutations occur in genes that encode signal proteins critical for cellular proliferation and survival

• Most “driver mutations” have been identified in adenocarcinomas.

Driver Mutations and Amplification

EGFR

ALK

ROS

KRAS

L858R +: 4 weeks of erlotinib therapy

CT scans of 2/26/14 & 7/2/14

ALK Fusion on Crizotinib

Changes in Last 5-10 Years

•Sensitizing somatic mutations in adenocarcinoma: EGFR, ALK, ROS-1

•EGFR (T790M) inhibitors

– Rociletinib; AZD 9291

•Second line ALK inhibitors

– Ceritinib; Alectinib

•Immune Check-Point Inhibitors with Anti-PD1 or Anti-PDL1 Inhibitors

Randomized Trials of EGFR TKI vs CT in 1st Line Rx

Study ORR PFS (mo) HR OS

EURTAC 58% vs 15% 9.7 vs 5.2 0.37 ND

OPTIMAL 83% vs 36% 13.1 vs 4.6 0.16 ND

NEJ 002 74% vs 31% 10.8 vs 5.4 0.30 ND

WJTOG 3405 62% vs 31% 9.2 vs 6.3 0.49 ND

IPASS 71% vs 47% 9.5 vs 5.5 0.19 ND

LUX LUNG 3 56% vs 23% 11.1 vs 6.9 0.58 ND

LUX LUNG 6 67% vs 23% 11.0 vs 5.6 NR NR

The relative frequencies of the various mechanisms of acquired resistance.

Yu H A et al. Clin Cancer Res 2013;19:2240-2247

©2013 by American Association for Cancer Research

AZD9291 in EGFR Resistant NSCLC

Janne, et al. NEJM 2015; 372:1689

• All patients had sensitizing mutations and progression on EGFR TKIs

• 127 Patients with EGFR T790M Mutations

– RR of 61% (52-70)

• 61 Patients Without T790M Mutations

– RR of 21% (12-34)

• Median PFS of 9.6 Months in T790M Positive

– PFS of 2.8 months in T79OM negative

Janne, et al. NEJM 2015; 372:1689

Janne, et al. NEJM 2015; 372:1689

Before and 14 days after start of crizotinib in ALK mutation

Rociletinib in EGFR Mutated NSCLC

Sequist et al. NEJM 2015;372:1700

• Tumor biopsy was mandatory and T790M positivity had to be confirmed in Phase II

• 172 patients screened

– Genotyping possible in 148 (86%)

– 78 (53%) had T790M mutation

• Majority of testing failures due to Insufficient Tumor Tissue in Biopsy Sample

•Tumor cells release free DNA into the blood

•Blood sample can identify both genetic and epigenetic aberrations of cancers

•Systematically track genomic changes

Nature Rev Clin Oncol 2013; 10:472-484

Nature Rev Clin Oncol 2013; 10:472-484

How Do PD-L1 Blockade and PD-1 Blockade Differ?

Freeman & Sharpe, Nat Immun 2012; 13 (113) Presented by: Natasha Leighl at ASCO Annual 13 Meeting

MPDL3280A (Anti-PDL1) Inhibits the Binding of PD-L1 to PD-1 and B7.1

Blocking PD-L1 restores T-cell activity, resulting in tumor regression in preclinical model.

Binding to PD-L1 leaves PD-1/PD-L2 interaction intact and may enhance efficacy and safety.

Nivolumab as Second Line Treatment in Squamous Cell Lung Cancer

Brahmer, et al. NEJM 2015;373:123

• 272 patients randomized to nivolumab3mg/kg every two weeks or docetaxel75mg/m2 Every Three Weeks

• MST 9 vs 6 months in favor of nivolumab

– HR 0.59 (41% lower risk death)

• One Year Survival 42% vs 24%

• Response Rate 20% vs 9%

• Grade ¾ Toxicity 7% vs 55%

Brahmer et al NEJM 2015; 373:123-35

Brahmer et al NEJM 2015; 373:123-35

Survival with Nivolumab in

Previously Treated NSCLC

All Doses

(n=128)

3mg/kg

(n=37)

Median OS 9.9 mos 0

1 Year (%) 42 56

2 Year (%) 24 42

3 Year (%) 18 27

Gettinger et al. J Clin Oncol 2015; 33:2004

Gettinger et al. J Clin Oncol 2015; 33:2004

Gettinger et al. J Clin Oncol 2015; 33:2004

Pembrolizumab Treatment

in Second Line NSCLC

•495 Patients Treated at Varying Doses and Schedules

•RR of 19%; DUR 12.5 mos; MST 12 mos

•With 50% Staining of Cells with PDL-1 (cancer and mononuclear inflammatory cells)

– RR 45%; PFS 6.3 mos; OS not reachedGaron et al. NEJM 2015: 372:2018-28

Postow et al J Clin Oncol 2015; 33:1974-82

Immunotherapy: Lung Cancer

• Nivolumab Has Been Approved for Second-Line Therapy for Non-Small Cell Lung Cancer

• Estimated Cost of $100,000/Year

$10,000 per treatment approximately

•100 experts in CML drew attention to high prices of cancer drugs

• Lower the prices of cancer drugs to allow more patient to afford them

• Maintain sound long-term healthcare policies

Blood 2013: 121:4439

Pricing of Oncology Drugs

“The Notion That Drug Prices

Are Linked to Anything

Coherent Like Value or

Benefit Has Been Debunked.”

Dr. Peter Back - MSKCC

Drug Abacus.org

Research tool created at MSKCC to compare cost of 54 Oncology Drugs approved since 2001

Screening and Nodule Evaluation

Lung Cancer

•228,000 new cases in 2013

– 60% will be dead within one year

• Symptomatic lung cancer is advanced stage disease and not curable

Lobar Collapse

CP1066773-34

National Lung Cancer

Screening Trial (NLST)

CP1066773-57

SmokerFormer smoker

30 pk yrAge 55-74

SmokerFormer smoker

30 pk yrAge 55-74

40,000PLCO40,000PLCO

10,000ACRIN10,000ACRIN

RandomizedRandomized

Low-dose fast spiral CTLow-dose fast spiral CT

CXRCXR

YearsYears

00 11 22

Lung Cancer Mortality:October 2010

ARM

Lung

Cancer

Deaths

Lung

Cancer

Mortality per

100,000 PY

Reduction

in Lung

Cancer

Mortality

LDCT 356 247 20%

CXR 443 309

True and False Positive Screens

Screen Results T0 T1 T2

Total Positive 7,193 6,902 4,052

Lung Cancer 270 (4%)

168 (2%)

211 (5%)

No Lung Cancer 96% 98% 95%

Low Dose CT

Lung Cancer Stage I

•NELSON 64% (N Eng J Med)

•NLST 63%

CP1066773-42

CP1066773-43

Predictive Value of LDCT

Nodule Size PPV%

≥4mm 3.8

4-6mm 0.5

7-10mm 1.7

11-20mm 11.9

21-30mm 29.7

>30mm 41.3

Hilar or Mediastinal Adenopathy 18.5

• Negative Predictive Value 99.9%NLST Team. NEJM 2013; 368:1980-91

Two-Year Probability of Lung Cancer

by Nodule Size: NELSON

Horewig et al. Lancet Oncol 2014; Pub online Oct 2

Size in mm

2-Year

Probability

<4 0.6%

5 to <6 0.9%

6 to <7 0.4%

7 to <8 1.8% P=<.001

8 to <10 2.9% P=<.001

Two-Year Probability of Lung Cancer

by Nodule Size: NELSON

Horewig et al. Lancet Oncol 2014; Pub online Oct 2

Size in mm

2-Year

Probability

8 to <10 2.9%

10 to <15 11.1%

15 to <20 19.6%

20 to <30 25.0%

≥30 31.6%

Lung Cancer Risk Prediction:PLCO Model

Tammemagi et al. NEJM 2013;368:728

Age

Education

Body Mass Index

Family History Lung Cancer

History of COPD

Race

Smoking Status (NS, F, C)

Smoking Intensity

Smoking Duration

Quit Time in Former Smokers

Spread sheet calculator of Lung Cancer risk and Lung

Nodule Risk: Available online

http://www.brocku.ca/lung-cancer-risk-calculator

ACR LungRADS®Category

Descriptor

Category

Descriptor

Primary

Category

Incomplete - 0

Negative No nodules & definitely benign nodules 1

Benign

Appearance or

Behavior

Nodules with a very low likelihood of

becoming a clinically active cancer due to

size or lack of growth2

Probably benign

Probably benign finding(s) - short term

follow up suggested; includes nodules with

a low likelihood of becoming a clinically

active cancer

3

SuspiciousFindings for which additional diagnostic

testing and/or tissue sampling is

recommended

4A

4B

ACR LungRADS®

CategoryCategory

Descriptor

Categor

yFindings Management

Negative

No nodules

and definitely

benign

nodules

1no lung nodules

Continue

annual

screening

with

LDCT in 12

months

nodule(s) with specific calcifications:

complete, central, popcorn, concentric

rings and fat containing nodules

Benign

Appearanc

e or

Behavior

Nodules with a

very low

likelihood of

becoming a

clinically active

cancer due to

size or lack of

growth

2

solid nodule(s):

< 6 mm

new < 4 mm

part solid nodule(s):

< 6 mm total diameter on baseline

screening

non solid nodule(s) (GGN):

< 20 mm OR

≥ 20 mm and unchanged or slowly

growing

category 3 or 4 nodules unchanged for ≥ 3

months

ACR LungRADS®

Category Category Descriptor Category Findings Management

Probably

Benign

Probably benign

finding(s) - short term

follow up suggested;

includes nodules with a

low likelihood of

becoming a clinically

active cancer

3

solid nodule(s):

6 month

LDCT

≥ 6 to < 8 mm at baseline

OR

new 4 mm to < 6 mm

part solid nodule(s)

≥ 6 mm total diameter

with

solid component < 6 mm

OR

new < 6 mm total

diameter

non solid nodule(s) (GGN) ≥

20 mm on baseline CT or new

ACR LungRADS®Category Category Descriptor Category Findings Management

Suspiciou

s

Findings for

which additional

diagnostic testing

and/or tissue

sampling is

recommended

4A

solid nodule(s):

3 month

LDCT; PET/CT

may be used when

there is a ≥ 8 mm

solid component

≥ 8 to < 15 mm at baseline OR

growing < 8 mm OR

new 6 to < 8 mm

part solid nodule(s:

≥ 6 mm with solid component ≥ 6 mm to < 8

mm OR

with a new or growing < 4 mm solid

component

endobronchial nodule

4B

solid nodule(s)chest CT with or

without contrast,

PET/CT and/or

tissue sampling

depending on the

*probability of

malignancy and

comorbidities.

PET/CT may be

used when there is

a ≥ 8 mm solid

component.

≥ 15 mm OR

new or growing, and ≥ 8 mm

part solid nodule(s) with:

a solid component ≥ 8 mm OR

a new or growing ≥ 4 mm solid

component

4X

Category 3 or 4 nodules with additional features

or imaging findings that increases the suspicion

of malignancy

Screening for Lung Cancer: US Preventive Services Task Force

•USPSTF recommends annual screening for lung cancer with LDCT in adults aged 55-80years

•30 pack year smoking history and currently smoke or have quit within the past 15 years

74 page report with details on an approved screening program and center requirements

November 10, 2013CMS issues preliminary approval

Must collect and submit data to CMS

Data Type

• Facility

• Radiologist

• Patient

• Ordering practitioner

• Demographics

• Indication

• Smoking history

• Scanner/radiation dose

• 4 more items on outcomes

Minimum data elements

• Identifier

• NPI

• Identifier

• NPI

• DOB, gender, race/ethnicity

• LC screening; no symptoms

• Current, former, yrs quit

• Manufacture/model/dose

CP1081380-27