James R. Jett, MD National Jewish Health Denver, Colorado Lung Cancer: 2015
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