\/,ale CANCER J ( CENTER A Comprehensive Cancer Center Designated by the National Cancer Institute

Pathophysiology of Tobacco Induced Cancers

Roy S. Herbst, MD, PhD Ensign Professor of Medicine Professor of PharmacologyChief of Medical Oncology

Director, Thoracic Oncology Research ProgramAssociate Cancer Center Director for Translational Research

February 27, 2014

Goals of this presentation

• Pathogenesis of tobacco induced cancer – Epidemiology and mechanism – Focus on lung and head and neck cancer

• Joint AACR/NCI efforts related to tobacco control – Tobacco use in patient’s receiving treatmentfor cancer

– Clinical trials

• New Approaches to treatment of tobacco induceddisease- the lung cancer master protocol

Goals of this presentation

• Pathogenesis of tobacco induced cancer – Epidemiology and mechanism – Focus on lung and head and neck cancer

health consequences causally linked to smok ing

Cancers

Oropha

Acute myeloid leukemi

Chronic Diseases

.-------- Stroke

~ ---- Blindness , cataracts , age-related macular degeneration _,,,,,..._ .. , L- --- Congenital defects-maternal smoking: orofacial clefts

, ,,,.~--- Periodo ntitis

~ -- Aort ic aneu rysm, early abdomina l aortic ath eroscleros is in young adults

Coronary heart disease

Pneumon ia

1111---+-- Atherosclerot ic periph eral vascu lar disease

1-+---¼- -+- - Chronic obstru ctive pulmonary disease, tuberculosis, ----- asthma , and other respira tory effects

Diabetes

Reproductive effects in women (inclu ding reduced fert ility)

Ectopic pregnancy

Male sex ual functio n-e rectile dys functi on

- n heuma toid arthritis

Immun e function

Overall diminish ed healt h

Source: USDHHS 2004 , 2006 , 20 12. Note: The condit ion in red is a new disease that has been causally linked to smoking in this repor t.

The Health consequences causally linked to smoking

Tobacco is the Single Largest Cause of Cancer in the World

• Tobacco use causes cancer in no less than 18 organ sites.

• Smoking causes more than 85% of lung cancers.

• One in three cancer deaths in the U.S. is directly linked to tobacco.

• The 2014 Surgeon Generals Report added the association of tobacco with hepatocellular and colorectal cancer

Epidemiology of Tobacco-Related Cancers in the US, Estimated in 2012

Cancer type # cases # deaths Lung 226,160 160,340 Head and neck* 52,610 11,500 Esophageal 17,460 15,070 Stomach 21,320 10,540 Pancreas 43,920 37,390 Kidney 64,770 13,570 Bladder 73,510 14,880 Uterus 47,130 8,010 Cervix 12,170 4,220 Colon/rectum 143,460 51,690 Ovary 22,280 15,500 AML 13,780 10,200

* larynx, oral cavity, nasopharynx, pharynx NCI SEER

Epidemiology of Tobacco-Related Cancers Worldwide in 2008

Cancer type # cases # deaths Lung 1,606,911 1,375,919 Head and neck* 631,786 355,217 Esophageal 481,645 406,198 Stomach 987,904 736,976 Pancreas 278,470 266,543 Kidney 264,146 110,824 Bladder 382,130 150,143 Uterus 288,265 73,818 Cervix 529,601 274,668 Colon/rectum 570,795 288,323 Ovary 222,613 139,472

* larynx, oral cavity, nasopharynx, pharynx WHO GLOBOCAN 2008

How Smoking Causes Cancer • Cigarette smoke contains more than 7,000 compounds of which >60 are known carcinogens (600 added to enhance flavor/nicotine absorption)

• Inhaling this mix of chemicals induces tissue injury and changes in the cellular environment fostering the proferation and transformation into cancer

• Mutations result in loss of normal growth control, silencing of tumor progression genes, and promotion of cancer

• Field effects, second (or more) primary cancers are common

9

Effects of stopping smoking at various ages on the cumulative risk (%) of death from lung cancer by age 75

for men CUMULATIVE RISK (%) 18

15

12

9

6

3

0

Current cigarette smoker Stopped smoking at 60 Stopped smoking at 50 Stopped smoking at 40 Stopped smoking at 30 Lifelong non-smoker

45 50 55 60 65 70 75

Age AGE

Peto, R., BMJ 2000, 321(7257):323-

eliited-

·~ Common

P,.,._orn'llOI o..,.r, · -,....,..1o::a,1~.,,. r

wtltn<ltut:aJfJLN'affi -"'=PY

Cana,r k

Molecular Carcinogenesis of Lung Cancer

RS Herbst, et al, N Engl J Med 2008.

Molecular Carcinogenesis of Head and Neck Cancer

Mild Moderate Severe Carcinoma Invasive Normal Hyperplasia Dysplasia Dysplasia Dysplasia in situ Carcinoma Metastasis

E-cadherin CXCR4/SDF-1 VEGF(R)s, PDGF(R) FGF(R), TGFα/β(R) ILK-8(R)

LOH: 3p14, 9p21, 17p13

LOH: 8p, 11q, 13q,14q

EGFR, Rb, p53, p65, Cox-2, p16, Cyclin D1, PTEN

MMPs

LOH: 6p, 4q27, 10q23

Chemoprevention Therapy

Haddad RI and Shin DM. NEJM 2008;359:1143-1154.

Complexity of Tobacco-Related Carcinogenesis

Early Intermediate Late

Normal Hyperplasia Dysplasia CIS Invasive Epithelium Carcinoma 3p LOH/Small Telomeric Deletions 3p LOH/Contiguous Deletions

Microsatellite Alterations 9p21 LOH

Telomerase Dysregulation Telomerase Upregulation MYC Overexpression

8p21-23 LOH Loss of Fhit immunostaining

p53 LOH TP53 Mutations

Aneuploidy

Methylation 5q21 APC-MCC LOH

Wistuba, et al. Oncogene 2008

HrtO

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40

~ 30 O• i 25

.e 20 ,o

j 115

:;i! 10

5

o ln.(,~I. ~ ~ i ,- r-- ~

273

248

157

Cigarette Smoke Carcinogen Adducts at Lung Cancer Mutational Hotspots in P53 • Identification of p53 • Cigarette smoke carcinogen BPDE

G:C to T:A mutations in adducts in p53 mapped to guanines in lung cancer smokers codons 157, 248, and 273 - major

mutational hotspots in human lung cancer

Frequency of G:C to T:A transversions (%)

Takeshima et al. Lancet 1993; 342:1520-21 Dennisenko et al. Science 1996;274:430-432.

•

Widespread Dispersed p53 Mutation in Respiratory Epithelium of a Smoker

66-yr-old Smoker – Male TP53 Mutation Codon 245 (G:C to T:A)

Right Left

Mutant Wild-Type

Franklin WA et al. J Clin Invest. 1997;100:2133-2137.

itiation of cigarette smoking,' nicotine addiction

Regular cigarette smoking

Receptor binding

Uptake of Metabolic carcinogens activat ion

Metabolic detoxification

Excretion

Uptake of cocarcinogens and tumor promoters

Protein kinase A and B activation and other changes

DNA Persistence adducts miscoding

Repa~

Apoptosis

Normal DNA

Mutations in oncogenes and tumor­suppressor

genes

Gene promoter hypermethylation

Tumor-suppressor gene inactivation

and other changes

Loss of normal growth

control mechanisms

Cancer

Link between Cigarette Smoking and Cancer through Carcinogens in Tobacco Smoke

Genetic Profiles by Histologic Subtype Oncogenic drivers differ between adenocarcinomas and squamous cell carcinomas

Adenocarcinoma

• KRAS.

• EGFR

• ALK

PIK3CA

HER2

• BRAF

ROS

• RET

NRAS

• MET

Other/unknown

Squamous cell carcinoma

• FGFR

PIK3CA

• KRAS

• PDGFR

• DDR2

• EGFR

NRAS

Other/unknown

Sequist et al., Ann Oncol 22:2616, 2011; Bergethon et al., JCO Jan 3, 2012; Weiss et al., Sci Transl Med 2:62ra93. 2010; Kris et al., WCLC 2011; Hammerman et al., Cancer Discovery 1 :78, 2011; AJ Iafrate, personal communication

Lung Cancer Mutation Consortium: Squamous Cell Cancers also have driver mutations

Goals of this presentation

• Pathogenesis of tobacco induced cancer – Epidemiology and mechanism – Focus on lung and head and neck cancer

• Joint AACR/NCI efforts related to tobacco control – Tobacco use in patient’s receiving treatmentfor cancer

– Clinical trials

• New Approaches to treatment of tobacco induceddisease- the lung cancer master protocol

Pubi<..h<d ~F"" April 13, 2010 . OOl· 10 11581!nl8 ,5472 CAN,11).11)87

M,( ·""l American Association .i7n "-. forCa11cerR esenrch

Tobacco and Cancer: An American Association for Cancer Research Policy Statement l<asiso mayaJula Vlswanath , Roy S. Her'blS.t, St&J)h.3nle R, Land , Soolt J . U isehOw , 3nd Ptl at" G . Shield $; Writin g COnvnitl:ee f or the AACR T3$k Foree on TOb.;"\C(Xl Md c.-mc:t r

E"xll!!'C-ulive Summary

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Tobacco and Cancer: An AACR Policy Statement

• Includes research and policy recommendations for:

– Preventing tobacco use

– Treating tobacco addiction and fostering cessation

– Reducing exposure to second hand smoke

– Addressing tobacco-related cancer Cancer Research, April 15, 2010 3419-3430

ASSESSING ANO TREATING TOBACCO USE BY

CANCER PATIENTS: RECOMMENDATIONS FROM THE

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RECOMMENDATIONS

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Assessing Tobacco Use by Cancer Patients and Facilitating Cessation: An AACR Policy Statement

• Primary recommendations: • Provide patients in all clinical cancer

settings, including clinical trials, with evidence-based tobacco cessation assistance

• Evaluate the confounding effects of tobacco on cancer treatment, disease progression, comorbid events, and survival in all oncology clinical trials from registration to survival endpoints.

Clinical Cancer Research, April 15, 2013 19; 1941

Problem (Clinical) Cancer patients and survivors who smoke

cigarettes have worse health outcomes (including higher all-cause and cancer-specific mortality, and risk of tobacco-related second primary cancer).

Smokers may have higher risk of recurrence, poorer response to treatment, and increased toxicity.

* Phipps, 2011 (colorectal cancer)** Kenfield, 2011 (prostate cancer)

Clinical significance of smoking by cancer patients

• Relative risk of all-cause mortality* – Current smokers 1.5 (relative to never smokers) – Former smokers 1.3

• Relative risk of cancer-specific mortality** – Current smokers 1.6 (relative to never smokers) – Former smokers 1.05

Problem

There are many scientific questions related to tobacco use in the cancer patient population.

Current approaches to data collection: - Not widely assessed in trials or practice - Inconsistent tobacco use assessment methods - Little follow-up during/after treatment

Current practice

• NCI-Designated Cancer Centers – < 50% include tobacco use as a vital sign in the

medical record

• NCI-funded phase III Cooperative Group trials – 22% record cigarette smoking status at

enrollment, and – 4% during follow-up.

Goldstein, NTR, 2012; Warren, IJC, 2012

NCI-AACR Cancer Patient Tobacco Use Assessment Task Force

• History – Formed March, 2013 – Conference calls, writing groups, and in-person meeting September 2013

(Bethesda) • Goal

– Develop recommendations for assessing and documenting tobacco use in clinical trials

– Identify research priorities • Progress

– Drafted two tiers of measurement items and protocol for the timing and conduct of the assessment in cancer clinical trials. • Tier 1: minimum set of baseline and follow-up items recommended for

clinical trials in any cancer patient or survivor study. • Tier 2: longer menu of curated items for use when more comprehensive

assessment is feasible. • Items focus on tobacco use history, status, and intensity

– Recommended assessment items for specific NCTN trials in development

Draft recommended measures Tier 1 (minimal) paraphrased

Baseline: • Ever smoked 100+ cigarettes in lifetime? • How long since smoked? • How many years smoked? • Average number of cigarettes per day?

Follow-up: • How long since smoked?

Task Force Roster Jeffrey S. Abrams, MD Thomas H. Brandon, PhD Jan C. Buckner, MD Paul M. Cinciripini, PhD K. Michael Cummings, PhD, MPH Carolyn Dresler, MD, MPA, Sonia A. Duffy, PhD, RN, FAAN Michael C. Fiore, MD, MPH, MBA Ellen R. Gritz, PhD Dorothy K. Hatsukami, PhD Roy S. Herbst, MD, PhD Jennifer A. Hobin, PhD Fadlo R. Khuri, MD, FACP Stephanie R. Land, PhD Scott J. Leischow, PhD Sandra Mitchell, CRNP, PhD, AOCN Carol Moinpour, PhD

Jamie S. Ostroff, PhD Sheila Prindiville, MD, MPH Nancy Rigotti, MD Linda Sarna, PhD, RN, FAAN, AOCN Robert A. Schnoll, PhD Peter Shields, MD Benjamin Toll, PhD K. (Vish) Viswanath, PhD

Graham Warren, MD, PhD

,•\ •. •

• -;. ! ... ..~· .. ~·· ,, ._ . .,..,

E":- Molecular Cancer

Therapeutics - ~-=:=

• Research and review articles published in AACR journals • Editorial Overview: AACR Celebrates 50 Years of Tobacco

Research and Policy • Commentary from Howard Koh • Q&As with Howard Koh and Mitchell Zeller

MEmNG

SAN DIEGO

Tobacco Science and Policy at AACR Annual Meeting 2014

• Honoring the 50th Anniversary Surgeon General’s Report—The Health Consequences of Smoking: 50 Years of Progress Speakers: Roy S. Herbst, Jonathan Samet, Graham Warren, Robert Croyle, Mitchell Zeller

• Advancing Tobacco Regulatory Science: Meet Experts in FDA CTP Speakers: Carolyn M. Dresler, Cathy L. Backinger, Dana M. van Bemmel, Nicolette Borek

AACR-ASCO Policy Statement on Electronic Cigarettes

• Subcommittee of AACR and ASCO members

• Statement will include recommendations for – Research – Clinical practice – Regulation

Goals of this presentation

• Pathogenesis of tobacco induced cancer – Epidemiology and mechanism – Focus on lung and head and neck cancer

• Joint AACR/NCI efforts related to tobacco control – Tobacco use in patient’s receiving treatment for

cancer – Clinical trials

• New Approaches to treatment of tobacco induced disease- the lung cancer master protocol

0 JI.PC or

lumor cell

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Targeting microRNA

Targeting EGFR Targeting Resistance PD-1/B7-H1(PD-

L1)

Targeting lung cancer risk characteristics for personalized prevention by smoking cessation

iI I

I

BATTLE-2 – Targeting Kras

EML4-ALK Fusion or EGFR Μut exclusion

Protocol enrollment Biopsy performed

Stage 1: (n=200) Adaptive Randomization by KRAS mut status

Primary endpoint: 8-week disease control (N = 400)

Sorafenib E+MK-2206 (AKTi)

MK-2206+ AZD6244 (MEKi)

Stage 2: (n=200) Refined Adaptive Randomization

“Best” discovery markers/signatures

Erlotinib

Statistical modeling and biomarker selection

Discovery Markers:

• Protein expression (IHC): p-AKT (Ser473), PTEN, HIF-1α, LKB1

• Mutation analysis (Sequenom): PI3KCA, BRAF, AKT1, HRAS, NRAS, MAP2K1 (MEK1), MET, CTNNB1, STK11 (LKB1)

• mRNA pathways activation signatures: Affymetrix® - BATTLE-1: WT-EGFR-

Erlotinib, EMT, and Sorafenib - BATTLE-2: new “discovery”

signatures

• Protein profiling – RPPA (n=174) • NGS-Foundation Medicine • RNA sequencing

NCI RO1 funded, Yale, MDACC

~ FNIH ; Foundation for the National Institutes of Health

• • National

Clinical TrialsNetwork

S1400 Master Protocol Unique Private-Public Partnerships with the NCTN

Alliance

ECOG-Acrin

NRG NCI-C

SWOG S1400 Master

Protocol

Rationale for Master Protocol Design • Multi-arm Master Protocol • Homogeneous patient populations & consistent eligibility

from arm to arm • Each arm independent of the others • Infrastructure facilitates opening new arms faster • Phase II-III design allows rapid drug/biomarker testing for

detection of “large effects” • Screening large numbers of patients for multiple targets by a

broad-based NGS platform reduces the screen failure rate • Provides a sufficient “hit rate” to engage patients & physicians • Bring safe & effective drugs to patients faster • Designed to faciliate FDA approval of new drugs

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nature

Significantly mutated genes in lung SQCC.

PS Hammerman et al. Nature 000, 1-7 (2012) doi:10.1038/nature11404

Common Broad Platform CLIA Biomarker Profiling*

I Biomarker A I I Biomarker B I I Biomarker C I

• I • • I • • I •

Non-mate

I Biomarker D I

• I •

Non­match drug

.............,,= =-----'

CT*

MASTER PROTOCOL

Biomarker C

TT C+CT CT*

Biomarker Β

TT B CT*

Biomarker A

TT A CT*

Common Broad Platform CLIA Biomarker Profiling*

Biomarker D

TT D+E E*

Non-match drug

Non-match S1400

Endpoint PFS/OS

Endpoint PFS/OS

Endpoint PFS/OS

Endpoint PFS/OS

Phase II/III Biomarker-Driven Master Protocol for Second Line Therapy of Squamous Cell Lung

Cancer

Non-mate -----i

Common Broad Platform CLIA Biomarker Profiling*

13K CDK4/6 FGFR GF M:PIK3CA mut M: CCNDl, CCND2, M: FGFR ampl,

mut, fusion M :c-Met Expr

CCND3, cdk4 ampl

I\ DC-003... I ~~ D-033299

• I • • I • • • I • I

TT=Targeted therapy, CT=chemotherapy (docetaxel), E=erlotinib *Archival FFPE tumor, fresh CNB if needed

Target/M: Drug target and biomarker

•

CT* MASTER PROTOCOL

AZD4547 CT*

Common Broad Platform CLIA Biomarker Profiling*

AMG102 +E

E*

Non-match S1400

Endpoint PFS/OS

Endpoint PFS/OS

Endpoint PFS/OS

Endpoint PFS/OS

PI3K CDK4/6 FGFR M:PIK3CA mut M: CCND1, CCND2, M: FGFR ampl,

CCND3, cdk4 ampl mut, fusion

Anti-PD-L1:

MEDI4736 HGF M:c-Met Expr

GDC-0032 CT* PD-0332991 CT*

TT=Targeted therapy, CT=chemotherapy (docetaxel), E=erlotinib *Archival FFPE tumor, fresh CNB if needed

Target/M: Drug target and biomarker

of CANCER RESEARCH

~ FiNIH ; Foundation for llhe National In titute ofH alth

I I

Sites 1,2,3…10Sites 1,2,3…10Sites 1,2,3…10

The Lung Master Protocol trial will be managed with multiple partners

Oversight Committee NCI, ex-Industry, Advocates, PI’s (ex-officio), FNIH

[supported by FNIH]

Executive Operations Group Roy Herbst, Vali Papadimitrakopoulou, co-

chairs

Partner Science Focus Group

Contracts, Fundraising, Data Sharing, IP

Drug and Biomarker Selection Committee

Assay Company RFP, selection

Project Management Office FNIH, SWOG, FOCR

NCTN, CTSU, CTEP, oversight

Project Management

DSMB

Working Groups

IND management

Clinical Project Management

Sites 1,2,3…n

Conclusions

• Association of tobacco with cancer is well documented

• Unique concerns in patient’s getting therapy for cancer- issues being addressed

• While primary and secondary prevention is of course critical- better therapeutic options/trial designs for smoking related cancers are underway

THANK YOU!