Press Conference - International Association for the Study...

Press ConferenceWednesday, Sept. 9, 2015

9:45 a.m. – 10:45 a.m. MDTDial-In Information & Agenda:

wclc2015.iaslc.org/press-media/Please hold all questions until the end.

David R. Gandara, MDUniversity of California Davis

Comprehensive Cancer Center

“Science Drives Advances in Lung Cancer” at WCLC 2015:

“Eating the Elephant”

“Eating the Elephant:”An analogy to defeating cancer

“ If you want to eat an elephant, you need a strategy”

“ If you try to do it in one bite, you willchoke on it”

M. Vestager. – May 25, 2015EU Antitrust Chief

& Danish politician

World Conference Lung Cancer (WCLC) 2015:Science Drives Lung Cancer Advances

WCLC 2015

Prevention, Screening,

Tobacco Control

Biology, Pathology, Molecular

Diagnostics

Treatment

Palliative Care,

Nursing, Advocacy

Plus Other Thoracic

Malignancies

Multidisciplinary Research Teams

“Transformative”-Clinical Practice

-Standards of Care

“Personalized Care”

“Bench to Bedside”

Refining the Concept of “Bench to Bedside”Basic

Laboratory Research

Translational Research

(Clinical Trials)Clinical Care

Discovery of “Driver”

Oncogenes

Development of Predictive Biomarkers

(Clinical Trials)

Biomarker-driven patient

care(e.g. EGFR TKIs)

Technology for Next

Generation Sequencing

(NGS)

Development of NGS for Predictive

Biomarkers(Clinical Trials)

NGS-driven patient care

(e.g. Genomic-driven therapy)

Understanding of PD-L1biology


(Clinical Trials)

PD-L1-directed patient care

(Biomarkers??)

The field of Oncology has never moved at a faster pace than now (The future is now)Basic

Laboratory Research



Technology for Next


(NGS)

Development of tumor NGS for Predictive Biomarkers

(Clinical Trials)



Technology for Next Generation

Sequencing (NGS)in plasma(cfDNA)

Development of plasma NGS for

Predictive Biomarkers

(Clinical Trials)

Plasma NGS-driven patient care


Few would have predicted the rapid pace of these transitions which are “Transformative”

How did we get to this point so fast?Basic

Laboratory Research



Discovery of “Driver”

Oncogenes


(Clinical Trials)

Biomarker-driven patient

care(e.g. EGFR TKIs)

Technology for Next


(NGS)

Development of NGS for Predictive

Biomarkers(Clinical Trials)



Understanding of PD-L1biology


(Clinical Trials)

PD-L1-directed patient care

(Biomarkers??)

Li, Mack, Gandara et al. JCO. 2013 (adapted from Pao et al).

Evolution of NSCLC Subtyping From Histologic to Molecular-Based

NSCLCas one disease

EGFR

From Li, Gandara et al. JCO. 2013.

Integration of Biomarkers Into Clinical Practice: Past, Current & Future

Near-Future Approach (Patient-Based Therapy):Genomic profiling by high throughput next generation sequencing

for decision-making in individual patients

1. HistomorphologicalDiagnosis: Cancerous

Evolving Approach (Target-Based Therapy V2.0):Multiplexed molecular tests with increased sensitivity & output

for decision-making in individual patients

Current Approach (Target-Based Therapy V1.0):Single gene molecular testing for decision-making in individual

patients

2. Molecular Diagnosis:Extract tumournucleic acids:

Archival cancer specimensArchival FFPE tumour

specimens

Macro- or Micro-dissection of

Tumours

DNA and RNA

Empiric Approach (Past)(Compound-Based Therapy):

Clinical-histologic factors to select drugs for individual patients

Representative technologies:

Single Biomarker Tests:• Sanger DNA Sequencing

• RT-PCR• FISH• IHC

Multiplex, Hot Spot Mutation Tests:• PCR-based SNaPshot

• PCR-based Mass Array SNP• Sequenom

Initial High-Throughput Technologies:• SNP/CNV DNA microarray

• RNA microarray

Next-Generation Sequencing (NGS):• Whole Genome or Exome Capture Sequencing (DNA)• Whole or Targeted Transcriptome Sequencing (RNA)

• Epigenetic profiling

Plasma cfDNA by NGS

Based on cfDNA analysis, patient tarted on clinical trial of 3rd gen EGFR TKI AZ9291Repeat PET scan 2 weeks later: Major Response.

Case Example: 50 y/o woman with EGFR-mutated lung cancerAt relapse after TKI, re-biopsy shows EGFR E19del, T790M-

Next Step: Plasma Next Gen Sequencing for cell free (cf)DNA

At start of AZD9291

2 weeks after

Lessons learned from this case?Rapid change in the diagnostic & therapeutic landscape

We better have our “running shoes” on if we are to keep up.

Rationale for Checkpoint Immunotherapy• Cancer cells have mutations that make them

recognizable by the immune system (neo-antigens)

• Cancer cells can evade immune surveillance by expressing proteins such as PD-L1 (a potential biomarker)

• Inhibiting PD-L1/PD-1 can restore anti-tumor T-cell activity, leading to

immune-mediated response

Cancer cells evade

T cell killing by

expressing PD-L1

XPD-1

PD-L1MHC I

T cell receptor

Tumor cell

CD8+ CytotoxicT Lymphocyte

(CTL)

Mutation

B7.1

PD-L1 biomarker correlates with response-True in Non-squamous-Not true in Squamous

lung cancer

Paz-Ares: ASCO 2015Spigel: ASCO 2015

GDC-0032 Vs SoC

PalbociclibVs SoC AZD4547

Vs SoC

FGFR1CDK4/61PI3K1

Non-matchImmunotherapy Sub-studies

Nivo/IpiNivolumab

BMN 673Vs SoC

GDC-0032 Palbociclib AZD4547 BMN 673

Stage 1

Stage 2

HRD2Checkpoint

Naive1

MEDI4736/Treme

Vs SoC

Checkpoint Refractory2

Matched Sub-studies

1 Revision #3: Expected September/October 2015 SoC: Standard of Care therapy2 Revision #4: Expected December 2015/January 2016

Lung-MAP (S1400) Trial for Genomic-driven Therapiesin Advanced Squamous Lung Cancer

(Updated for Fall 2015 with Revs # 3 & 4)

12

Tumor Analysis by Next Gen Sequencing (Foundation Medicine)

PIs: V. Papadimitrakopoulou, R. Herbst

“ If you want to eat(defeat) LUNG

CANCER, you needa strategy”

“Eating the Elephant:An analogy to defeating Cancer

There is no single solution to defeating Lung Cancer.

Like the elephant, it will take many bites.

http://www.quotehd.com/quotes/creighton-abrams-soldier-quote-when-eating-an-elephant-take-one-bite-at-a

http://www.quotehd.com/quotes/creighton-abrams-soldier-quote-when-eating-an-elephant-take-one-bite-at-a

PLEN04.03: Randomized phase III trial of adjuvant chemotherapy with or without bevacizumab in resectednon-small cell lung cancer (NSCLC): Results of E1505 – Heather Wakelee, USA

Randomized phase III trial of adjuvant chemotherapy with or without bevacizumab in resected non-small

cell lung cancer (NSCLC): Results of E1505

H.A. Wakelee1, S.E. Dahlberg2, S.M. Keller3, W.J. Tester4, D.R. Gandara5, S.L. Graziano6, A. Adjei7, N. Leighl8, S.C. Aisner9, J.M. Rothman10, J. Patel11, M.D. Sborov12, S.R. McDermott13, R. Perez-Soler14, A.M. Traynor15, C. Butts16, T.

Evans17, L. Horn18, S.S. Ramalingam19, J. Schiller20 on behalf of ECOG-ACRIN1Medicine (Oncology), Stanford Cancer Institute/Stanford University, Stanford, CA/USA, 2Dana-Farber Cancer Institute/Harvard University, Boston,

MA/USA, 3Cardiovascular and Thoracic Surgery, Montefiore Medical Center, Bronx, NY/USA, 4Albert Einstein Medical Center, Philadelphia, PA/USA, 5UC Davis Comprehensive Cancer Center, Sacramento/USA, 6Medical Oncology, SUNY Upstate Medical University, Syracuse, NY/USA, 7Medicine,

Roswell Park Cancer Institute, Buffalo, NY/USA, 8Princess Margaret Cancer Centre, Toronto, ON/Canada, 9Rutgers New Jersey Medical School, Newark, NJ/USA, 10The Regional Cancer Center, Erie, PA/USA, 11Northwestern University, Chicago, IL/USA, 12Edina Clinic, Edina/USA, 13Medical

Oncology, The Adelaide and Meath Hospital, Dublin, Dublin/Ireland, 14Oncology, Montefiore Medical Center, Bronx, NY/USA, 15University of Wisconsin, Madison, WI/USA, 16Division of Oncology, University of Alberta, Edmonton, AB/Canada, 17 University of Pennsylvania, Philadelphia, PA/USA,

18Vanderbilt University Medical Center, Nashville, TN/USA, 19Winship Cancer Institute, Emory University, Atlanta, GA/USA, 20Hematology/Oncology, UT Southwestern, Dallas/USA


RANDOM IZE

1:1

STRATIFIED:

1) Cisplatin Doublet* 2) Stage (~25% IB,~ 50%II,~25% III)3) Histology (~30% Squam)4) Gender (~50:50)

Arm A:ChemotherapyX 4 cycles*

ELIGIBLE: Resected (N=1501)Early stage NSCLC6-12 weeks post-op

Arm B:Chemotherapyx 4 cycles* +Bevacizumab^X 1 year

*Investigator Choice of 4 chemotherapy regimens Cisplatin /Vinorelbine ~25%Cisplatin /Docetaxel ~25%Cisplatin /Gemcitabine ~20%Cisplatin /Pemetrexed ~30%^Bevacizumab 15 mg/kg IV q 3 weeks for up to 1 year

•Adjuvant cisplatin-based chemotherapy for completely resected early stage NSCLC provides a modest overall survival benefit of ~ 5%•Bevacizumab, VEGF antibody, improved response, PFS and OS in metastatic NSCLC when added to platinum-based chemotherapy (E4599)

Primary endpointoverall survival

No unexpected toxicitySignificant increase in neutropenia, hypertensionNo significant difference in treatment related deaths (2% vs 3%)


0.0

0.2

0.4

0.6

0.8

1.0

Months from Registration

Ove

rall

Sur

viva

l Pro

babi

lity

0 12 24 36 48 60 72 84

Chemo (208 events/ 749 cases)Chemo + Bevacizumab (204 events/ 752 cases)

0.0

0.2

0.4

0.6

0.8

1.0

Months from Registration

Dis

ease

-Fre

e S

urvi

val P

roba

bilit

y

0 12 24 36 48 60 72 84

Chemo (338 events/ 749 cases)Chemo + Bevacizumab (334 events/ 752 cases)

Overall Survival Disease Free SurvivalOS hazard ratio (B:A): 0.99 95% CI: (0.81-1.21) p=0.93

DFS hazard ratio (B:A): 0.98 95% CI: (0.84-1.14) p=0.75

PLEN.07 : Stopping Smoking Reduces Mortality – Ugo Pastorino

Stopping Smoking Reduces Mortality in Low-Dose Computed Tomography

(LDCT) Screening VolunteersUgo Pastorino, Thoracic Surgery,

Istituto Nazionale dei Tumori, Milan, Italy

PLEN.07 - Presidential SymposiumPlenary Hall (Bellco Theatre) 09/09/2015, 11:51 AM


Stopping smoking in LDCT screening3,381 subjects – 32,858 PY – median 8.7 yrs

EX = ex-smokerswho had stopped smoking at the time of accrual / randomization in the LDCTscreening study

QUIT = quitterswho were active smokers at the time of accrual / randomization, but stoppedsmoking at least one year before the end of follow-up or death

CURRENT = active smokerswho continued to smoke during LDCT screening period, or stoppedsmoking less than one year before the end of follow-up or death


Smoking & mortality (Relative Risk adjusted by covariate/regression model)

Mort / 100,000 PY RR CI 95%

CURR vs EX/QUIT 846 vs 726 0.74 0.58- 0.95

CURR vs EX/QUIT > 2yrs* 846 vs 613 0.61 0.46- 0.80

CURR vs QUIT > 2yrs* 846 vs 565 0.57 0.38- 0.85

CURR vs EX > 2yrs* 846 vs 613 0.63 0.46- 0.88

* Excluding 239 quitters who stopped smoking < 2 yrs before the end of follow-up or death


p-value Log-Rank test: 0.0572

Stopping smoking & mortality

CURRENT

EX / QUIT


28% of baseline smokers stop during LDCT

pharmacological support is more effective

lung cancer causes < 30% of all deaths

stopping smoking reduces total mortality by > 25%

benefit is 3 to 5-fold greater than LDCT screening

next step: test prevention vs. screening

Conclusions

Multiregion whole exome and transcriptome sequencing defines the genomic spectrum of EGFR M+ NSCLC and

reveals novel mechanisms of TKI resistance

Daniel SW TAN1,2,3, R. Nahar2, A. Takano4, A. Khng2, T. Zhang2, T. Koh5, A. Gogna6, K.H. Lim4, W.A. Zaw1, X. Liu2, A. Teo2, C. Chan2, Y.Y. Lee2, N.G Iyer3, L.H. Chen2,3, M.K. Ang1, Q-S. Ng1, C-K. Toh1, R. Kanesvaran1,

A. Jain1, A. Devanand6, V. Krishnan2, P. Ng2, B.S. Tan5, C.H. Lim7, B. Chowbay8, W.T. Lim1, W.L. Tam2, B. Lim2, E.H. Tan1, W. Zhai2, A.M. Hillmer2

PLEN 04: Multiregion whole exome and transcriptome sequencing of EGFR M+ NSCLC – Dr Daniel SW Tan

1Division of Medical Oncology, National Cancer Centre Singapore; 2Genome Institute of Singapore; 3Cancer Therapeutics Research Laboratory, NCCS; 4Department of Pathology, Singapore General Hospital;

5Division of Surgical Oncology, NCCS; 6Department of Diagnostic Radiology, SGH; 6Department of Respiratory and Critical Care Medicine, SGH; 7Department of Cardiothoracic Surgery, NHCS; 8Clinical Pharmacology

Laboratory, NCCS


Disclosures• Advisory Role and Consultant: Novartis, Bayer, Boehringer Ingelheim• Travel fees: Novartis, Merck, Pfizer• Research Funding: Novartis


Background• EGFR mutations (M+) are amongst the commonest druggable alterations in NSCLC

• We sought to examine the genomic architecture and spectrum in treatment naïve and TKI resistant EGFR M+ NSCLC

ResectedTKI naïve

NSCLC Surgery

Cell population expansion

Cohort 1: Stage I & IIAim 1: Determine clonal architecture through multi-sector sequencing

EGFR TKI Resistant

BiopsiesEGFR TKI

Cohort 2: Stage IVAim 2: Elucidate mechanisms of EGFR TKI resistance through integrative omics


Methods• Aim 1: Multi-sector sequencing on spatially separated regions from resected

EGFR M+ lung adenocarcinoma (9 patients, 47 sectors)

Illumina Hi-Seq


Patient A021: EGFR L858R

EGFRTP53

R1 R2 R3 R4 R5

Tip (private)

Branch (shared)

Trunk (common)

LRP2EML5

ADCY8

CAPN8MED12

OR10C1

KCNK10

R2 R1

R3

R4

R5

MED12

EGFRTP53

LRP2EML5ASCY8

5

SNVs

Aim 1


Mutational burden and hierarchy in TKI naiveresected EGFR M+ NSCLC (n=8; 46 sectors)

A001L858R

A006Ex 19 del

A014L858R

A021L858R

A017L858R

A027Ex 19 del

A022Ex 20 ins

A028L858R

TP53EGFR EGFR

PTENMAP3K19

TP53EGFR

ARID1BTP53EGFR

TP53EGFR EGFR EGFR EGFR

Mutation burdenPer sector: median 48 (9 – 98)Per tumor: median 77 (32–146)

Private

Shared

Trunk

100

No

of m

utat

ions

50

All EGFR mutations occurred in the trunk

T790M was not detected in any sectors despite ultra deep sequencing

Aim 1


TKI resistance signature implicates co-existing trunk drivers in primary TKI resistance

A014: 67M/never smoker EGFR L858R/ Stage IBRelapsed within 5 months of surgery

Naïve (n=6) Resistant (n=20)Naïve (n=2)

EGFR L858RCLIP1PTEN splice siteMAP3K19


EGFR TKI resistant NSCLC is heterogeneous and therapeutically relevant subgroups co-exist

T790M negative

25%

MET13%

HER2+MET

4%HER2

4%

T790M+42%

T790M++HER2

4% T790M++MET

8%

High Mutation Burden, 16%• Smokers• APOBEC signature

n=24

Aim 2

T790M positive (54%)T790M negative (46%)


CONCLUSIONS

• Genomic architecture of TKI naïve East Asian EGFR M+ NSCLC – EGFR mutations are truncal events– Low mutation burden– High clonal diversity (branch/private > trunk)

• Mutation burden is relatively higher in TKI resistant samples– Association with smoking and APOBEC signature in a subset of EGFR M+ NSCLC

• Multiple potential mechanisms of TKI resistance co-exist– e.g. MED12 alterations may be subclonal mediators of resistance– One patient with co-occurring trunk drivers demonstrated primary TKI resistance

A Randomized, Phase III Study Comparing Carboplatin/Paclitaxel or

Carboplatin/Paclitaxel/Bevacizumab with or without Concurrent Cetuximab in Patients with Advanced

Non-Small Cell Lung Cancer (NSCLC): SWOG S0819

3612: A Randomized, Phase III Study Comparing Carboplatin/Paclitaxel or Carboplatin/Paclitaxel/Bevacizumab with or without Concurrent Cetuximab in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC): SWOG S0819 – R. Herbst

Roy S. Herbst, MD, PhD, Mary W. Redman, PhD, Edward S. Kim, MD, Thomas J. Semrad, MD, Lyudmila Bazhenova, MD, Gregory Masters, MD; Kurt Oettel, MD; Perry

Guaglianone, MD , Christopher Reynolds, MD, Anand Karnad, MD, Susanne M. Arnold, MD, Marileila Varella-Garcia, PhD, James Moon, MS, Philip C. Mack, PhD, Charles D.

Blanke, MD, Fred R. Hirsch, MD, PhD, David R. Gandara, MD


BACKGROUND: CETUXIMAB AND NSCLC

J. Mendelsohn Endocr Relat cancer 2001;8, 3-9P.M. Harari Endocr Relat Cancer 2004;11, 689-708

Cetuximab*Bevacizumab

PaclitaxelCarboplatinCetuximab

*Bevacizumab

*Bevacizumab

PaclitaxelCarboplatin

*Bevacizumab

OBJECTIVES

Co-Primary:• PFS in EGFR FISH+ patients• OS in entire study population

Secondary:• OS and PFS by Bevacizumab

appropriate/inappropriate• Safety/toxicity by treatment

arm

Exploratory (due to SQUIRE study):• OS and in entire study and

FISH+ for SCCA patients

RANDOMIZE

NSCLCAdv Stage

Tumor Tissueavailable

• Study accrual: 7/15/2009- 6/1/2014*In Bevacizumab Appropriate: as piloted in S0536

SWOG 0819: PHASE III SCHEMA

Stratification Factors: 1) Appropriate for

Bevacizumabtreatment: yes vs. no

2) Smoking status: current or former vs. never

3) Stage: M1a vs M1b



EGFR FISH-positive

• ⩾40% of cells displaying ⩾4 copies of the EGFR signal, or

• EGFR to CEP7 ratio ⩾2 over all scored nuclei, or

• Gene clusters (⩾4 spots) or ⩾15 copies of the EGFR signals in ⩾10% of tumor cells.

BACKGROUND: COLORADO SCORING CRITERIA EGFR GENE AMPLIFICATION BY FISH

M. J. Varella-Garcia et al. Clin Pathol. 2009 Nov;62(11):970-977F.R. Hirsch et al. JCO 2008;26:3351-3357


S0819 RESULTS: ENTIRE STUDY POPULATION

35

EGFR FISH + PATIENTS

OS

0%

20%

40%

60%

80%

100%

0 12 24 36 48 60Months After RegistrationPatients at Risk

656tuximab Arm 446tuximab Arm 287tuximab Arm 153tuximab Arm 76tuximab Arm 48tuximab Arm 28tuximab Arm 11tuximab Arm 5tuximab Arm 2tuximab Arm 1tuximab Arm657Control Arm 448Control Arm 246Control Arm 141Control Arm 94Control Arm 50Control Arm 36Control Arm 13Control Arm 6Control Arm 2Control Arm 1Control Arm

Cetuximab ArmControl Arm

N656657

Events536558

Medianin Months

10.99.4

95%Conf. Int.

(9.6 - 12.0)(8.7 - 10.3)

P = 0.34HR=0.94 (0.84-1.06)

Overall Survival Progression Free SurvivalOSHR=0.94 (0.84-1.06)

p=0.34

PFSHR=0.98 (0.87-1.09)

P=0.68

PFS

0%

20%

40%

60%

80%

100%


199C t i b A 78C t i b A 26C t i b A 10C t i b A 3C t i b A 1C t i b A 0C t i b A 0C t i b A 0C t i b A 0C t i b A 0C t i b A


N199201

Events191197

Medianin Months

5.44.8

95%Conf. Int.(4.5 - 5.7)(3.9 - 5.5)

P = 0.37HR=0.91 (0.74-1.12)

OSHR=0.83 (0.67-1.04)

p=0.10

PFSHR=0.91 (0.74-1.12)

P=0.37

Overall Survival Progression Free Survival

All Bevacizumab Appropriate Patients

0%

20%

40%

60%

80%

100%


279mab Arm 201mab Arm 138mab Arm 74mab Arm 41mab Arm 23mab Arm 13mab Arm 7mab Arm 4mab Arm 2mab Arm 1mab Arm275ontrol Arm 212ontrol Arm 129ontrol Arm 79ontrol Arm 52ontrol Arm 32ontrol Arm 25ontrol Arm 10ontrol Arm 5ontrol Arm 2ontrol Arm 1ontrol Arm


N279275

Events219220

Medianin Months

12.711.6

95%Conf. Int.

(10.9 - 13.4)(10.5 - 13.8)

P = 0.70HR=1.04 (0.86-1.25)

BEVACIZUMAB INAPPROPRIATE


Bevacizumab Appropriate, FISH+

0%

20%

40%

60%

80%

100%


86Cetuximab Arm 71Cetuximab Arm 57Cetuximab Arm 32Cetuximab Arm 16Cetuximab Arm 10Cetuximab Arm 4Cetuximab Arm 3Cetuximab Arm 1Cetuximab Arm 1Cetuximab Arm 1Cetuximab Arm80Control Arm 64Control Arm 45Control Arm 31Control Arm 17Control Arm 12Control Arm 9Control Arm 2Control Arm 1Control Arm 0Control Arm 0Control Arm


N8680

Events6763

Medianin Months

15.513.2

95%Conf. Int.

(13.4 - 18.4)(11.2 - 19.1)

P = 0.88HR=0.97 (0.69-1.38)

0%

20%

40%

60%

80%

100%


377tuximab Arm 245tuximab Arm 149tuximab Arm 79tuximab Arm 35tuximab Arm 25tuximab Arm 15tuximab Arm 4tuximab Arm 1tuximab Arm 0tuximab Arm 0tuximab Arm


N377382

Events317338

Medianin Months

9.28.2

95%Conf. Int.

(8.2 - 10.9)(7.3 - 8.7)

P = 0.12HR=0.88 (0.76-1.03)

S0819 RESULTS: BEVACIZUMAB APPROPRIATE

Bev Appropriate, FISH + (OS)All Bev Appropriate OSHR=1.04 (0.86-1.25) p=0.70

Bev Appropriate FISH + OSHR=0.97 (0.69-1.38)

p=0.88

All Bev Appropriate Patients (OS)

All Bev Inappropriate OSHR=0.88 (0.76-1.03)

p=0.12

Bev Inappropriate FISH + OS

HR=0.75 (0.57-0.998) P=0.048

Bevacizumab Inappropriate, FISH+

0%

20%

40%

60%

80%

100%



N113121

Events94

107

Medianin Months

11.28.7

95%Conf. Int.

(8.6 - 12.9)(5.9 - 9.7)

P = 0.048HR=0.75 (0.57-0.998)

Bev Inappropriate, FISH + (OS)All Bev Inappropriate (OS)


0%

20%

40%

60%

80%

100%

0 12 24 36 48 60Months After Registrationatients at Risk


N5556

Events5052

Medianin Months

11.86.4

95%Conf. Int.

(8.6 - 13.5)(4.2 - 8.7)

P = 0.006HR=0.56 (0.37-0.84)

S0819 RESULTS: Squamous Cell Carcinoma (SCCA) FISH +

SCCA FISH+ OSHR=0.56 (0.37-0.84) p=0.006

SCCA FISH + (OS)

S0819Adverse Events

Cetuximab Arm Control ArmNo Bev (N=365) Bevacizumab (N=262) No Bev (N=367) Bevacizumab (N=265)

Grade 3/4 Grade 5 Grade 3/4 Grade 5 Grade 3/4 Grade 5 Grade 3/4 Grade 5Blood/Bone Marrow 44% 44% 33% 37%

Metabolic/Laboratory 18% 20% 12% 14%Gastrointestinal 14% 16% 1% 10% 16%

Infection 9% 1% 11% 1% 9% 1% 11%Pulmonary/Upper Respiratory 7% 1% 8% 3% 1% 5%

Dermatology/Skin 7% 17% 0.3% 0.4%Allergy/immunology 7% 6% 2% 1%Renal/Genitourinary 1% 1%

TOTAL 66% 4% 77% 6% 54% 2% 69% 2%


Summary1. Co-Primary Objective: No Benefit in OS for entire study

population (N=1333, HR=0.94, p=0.34)2. Co-Primary Objective: No benefit in PFS in EGFR FISH +

population (n=400, HR=0.91, p=0.37)3. Secondary Objective: Indication of benefit for OS in EGFR

FISH + population, but not statistically significant (n=400, HR=0.83, p=0.10)

4. Secondary Objective: Indication of benefit on OS among Bevacizumab – inappropriate, EGFR FISH + patients (n=759, HR=0.75, p=0.048)

5. Exploratory Objective: In squamous cell FISH + patients, a significant improvement in OS (n=321, HR=0.56, p=0.006)


IMPLICATIONS AND FUTURE PLANS1. Large Intergroup study completed – acceptable toxicity of

the regimen2. These data along with the recent SQUIRE results suggest a

role for EGFR FISH in selecting patients for therapy with EGFR antibodies (Cetuximab and Necatumab)- especially when Bevacizumab is not used

3. Analysis of EGFR H Score and KRAS mutation ongoing, to be presented at ASCO 2016

4. Squamous Cell is an important area- Lung MAP is the next step!


Presentation Number: Presentation Title – Presenting Author

• Public private partnership• Leverages NCTN Network• Biomarker selected trials• >100 million of industry support• FDA collaboration- seeks to get

drugs approved and to patients!• Genomic profiling delivered to the

community• A new paradigm for drug

development and scientific discovery

S1400DFGFR

FGFR ampl,mut, fusion

S1400CCDK4/6

CCND1, CCND2, CCND3, cdk4 ampl

ScreeningSquamous Cell Lung Cancer

S1400ANon-match

S1400BPI3K

PIK3CA mut

1 GDC-0032 2 Docetaxel

1 Palbociclib2 Docetaxel

1 AZD45472 Docetaxel

1:11:11:1

Arm1

Arm2

Arm1

Arm2

Arm1

Arm2

Arm1

1 Medi4736

Current Trial Schema[Revision #2 Activated 5/26/15]

GDC-0032 SoC

PalbociclibSoc

AZD4547SoC

GDC-0032 Palbociclib AZD4547

FGFR1CDK4/61PI3K1

Non-matchSub-studies

Nivo/IpiNivolumab

BMN 673SoC

BMN 673

Stage 1

Stage 2

HRD2 Checkpoint Naive1

MEDI4736

CheckpointRefractory2

Matched Sub-studies

1 Revision #3: Expected September/October 20152 Revision #4: Expected December 2015/January 2016

Updated Lung-MAP Trial Schema(Expected with Revisions # 3 & 4)

Fred R. Hirsch*

Theresa Boyle, Nick Thatcher, Luis Paz-Ares, Marileila Varella-Garcia, Ashley Kowalewski, Rebecca R. Hozak, Gu Mi, Symantha Melemed,

Charles W. Caldwell, Raffael Kurek, Mark A. Socinski

*Presenting author

Presentation Number: EGFR IHC and FISH correlative analyses (SQUIRE Trial) – Dr. Fred Hirsch

32.05: EGFR IHC and FISH Correlative Analyses (SQUIRE trial): Necitumumab + Gemcitabine-Cisplatin vs Gemcitabine-Cisplatin in 1st-

line Squamous NSCLC

32.05: EGFR IHC and FISH Correlative Analyses (SQUIRE Trial) – Fred Hirsch

SQUIRE: Necitumumab in Advanced 1st-line Squamous NSCLC1

• Primary endpoint: overall survival• Mandatory tissue collection from archived tumor

Necitumumab is a second-generation human IgG1 anti-EGFR monoclonal antibody.

Dosing regimen: GC (G=1250 mg/m2 IV days 1, 8; C=75 mg/m2 IV day 1) + N (800 mg absolute dose IV) or GC alone (every 21 days up to 6 cycles)

Randomization (R) stratified by: ECOG PS and region

CRPRSD

Gem-Cis + NECI (GC+N)(N = 545)

Maximum of 6 cycles

1093 patients• First-line Stage IV

sq- NSCLC

• ECOG PS 0-2

NECI (N)

Gem-Cis (GC) N = 548

RPD

PD

PD

1Thatcher N, et al. Lancet Oncol 2015;16(7):763-74

Presenter

Presentation Notes

Speaker notes EGFR protein positivity was not required for enrollment EGFR protein expression has not been shown to be predictive

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40

0

20

40

60

80

100

SQUIRE Primary Outcome: Overall Survival ITT1

GC+NN=545

GCN=548

Stratified HR (95% CI) 0.84 (0.74, 0.96)Stratified p-value (log-rank) 0.01Median, months (95% CI) 11.5 (10.4, 12.6) 9.9 (8.9, 11.1)

Time Since Randomization (Months)

Ove

rall

Surv

ival

(%)

GC+N GC

1Thatcher N, et al. Lancet Oncol 2015;16(7):763-74

Presenter

Presentation Notes

Speaker notes SQUIRE was a positive trial with meaningful OS benefit Primary objective was met, Median survival with Gem-Cis + Neci significantly longer than with Gem-Cis with 16% reduction in the risk of death in favor of neci arm OS benefit was observed across clinically relevant subgroups PFS was also significantly longer in the Gem-Cis + Neci group

Overall Survival in EGFR FISH Positive* Patients

GC+N GC

GC+NN=111

GCN=97

Unstratified HR (95% CI) 0.70 (0.52, 0.96)Median, months (95% CI) 12.6 (11.5, 15.9) 9.2 (7.2, 12.1)

*Based on Colorado Classification (Varella-Garcia M, et al. J Clin Pathol 2009;62(11):970-7)

Time Since Randomization (Months)0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40

Ove

rall

Sur

viva

l (%

)

0

20

40

60

80

100

Tumor samples were available with valid FISH results obtained for 51% of ITT population

Presenter

Presentation Notes

Speaker notes

Subgroup Analysis for Positive or Negative EGFR Copy Number Gain

Positive* Negative*

GC+N(N=111)

GC(N=97)

GC+N(N=171)

GC(N=178)

OSmOS, months 12.6 9.2 11.1 10.7

HR within expression level (95% CI) 0.70 (0.52-0.96) 1.02 (0.80-1.29)

Interaction p-value 0.066PFS

mPFS, months 6.1 5.1 5.6 5.5

HR within expression level (95% CI) 0.71 (0.52-0.97) 1.04 (0.82-1.33)

Interaction p-value 0.057*Based on Colorado Classification (Varella-Garcia M, et al. J Clin Pathol 2009;62(11):970-7)

Tumor samples were available with valid FISH results obtained for 51% of ITT population

Presenter

Presentation Notes

Speaker notes Assessed correlation between treatment effect with EGFR copy number gain in the 51% of patients who had available results For both OS and PFS, we observed a trend for greater treatment effect in EGFR copy number gain positive patients than in the negative patients For both OS and PFS, the effects were not statistically significant EGFR copy number gain will also be assessed further in future trials Considerations: p-values were not adjusted for multiplicity across clinical endpoints, marker cutpoints, or different markers we have assessed

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