1

David R. Gandara, MDUniversity of California DavisComprehensive Cancer Center

Translational Research in Non–Small Cell Lung Cancer (NSCLC): What Are the Available “Tools” & How Can You Use Them?

2

From “All Patients Are the Same” to Inter- and Intra-Patient

Heterogeneity in Tumour Biology & Immuno-Biology

From Histology to Prognostic and/or

Predictive Biomarkers

Adapted from Gandara et al. Clin Lung Cancer. 2012.

Personalised Therapy for Individual Patients With

NSCLC

Translational Research

Available “Tools” for Translational Research in NSCLC: Interaction of Pathology, “Omics,” and Immuno-Biology

3

Moving From Histologic Classification to Molecular Classification of NSCLC Patients Into Prognostic or Predictive Subgroups for Therapy

• Histologic subtyping groups tumours based on microscopic pattern recognition by a pathologist

• At best, Histology = “crude molecular selection”

Positive ALK FISH

EGFR Mutation

4

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

Evolution of NSCLC Subtyping From Histologic to Molecular-Based

NSCLCas one disease

ALK

EGFR

FirstTargeted Therapiesin NSCLC

5

Adapted from The Cancer Genome Atlas Project: Govindan & Kondath et al. Nature. 2013.

Magnitude of Genomic Derangement Is Greatest in Lung Cancer

1 / Mb

10 / Mb

100 / Mb

0.1 / Mb

81 64 38 316 100 17 82 28n=109 119 21 40 20

Hematologic & Childhood Cancers

Carcinogen-induced Cancers

??

Ade

nom

a

Squ

amou

s

Ovarian, Breast, Prostate Cancers

MutationsPer Mb DNA

6

Lung Cancer Complexity on an Individual Patient Basis: Squamous-Cell Lung Cancer Examples (“Circos”)

LUSC-34-2600 LUSC-43-3394

LUSC-56-1622 LUSC-60-2695 LUSC-60-2711 LUSC-60-2713

LUSC-66-2756 LUSC-34-2609

From Ramaswamy Govindan. TCGA (The Cancer Genome Atlas).

7

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. Histomorphological Diagnosis:

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 tumour nucleic acids:

Archival cancer specimens

Archival 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 profilingPlasma cfDNA by NGS

8

Comprehensive Cancer Genomic Test: 200+ Genes

<14 days

Foundation Medicine One

9

Guardant360 Panel 2015: Plasma NGS

Point Mutations

AKT1 ALK APC ARAFAR ARID1A ATM BRAFBRCA1 BRCA2 CCDN1 CCND2CCNE1 CDH1 CDK4 CDK6CDKN2A

CDKN2B CTNNB1 EGFR

ERBB2 ESR1 EZH2 FBXW7FGFR1 FGFR2 FGFR3 GATA3GNA11 GNAQ GNAS HNF1AHRAS IDH1 IDH2 JAK2JAK3 KIT KRAS MAP2K1MAP2K2 MET MLH1 MPLMYC NF1 NFE2L2 NOTCH1

NPM1 NRAS NTRK1 PDGFRA

PIK3CA PTEN PTPN11 RAF1RET RHEB RHOA RIT1ROS1 SMAD4 SMO SRCSTK11 TERT** TP53 VHL

Amplifications

AR

BRAF

CCNE1

CDK4

CDK8

EGFR

ERBB2

FGFR1

FGFR2

KIT

KRAS

MET

MYC

PDGFRA

PIK3CA

RAF1

FusionsALK

RET

ROS1

NTRK1

IndelsEGFR exon 19 deletions

EGFR exon 20 insertions

*Complete exon coverage for genes in bold; **Includes TERT promoter region.

Complete* or Critical Exon Coverage in 68 Genes

“Targeted Therapy”Chemotherapy

Checkpoint ImmunotherapyTargeted

TKIs:-EGFR-ALK

-ROS1

Anti-PD-1 and PD-L1

Anti-CTLA-4

? TargetedNintedinib?

Necitumumab?Ramucirumab?

HistologicSubtyping for

Chemotherapy

Translational Research Opportunities: How do we optimize use of these “tools” (therapeutic modalities) in order to create

new treatment paradigms?

Available “Tools” for Translational Research in Advanced NSCLC

11

Oncogene-drivenNSCLC

Gandara, Redman et al. Clin Lung Cancer. 2014.

Targeted Therapies in Oncogene-Driven NSCLC:De Novo & Acquired Resistance

• Targeted Therapies against Oncogene-Driven Cancers, EGFR mutation+ (erlotinib) or ALK-fusion+ (crizotinib), improve response and PFS when compared with chemotherapy

• Even in these most sensitive cancers, approximately 25% to 40% do not respond to TKI therapy (de novo resistance)

• Even in these most-sensitive cancers, acquired resistance is universal, with PFS averaging ≈10-14 months

12

Evolutionary Biology & Acquired Tumour Resistance

• Intra-tumour heterogeneity is present at baseline (scenarios 1 & 2)

• Reducing sensitive clones by therapy permits unopposed growth of less fit resistant clones

or emergence of a new clone (“Tumour Darwinism”)

• Separating “new drivers” from “passengers” is complex

• This process is dynamic, not static

• Original sensitive clone is still present ]. at time of resistance

Adapted from Gandara et al. Clin Lung Cancer. 2012.

Evolutionover time

with therapy

“Driver” Oncogene

New“Driver”

Evolutionover time

with therapy

“Driver” Oncogene

New“Driver”

Scenario 1 Scenario 2

OriginalSensitive

Clone

13

Available “Tools” for Translational Research:Re-Biopsy to Assess Tumour Evolution

Adapted from: Gandara. ASTRO/ASCO/IASLC Symposium on Molecular Testing, 2012.

PulmonologistInterventional Radiologist

Surgeon

Identify Target Lesion

Biopsy

Histology Evaluation

Determine Therapy

Pathologist

OncologistMultidisciplinary

Team (Tumour Board)

Molecular Biomarker Testing

Identify Patient

Referring Physician

Med OncologistThoracic Surgeon

Radiation Oncologist Pulmonologist

RadiologistPathologist

When Progression Re-Biopsy

Treat

Determine New Therapy

Treat

When Progression Re-Biopsy

14

Emergence of ALK Resistance Mechanisms After Crizotinib

Doeble, Camidge et al. CCR. 2012.

Consistent with mathematical models of evolutionary biology

• Secondary resistance ALK mutations• ALK gene copy number increase• Transition to EGFR mutation• Transition to KRAS mutation

15

Schema for Multidisciplinary Integration of Biomarker Testing in Advanced-Stage NSCLC: Looking for “Actionable” Oncogenes

Adapted from: Gandara. ASTRO/ASCO/IASLC Symposium on Molecular Testing, 2012.

PulmonologistInterventional Radiologist

Surgeon

Identify Target Lesion

Biopsy

Histology Evaluation

Determine Therapy

Pathologist

OncologistMultidisciplinary

Team (Tumour Board)

Molecular Biomarker Testing

Identify Patient

Referring Physician

Med OncologistThoracic Surgeon

Radiation Oncologist Pulmonologist

RadiologistPathologist

When Progression Re-Biopsy

Treat

Determine New Therapy

Treat

When Progression Re-Biopsy

Plasma cfDNA Plasma cfDNA

16

Association Between pEGFR mut+ at C3 and PFS/OS (Both Treatment Arms Combined)

OSPFS

18.2 31.9

C3 mut+C3 mut–

Median = 18.2 months(95% CI: 14.2–27.4)

Median= 31.9 months(95% CI: 23.5–undefined)

HR = 0.51 (95% CI: 0.31–0.84);

P=0.0066

7.2 12.0

C3 mut+

C3 mut–Median = 7.2 months

(95% CI: 6.0–7.8)Median =1 2.0 months

(95% CI: 9.6–16.5)HR = 0.32

(95% CI: 0.21–0.48);P<0.0001

Time (months)

OS

prob

abili

ty

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

Time (months)

PFS

prob

abili

ty

C3 mut+ 42 42 35 28 14 7 6 4 1 1 1 1 0 0 0 0 0C3 mut– 80 80 77 65 59 47 40 34 32 28 23 19 13 10 7 3 0

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

1.0

0.8

0.6

0.4

0.2

0

1.0

0.8

0.6

0.4

0.2

0

C3 mut+ 42 42 42 41 37 32 30 28 23 21 18 14 14 12 9 4 3 2C3 mut– 80 80 80 77 77 77 76 71 68 64 59 52 38 29 22 12 3 1

00

Patients, n Patients, n

Mok et al. WCLC 2013.

17

Systemic-PD

Approaches to Acquired Resistance in Oncogene-driven Cancers (EGFR MT & ALK Fusion)

Gandara et al. Clin Lung Cancer. 2014.

Switch Therapy:Chemotherapy or 2nd/3rd gen TKI

Add Therapy to TKI -Chemotherapy ?

-Another Targeted Agent?

Continue same TKI alone (post-progressive disease)

RECISTResponse

SubsequentSystemic PD

AdvancedNSCLC With

Oncogene-drivenCancer

Targeted TKI

-EGFR Mutation-ALK Fusion

Re-biopsy

18

IMPRESS: Phase III Trial of Post-progression Gefitinib/Chemotherapy vs Chemotherapy Alone in EGFR Mutation–Positive NSCLC After Prior Response (Acquired Resistance)

*CR/PR ≥4 months or SD >6 months.Mok et al. ESMO-Ann Oncol. 2014;25(suppl 4): abstr LBA2_PR.

Primary endpoint: PFSR1:1

PD

PD• Stage IIIB/IV NSCLC• EGFR mutation positive • WHO PS 0–1• Prior response* to 1st-line

gefitinib• PD <4 weeks prior to study

(n=265)

Placebo + cisplatin + pemetrexed

up to 6 cycles (n=132)

Gefitinib 250 mg + cisplatin + pemetrexed

up to 6 cycles (n=133)

PD

Secondary endpoints• OS, ORR, DCR• Safety and tolerability, health-related QoL

19

IMPRESS: Phase III Trial of Post-progression Gefitinib/Chemotherapy vs Chemotherapy Alone in EGFR Mutation–Positive NSCLC After Prior Response (Acquired Resistance)

Mok et al. ESMO-Ann Oncol. 2014;25(suppl 4): Abstract LBA2_PR.

OS (ITT; 33% of events)PFS (primary endpoint; ITT)Gefitinib(n=133)

Placebo(n=132)

Median PFS, months 5.4 5.4

HRa (95% CI) = 0.86 (0.65, 1.13); p=0.273

Response: 32% 34%

Gefitinib(n=133)

Placebo(n=132)

Median OS, months 14.8 17.2

Number of events, n (%) 50 (37.6) 37 (28.0)

HRa (95% CI) = 1.62 (1.05, 2.52); p=0.0291.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

0 2 4 6 8 10 12 14Time of randomisation (months)

Prob

abili

ty o

f PFS

Patients at risk:Gefitinib 133 110 88 40 25 12 60Placebo 132 100 85 39 17 5 40

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

0 2 4 6 8 10 12 14Time of randomisation (months)

Prob

abili

ty o

f PFS

Patients at risk:Gefitinib 133 125 111 88 64 43 27 19 12 8 4 2 00Placebo 132 129 119 94 76 55 39 27 16 10 7 4 20

16 18 20 22 24 26

Gefitinib (n=133)Placebo (n=132)

Gefitinib (n=133)Placebo (n=132)

20

Mechanisms of EGFR TKI Resistance (Selected)

2nd Gen EGFR TKIsie, Afatinib

Afatinib/Cetuximab3rd Gen- AZ9291, CO1686

Anti-ERBB3 drugsie, MM151 MoAB

MET Inhibitorsie, MET-Mab (MoAB) ARQ197 (TKI)

HSP inhibitorsie, Ganetespib AUY922

ie, BKM120 (PIK3CA)ie, MK2206 (AKT)

Adapted from Engelman et al.

• Secondary EGFR mutation (ie, T790m)

• Bypass signaling via ERBB3

• MET over-expression

• PIK3CA Mutation/AKT

& Others

21

Best Response in EGFR-Mutated T790M+ Cancers

CO-1686(Sequist: Targ Tx 2015)

AZD9291(Jänne: Targ Tx 2015)

22

23

ETCTN Project Team Proposals: AZD9291 in EGFR-mutated NSCLC Post-progression After Erlotinib

24

Clinical Trial Designs to Address Circumvention of Acquired Resistance in Oncogene-Driven NSCLC

Gandara et al. Clin Lung Cancer. 2014.

Targeted TKI Monotherapy(Standard of Care)

Multi-drug Targeted Therapy

Targeted TKI Monotherapy(2nd-Generation Agent)

Identificationof

Driver Oncogene

Advanced-Stage

NSCLC

Biopsy

Oncogene-drivenNSCLC

Prolongationof Remission

(delay time to PD)

EGFR Mutation

25

Phase II/III Trial of Afatinib With or Without Cetuximab in 1st-Line Therapy of EGFR-mutated NSCLC (S1403)

PIs: Goldberg, Lilenbaum, Politi.

Afatinib + Cetuximab*

Afatinib*

RANDOMISATION

Stage IIIB-IV NSCLC with EGFR mutation

1st LineEGFR TKI naive

*at PD: Biopsy for genomic study & PDX development (selected patients)

PD: progressive diseasePDX: patient-derived xenograft

26

BIBW

Cetuximab Cetux/BIBW

Cetux/BIBW

Pretreatment

H H H

HH

H

Pretreatment

Modulator Effects of EGFR MoAB Cetuximab:Afatinib (BIBW) + Cetuximab in EGFR T790M+ GEMMs

pEGFR

tEGFR

Actin

Control C B B+C

N T1 T2 T1 T2 T1 T2 T1 T2

Regales et al. J Clin Invest. 2009.

27

Afatinib + Cetuximab in EGFR-mutated NSCLC Refractory to EGFR TKI

Response rate: ≈30%Clinical benefit (DCR): 75%

Janjigian, Pao et al. Cancer Discovery. 2014;4:1036-1045.

28

Phase II/III Trial of Afatinib With or Without Cetuximab in 1st-Line Therapy of EGFR-mutated NSCLC (S1403)

PIs: Goldberg, Lilenbaum, Politi.

Afatinib + Cetuximab*

Afatinib*

RANDOMISATION

Stage IIIB-IV NSCLC with EGFR mutation

1st LineEGFR TKI naive

*at PD: Biopsy for genomic study & PDX development (selected patients)

PD: progressive diseasePDX: patient-derived xenograft

29

Strategies for Integrating Biomarkers Into Clinical Trial Designs for NSCLC When Viewed as a Multitude of Genomic Subsets

Evolution of NSCLC Histologic Subsets Genomic Subsets

Li, Mack, Kung, Gandara. JCO. 2013.

Unmet needs addressed by master protocols:

• How to develop drugs for uncommon-rare genotypes?

• How to apply broad-based screening (NGS)?

• How to achieve acceptable turn-around times for molecular testing for therapy initiation (<2 weeks)?

• How to expedite the new drug-biomarker FDA approval process (companion diagnostic)?

30

“Strategies for Integrating Biomarkers Into Clinical Development of New Therapies for Lung Cancer”A Joint NCI Thoracic Malignancies Steering Committee-FDA Workshop

• Trial Design Challenges in the Era of Biomarker-driven Trials– Innovative Statistical Designs– Challenges for Community Oncology Practice Participation– The Patient Perspective

• Drug & Biomarker Co-Development in Lung Cancer– Need for Early Co-Development– Need for Improved Pre-Clinical Models With Clinical

Relevance

• Development of Future Lung Cancer Trials– TMSC Master Protocol Task Force in NSCLC– Biomarker-driven trial designs in both early stage adjuvant

therapy & advanced-stage NSCLC– Account for inter-patient tumour heterogeneity & genomic

complexity of NSCLC

Bethesda MD – February 2-3, 2012

31

UmbrellaTrials

BasketTrials

Master Protocol Subtypes

Single Type of Cancer: Test multiple drug-biomarker combinations• BATTLE• I-SPY2• SWOG Lung MAP (S1400):

adv SCCA• ALCHEMIST: early stage

NSCLC• ALK Master Protocol: ALK+

NSCLC

Multiple Cancer Types: Test multiple drugs against single or multiple biomarkers• Imatinib Basket• BRAF+• NCI MATCH

32

Non-Match: Phase III trial of nivolumab vs placebo X 1 year after any adj tx

(EGFR & ALK testing performed by RGI)

ALCHEMIST Trial Schema

33

From S Malik: NCI.

ALK Master Protocol: Proposed Trial Design

34

Rationale for “MASTER PROTOCOL” in SCCA

• SCCA represents an unmet need

• Candidate molecular targets are available from results of TCGA & other studies, identified by a biomarker

• Drugs (investigational) are now available for many of these targets

• Trials can be designed to allow testing & registration of multiple new drug-biomarker combinations at the same time (“MASTER PROTOCOL” concept)

• Result of this concept is Lung-MAP (S1400), activated in June 2014

Therapeutic targets SCCA-TCGA 2012

35

S1400 Lung-MAP Protocol: A Unique Private-Public Partnership Within the NCTN

S1400Master Protocol

Alliance

ECOG-Acrin

NRGNCI-C

SWOG

36

S1400: MASTER LUNG-1: Squamous Lung Cancer — 2nd-Line Therapy

TT = Targeted therapy; CT = chemotherapy (docetaxel or gemcitabine); E = erlotinib.

Project Chair: V. PapadimitrakopoulouSteering Committee Chair: R. HerbstSWOG Lung Chair: D. Gandara

CT

Biomarker C

TT C+CT CT

Biomarker Β

TT B CT

Biomarker A

TT A CT

Primary Endpoint PFS/OS

BiomarkerProfiling (NGS/CLIA)

Biomarker D

TT D+E E

Primary EndpointPFS/OS

Non-MatchDrug

BiomarkerNon-Match

Multiple Phase II-III Sub-studies with Rolling Opening & Closure

Primary Endpoint PFS/OS

Primary Endpoint PFS/OS

37

LUNG-MAP (S1400): Squamous Lung Cancer — 2nd-Line Therapy

CT

AZD4547 CT

FGFRM: FGFR ampl, mut, fusion

PD-0332991 CT

CDK4/6M: CCND1, CCND2, CCND3, cdk4 ampl

Common Broad PlatformCLIA Biomarker Profiling◊

HGFM:c-Met Expr

AMG102+E E

Anti-PD-L1: MEDI4736

Non-match

Endpoint PFS/OS

Endpoint PFS/OS

Endpoint PFS/OS

Endpoint PFS/OS

GDC-0032 CT

CT = chemotherapy (docetaxel or gemcitabine); E = erlotinib.◊ Archival FFPE tumour, fresh CNB if needed.

Project Chair: V. PapadimitrakopoulouSteering Committee Chair: R. HerbstSWOG Lung Chair: D. Gandara

PI3KM:PIK3CA mut

38

LUNG-MAP (S1400): Squamous Lung Cancer— 2nd-Line Therapy

• Organisers: NCI-TMSC, FDA, FNIH, FOCR

• Participants: Entire North American Lung Intergroup(SWOG, Alliance, ECOG-Acrin, NRG, NCI-Canada)

• Screening: up to 1,000 patients/year

• With 4-6 arms open simultaneously, anticipate a hit rate ≈65% in matching a patient with a drug/biomarker arm

Interim Endpoint: PFS Primary Endpoint: OS

Genomic Screening(FM one)<2 weeks

PatientRegistration

ConsentTumour

CollectionRandomisation

Treatment

Assign TreatmentArm by Marker

NGS/IHC(Foundation

Medicine)

InvestigationalTargeted Therapy

Standard-of-Care Therapy

New TumourBiopsy

(if needed)

39

Squamous Lung Master Protocol Clinical Trial Assay Based on Foundation Medicine NGS Platform

1) DNA extraction 3) Analysis pipeline2) Library construction: selected cancer genes

• Based on FM T5 NGS platform

• Implemented as “mask” of T5 content and classification rules on called alterations

• Rules determine biomarker positive/negative status

Illumina HiSeq 2500

Classification rulesFoundation Medicine NGS test platform (CLIA/CAP)

PIK3CA mutationCCND1 amplification or CDKN2A/B deletion, and

RB1 wild-type

FGFR1/2/3/4 amplification,

mutation or fusion

PI3K inhibitor CDK4/6 inhibitor FGFR inhibitor

Classification rules (preliminary)

MET IHC (+)

MET pathwayinhibitor

Supplementary assays

All assays (-)

Anti-PD-L1 Ab

Non-match arm

Non-NGS biomarkers:

4) Master protocol CTA

40

Biomarker Trial Design Based on Comprehensive Genomic Profiling

PI3K/AKT/

mTOR

Cell Cycle FGFR0%

10%

20%

30%

40%

50%

60%

CCND2 amp

CCND3 amp

PIK3CAmutation

PIK3CAamp

PTEN loss

FBXW7 loss

STK11 loss

PIK3R1/2,TSC1/2, AKT1/2

CDKN2A/B loss

CCND1 amp

CDK6 ampCCNE1 amp

FGFR1 amp/mutation

FGFR3 amp

% of lung squamouspatientswith alteration

lead candidate biomarkers additional potential biomarkers

Screen success rate: up to ≈80% of patients, depending onbiomarkers selected

PI3K Cell Cycle25%

26%26%

PI3K FGFR5%4%47%

Cell Cycl

eFGFR

4%5%

46%

Non-

Match18%

41

What Are the Statistical Assumptions?Lung-MAP Sub-studies

    Phase 2 Phase 3

Sub-study IDPrevalence

EstimateApproximateSample Size

Approximate Time of

AnalysisSample

Size

Approximate Time of

AnalysisS1400A 56.0% 170 8 380 21

S1400B      

GNE+ 5.6%  78 288

FMI+ 8.0% 152 19 400 72

S1400C 11.7% 124 11 312 45

S1400D 9.0% 112 11 302 53

S1400E 16.0% 144 9 326 37

42

Is Lung-MAP Self-sustaining?Activation of Lung-MAP Within 1st Month (July 2014)

43

LUNG-MAP (S1400): Squamous Lung Cancer — 2nd-Line Therapy

CT = chemotherapy (docetaxel or gemcitabine); E = erlotinib.◊ Archival FFPE tumour, fresh CNB if needed.

Project Chair: V. PapadimitrakopoulouSteering Committee Chair: R. HerbstSWOG Lung Chair: D. Gandara

CT

AZD4547 CT

FGFRM: FGFR ampl, mut, fusion

PD-0332991 CT

CDK4/6M: CCND1, CCND2, CCND3, cdk4 ampl

Common Broad PlatformCLIA Biomarker Profiling◊

HGFM:c-Met Expr

AMG102+E E

Anti-PD-L1: MEDI4736

Non-match

Endpoint PFS/OS

Endpoint PFS/OS

Endpoint PFS/OS

Endpoint PFS/OS

PI3KM:PIK3CA mut

GDC-0032 CT

44

45

Is Lung-MAP “Self-sustaining”?

Lung MAP is designed to be adaptable with changes in the therapeutic landscape

• Example: recent approval of nivolumab in 2nd-line therapy of squamous lung cancer– Lung MAP modified to be 2nd-line and beyond (ie, some substudies are now 2nd-

3rd line, others 2nd-line)– One planned immunotherapy combination substudy is 2nd- line with nivolumab

control arm– Another planned substudy is 3rd-line after nivolumab PD

46

Hammerman et al. Nature. 2012.

Is Lung-MAP “Self-sustaining”?

• New Targets-New Opportunities– PARP– mTORC1/mTORC2

(RICTOR)– PI3K/PTEN– Wee-1 kinase– ATR – VEGFR2– TRK– Drug combinations

(Immunotherapies)

47

SUPPORTING COOPERATIVE GROUPS: ALLIANCE NCIC-CTG Everett Vokes, M.D. Glenwood Goss, M.D. University of Chicago Medical Center University of Ottawa ECOG/ACRIN NRG Suresh Ramalingam, M.D. Jeff Bradley, M.D. Emory University Washington University School of Medicine

SUPPORTING COOPERATIVE GROUPS: ALLIANCE NCIC-CTG Everett Vokes, M.D. Glenwood Goss, M.D. University of Chicago Medical Center University of Ottawa ECOG/ACRIN NRG Suresh Ramalingam, M.D. Jeff Bradley, M.D. Emory University Washington University School of Medicine