Innovation: Present Meets Future

(1)

Innovation: Present Meets Future

SOCIAL INNOVATION



 

Leading Innovation in the Cooperative Group

Setting

Craig Nichols, M.D.

BEST OF SWOG



 

Barlogie-Salmon Myeloma Committee

Robert Z. Orlowski, M.D., Ph.D.



 

Health Outcomes & Comparative Effectiveness

Committee

Scott D. Ramsey, M.D., Ph.D.



 

Lung Cancer Committee

(2)

SWOG Lung Commieee:

Innova>on meets the NCTN

David R. Gandara, MD

University of California Davis

Comprehensive Cancer Center

(3)

SWOG Lung Commieee:

Innova>on meets the NCTN

SWOG Lung

Commieee

Transi>on to

NCTN

Trans-‐

Disciplinary

Transla>onal

Transforma>ve

S1400

S1403

TMSC TM Working _Group Genomics Epigenomics Modeling Imaging Change in: -‐ Biologic Concepts -‐Clinical Prac>ce -‐Standard of Care

(4)

Developing SWOG Lung Trials

(Selected)

1. S1400: “Master Protocol” for Squamous Cell CA

(SCCA)-‐NSCLC second line therapy

2. S1403: Afa>nib +/-‐ Cetuximab in EGFR MT+ NSCLC

PI: V. Papadimitrakopoulou

PI: T. Lynch, S. Goldberg, K. Poli>

(5)

Unmet Needs in Clinical Trial Designs for NSCLC

when viewed as a Mul>tude of Genomic Subsets

Evolu>on of NSCLC àHistologic Subsets à Genomic Subsets

Li, Mack, Kung, Gandara: JCO 2013

Unmet Needs in Clinical Trials:

• How to develop drugs for

uncommon-‐rare genotypes?

• How to apply broad-‐based

screening (NGS)?

• How to achieve acceptable turn-‐

around >mes for molecular

tes>ng for therapy ini>a>on?

(<2 weeks)

• How to expedite the new drug-‐

biomarker FDA approval

(6)

“Strategies for Integra>ng Biomarkers into Clinical Development of New Therapies for Lung Cancer”

A Joint NCI Thoracic Malignancies Steering Commieee-‐FDA Workshop Bethesda MD – February 2-‐3, 2012

• Trial Design Challenges in the Era of Biomarker-‐driven Trials

• Innova>ve Sta>s>cal Designs

• Challenges for Community Oncology Prac>ce par>cipa>on

• The Pa>ent Perspec>ve

• 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 Clinical Trials

• TMSC Master Protocol Task Force in NSCLC

• Biomarker-‐driven trial designs in both early stage adjuvant therapy &

advanced stage NSCLC

• Account for inter-‐pa>ent tumor heterogeneity & genomic complexity

(7)

Master Lung-‐1 (S1400): A Biomarker-‐driven Mul>-‐Arm Phase II/III

Registra>on Protocol In Squamous Lung Cancer 2

nd

_{Line
Therapy}

(8)

• Mul>-‐arm Master Protocol

• Homogeneous pa>ent popula>ons & 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 tes>ng for

detec>on of “large eﬀects”

• Screening

large numbers of pa>ents for mul>ple targets by a

broad-‐based NGS plaVorm reduces the screen failure rate

• Provides a

suﬃcient “hit rate”

to engage pa>ents & physicians

• Bring safe & eﬀec>ve drugs to pa>ents faster

• Designed to faciliate

FDA approval

of new drugs

(9)

CT*

TT=Targeted therapy, CT=chemotherapy (docetaxel or gemcitabine), E=erlo>nib

S1400: MASTER LUNG-1:

Squamous Lung Cancer- 2

nd

_{Line Therapy}

Biomarker C TT C+CT CT* Endpoint (Interim PFS) OS Biomarker Β TT B CT* Endpoint (Interim PFS) OS Biomarker A TT A CT* Endpoint (Interim PFS) OS Biomarker Proﬁling (NGS/CLIA) Biomarker D TT D+E E* Endpoint (Interim PFS) OS Non-‐ Match Drug Biomarker Non-‐Match

PI: V. Papadimitrakopoulou (SWOG)

(10)

CT*

TT=Targeted therapy, CT=chemotherapy (docetaxel or gemcitabine), E=erlo>nib

S1400: MASTER LUNG-1:

Squamous Lung Cancer- 2

nd

_{Line Therapy}

FGFRi+CT CT* Endpoint (Interim PFS) OS FGFR ampl, Mut, Fusion CDK 4/6i CT* Endpoint (Interim PFS) OS CCND1 ampl or CDKN2 loss + RB WT PI3Ki CT* Endpoint (Interim PFS) OS PiK3CA Mut Biomarker Proﬁling (NGS/CLIA) HGFi+E E* Endpoint (Interim PFS) OS MET Expr PD-‐L1i Biomarker Non-‐Match

PI: V. Papadimitrakopoulou (SWOG)

(11)

S1400 (MASTER LUNG-1) Squamous Lung Cancer- 2

nd

_{Line Therapy}

• Organizers: FOCR, NCI-‐TMSC, FDA, FNIH

• Par>cipants: En>re North American Lung Intergroup

(SWOG, Alliance, ECOG-‐Acrin, NRG, NCI-‐Canada)

• Screening:

up to 1,000 pa>ents/year

• With 6 arms open simultaneously, an>cipate a “hit rate

>60% in matching a pa>ent with a drug/biomarker arm

Interim Endpoint: PFS Primary Endpoint: OS Genomic Screening <2 weeks Pa>ent Registra>o n Consent Tumor Collec>on Randomiza>on Treatment Assign treatment Arm by marker

NGS/IHC (Founda>on Medicine) Inves>ga>onal Targeted Therapy

Standard of Care Therapy

Genomic “Pre-‐screening” In selected pa>ents

(12)

Governance Structure: S1400 Master Lung-‐1 Project

Friends of Cancer Research

(13)

Developing SWOG Lung Trials

(Selected)

1. S1400: “Master Protocol” for Squamous Cell CA

(SCCA)-‐NSCLC second line therapy

2. S1403: Afa>nib +/-‐ Cetuximab in EGFR MT+ NSCLC

PI: V. Papadimitrakopoulou

PI: T. Lynch, S. Goldberg, K. Poli>

(14)

Targeted TKI Monotherapy (1st generation agent)

Multi-drug Targeted Therapy Targeted TKI Monotherapy

(2nd_{generation agent)} Identification of Driver Oncogene Advanced Stage NSCLC Biopsy

Clinical Trial Designs to address Circumven>on of

Acquired Resistance in Oncogene-‐Driven NSCLC

from Gandara & Redman: ASCO Ed Session 2013; in press Clin Lung Cancer

EGFR Mutation

(15)

Phase II/III trial of Afa7nib with or without Cetuximab

in

1

st

_{line
therapy
of}

_{EGFR-‐mutated
NSCLC
(S1403)}

Afa>nib + Cetuximab*

Stage IIIB-‐IV NSCLC with EGFR muta>on

1st_Line

EGFR TKI naive

Afa>nib* R A N D O M I Z A T I O N

*at PD: Biopsy for genomic study & PDX development (selected pa>ents)

PD: Progressive Disease PDX: pa>ent-‐derived xenograv

(16)

Afa>nib + Cetuximab in EGFR-‐mutated

NSCLC refractory to EGFR TKI

Response rate: 30%

Clinical beneﬁt (DCR): 75%

Janjigian, Pao et al. ESMO 2012

•  Why is response T790M-‐independent?

•  What is the mechanism of ac>on of this combina>on

by comparison to Afa>nib alone?

(17)

Phase II/III trial of Afa7nib with or without Cetuximab

in

1

st

_{line
therapy}

_{of
EGFR-‐mutated
NSCLC
(S1403)}

Afa>nib + Cetuximab*

Stage IIIB-‐IV NSCLC with EGFR muta>on

1st_Line

EGFR TKI naive

Afa>nib* R A N D O M I Z A T I O N

*at PD: Biopsy for genomic study & PDX development (selected pa>ents)

-‐Pilot project for SWOG Trans Sci Ctr

PD: Progressive Disease PDX: pa>ent-‐derived xenograv

(18)

SWOG Transla>onal Science Center:

Pilot PDX Project in S1403

SWOG

SWOG Sta>s>cal Center Cold Spring Harbor (CSHL) SWOG clinical trials Jackson Lab (JAX)

(19)

14 models 12 models 2 model 14 models KRAS Mutant EGFR Mutant ALK Mutant Triple WT

Innovation: Present Meets Future