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Lung Cancer 2012 Where We

Are and Where Were Heading
Pasi A. Jnne, M.D., Ph.D.
Lowe Center for Thoracic Oncology
Dana-Farber Cancer Institute

Strategies to Improve Outcome

of Lung Cancer Patients
Move away from approaching lung cancer
as one disease
Develop treatment strategies for
different subsets of lung cancer
Treatment improvements based on
Histology
Oncogenic alterations

Cisplatin/Pemetrexed vs
Cisplatin/Gemcitabine for Advanced NSCLC
Randomization Factors

Stage

Performance status

Gender

Histologic vs
cytologic diagnosis

History of brain
metastases

Cisplatin 75 mg/m2 day 1 plus

Pemetrexed 500 mg/m2 day 1

Each cycle repeated

q3 weeks up to 6 cycles
Cisplatin 75 mg/m2 day 1 plus
Gemcitabine 1250 mg/m2 days 1 & 8

Vitamin B12, folate, and dexamethasone given in both arms

Scagliotti GV, et al. J Clin Oncol. 2008;26(21):3543-3551.

Cisplatin/Pemetrexed vs
Cisplatin/Gemcitabine for Advanced NSCLC
Breakdown by Histology: Cis/Pem vs Cis/Gem
Nonsquamous

Squamous

Median CP

11.8 months
95% CI 10.4, 13.2

9.4 months
95% CI 8.4, 10.2

Median CG

10.4 months
95% CI 9.6, 11.2

10.8 months
95% CI 9.5, 12.1

CP v CG adjusted HR; 95% CI

0.81; 0.70, 0.94

1.23; 1.00, 1.51

Median CP

5.3 months
95% CI 4.8, 5.7

4.4 months
95% CI 4.1, 4.0

Median CG

4.7 months
95% CI 4.4, 5.4

5.5 months
95% CI 4.6, 5.9

CP v CG adjusted HR; 95% CI

0.90; 0.79, 1.02

1.36; 1.12, 1.65

Survival Probability

PFS Probability

Scagliotti GV, et al. J Clin Oncol, 2008;26(21):3543-3551.

Non Small Cell Lung Cancer:

From Histology To Genomics
Squamous cell cancer

Druggable genomic alterations

Kinases
Adenocarcinoma
Critical to growth
& survival of
NSCLC

EGFR

Unknown

KRAS

MET
Amplification
ERBB2
Amplification

MEK1

EML4-ALK

PIK3CA

ERBB2

BRAF

BRAF

OPTIMAL: Erlotinib vs.

Chemotherapy in EGFR Mutant NSCLC
Median progression-free survival
Erlotinib (N = 82): 13.1 months
Chemotherapy (N = 72): 4.6 months
HR 0.16 (95% CI 0.10-0.26)
Log-rank p < 0.0001

Zhou et al. Lancet Oncol 2011

EGFR Kinase Inhibitors 2012

Clinical activity in EGFR mutant NSCLC

1,2

1st line response rate: 60%-80%

1st line progression free survival 1014 months

Gefitinib and erlotinib superior to 1st line

chemotherapy1,3
Higher RR and longer PFS; no OS improvement
Better toxicity profile

However resistance develops in most if not all

patients
1

Mok et al. NEJM 2009; 2Rosell et al. NEJM 2009; 3Zhou et al. Lancet Oncol 2011

Soda et al. Nature 2007

Crizotinib is Clinically Effective in EML4-ALK

NSCLC

Kwak E et al. N Engl J Med 2010;363(18):1693-703. Copyright 2012 Massachusetts Medical Society.

Randomized phase III trial of crizotinib vs chemotherapy

in previously treated EML4-ALK NSCLC

Key Entry Criteria

Positive for ALK gene
translocation
Brain mets allowed
1 prior chemo
(platinum-based)

R
A
N
D
O
M
I
Z
E
N = 318

Crizotinib
N = 159

Pemetrexed or
Docetaxel
N = 159

Primary endpoint: PFS

Secondary endpoints: ORR, DR, DCR, OS, Safety, QoL, Biomarkers

Phase 3 study in previously

untreated NSCLC: A8081014
Trial design

Endpoints

Stratification

World-wide, multicenter,
randomized,
open-label, focused
screening

Primary: PFS*

ECOG PS (0/1 vs 2)

Secondary: 6- and 12-month OS; OS; ORR*;

DCR; DR; Safety; HRQoL; Lung cancerspecific symptoms; General health status;
Biomarkers; TTD; HCRU

Ethnicity (Asian vs non-Asian)

Brain metastases

*Based on RECIST v 1.1 and confirmed by independent radiology review

Key entry criteria

Diagnosis of locally
advanced/metastatic
non-squamous NSCLC;
ECOG 0-2
Positive for ALK

No prior treatment for

advanced disease

Brain metastases
allowed

R
A
N
D
O
M
I
Z
E
N=320

N = 160

N = 160

Arm A: Crizotinib 250 mg BID administered

on a continuous dosing schedule
Arm B: Pemetrexed/cisplatin or
pemetrexed/carboplatin
Day 1 of a 21-day cycle

Patients in Arm B who have RECIST-defined PD as

determined by the independent radiology review will be
allowed to cross over to Arm A
www.clinicaltrials.gov (NCT01154140)

Non small cell lung cancer from histology to

genomics
Squamous cell cancer

Adenocarcinoma

EGFR

Unknown

KRAS
MET
Amplification
ERBB2
Amplification

MEK1

EML4-ALK

PIK3CA

ERBB2

BRAF

BRAF

Dacomitinib (PF299804) in ERBB2 amplified NSCLC

Molecular analysis revealed a HER2-positive tumor

Patient was commenced on dacomitinib in December
2008 and experienced a partial response after 4 weeks
of 45 mg orally once daily with 21 days per cycle
Of particular interest was a notable reduction in the
patient's soluble extracellular domain HER2 levels
(non-invasive method for tracking treatment efficacy)

Kelly R J et al. JCO 2010

Pre-clinical efficacy of neratinib and afatinib

in ERBB2 mutant NSCLC
The subset of NSCLC patients with tumors carrying the
ERBB2 mutation may benefit from treatment with neratinib1
The major lung cancer-derived mutants of ERBB2 are
oncogenic and are associated with sensitivity to the
irreversible EGFR/ERBB2 inhibitor neratinib2
Clinical testing of afatinib/rapamycin in NSCLC patients with
tumors expressing HER2 mutations is warranted3

Shimamura Cancer Res 2006

Minami Oncogene 2007
3
Perera PNAS 2009
1

Clinical activity of neratinib and

temsirolimus in ERBB2 mutant NSCLC
"The combination of NER and TEM has demonstrated
preliminary antitumor activity in pts with HER2-dependent
NSCLC and BC, as well as other solid tumors."

Leena Gandhi ASCO 2011

Ongoing Phase II Trial of Dacomitinib

Cohort A:
Non- or former light smoker
or
EGFR mu
(1st line)
Cohort B:
HER-2 mu or HER-2 amp*

Serial T790M in blood Cohort A;

* [gene]/[centromere of chromosome 17] ratio >2

Cohort B: no limit on prior number of regimens

Dacomitinib
45 mg QD
N=80

Until
Progression

Summary of BRAF mutations from DFCI

NSCLC patients

Exon 11
mutations

V600E
G466V
G466R
G469 del
G469A
Inst T
D594G
D594N

Efficacy of Vemurafenib in BRAF V600E

Melanoma

Chapman PB et al. N Engl J Med 2011;364:2507-2516. Copyright 2012 Massachusetts

Medical Society.

Will BRAF inhibitors demonstrate activity in

lung/colon/etc tumors with BRAF V600E?
Vemurafenib (PLX4032) shows activity at 960 mg BID in metastatic CRC patients (n=19)*
with the BRAF V600E mutation

With permission from Kopetz et al. ASCO, 2

Phase II trial of
dabrafenib (GSK2118436)

Stage IV NSCLC
Previously treated
BRAF V600E mutant

Dabrafenib

Primary endpoint
Response Rate
Secondary
PFS
OS
Toxicity

Sample size: 40 patients

Mutation testing can be done in any CLIA lab
Correlative biomarkers: serum DNA for BRAF V600E

RAS Signaling

Adopted from Schubber et al, Nature Cancer Review 2007

Efficacy of trametinib (GSK1120212) in BRAF

mutant melanoma and KRAS mutant NSCLC

KRAS mutant NSCLC (n=14)

2 PR (20+ and 33+ wks)
7 SD (3 > 16 wks) and 5 PD
With permission from Falchook et al. ESMO 2010

Trametinib: KRAS-mutant NSCLC

K-ras mutations (n = 22)
PFS: Median (95% CI) = 3.8 (1.9-5.5) months
K-ras wild type (n = 8)
PFS: Median (95% CI) = 2.1 (1.8-5.2) months

Blumenschein. Proc Santa Monica Meeting, 2011

MEK114654 Phase II Study in KRASMutant NSCLC

n=80
Screen

Trametinib
(2 mg QD)

PFS

KRAS- MUT

n=40

Docetaxel

Trametinib 2 mg QD

PFS2

(75 mg/m2 every 3 wks i.v.)

Key study design features: 2:1 randomization; cross-over after PD

Population:
- KRAS-mutant Adenocarcinoma Stage IIIb / IV
- 2nd line population
- ECOG 0 or 1
Primary endpoints: PFS
Secondary endpoints: OS, ORR, DR, safety, biomarker validation

MEK114654 Phase II Study in KRASMutant NSCLC

n=80
Screen

Trametinib
(2 mg QD)

PFS

KRAS- MUT

n=40

Docetaxel

Trametinib 2 mg QD

PFS2

(75 mg/m2 every 3 wks i.v.)

Key studyAdditional
design features:
2:1of
randomization;
cross-over after PD
cohort
25 patients:
Population:BRAF mutant (both exon 11 and 15)
- KRAS
-mutant Adenocarcinoma Stage IIIb / IV
MEK
1 mutant
- 2nd mutant
line population
NRAS
- ECOG 0 or 1
Primary endpoints: PFS
Secondary endpoints: OS, ORR, DR, safety, biomarker validation

Randomized Phase II trial of

Selumetinib (AZD6224) vs. Chemotherapy
Selumetinib in
combination with

Patients:
NSCLC (IIIBIV)
2nd line patients
KRAS mutant
WHO PS 01

docetaxel
1:1 randomisation
Placebo in
combination with

Primary

Overall Survival

Secondary

Progression Free Survival

Objective Response Rate
Duration of Response
Use of plasma & serum as source
of CFDNA for analysis of KRAS
mutation status
Investigate PK of selumetinib

docetaxel

Sample size: 87
Study completed accrual; data will be presented at ASCO 2012

Randomized Phase II trial of

Selumetinib (AZD6224) vs. Chemotherapy
Selumetinib in
combination with

Primary

Overall Survival

progression-free survival,
objective response
rate, and
docetaxel
Secondary
Patients: alive and progression-free at 6 months were all
Progression Free Survival
Objective Response Rate
demonstrated with statistical significance, showing
NSCLC (IIIBIV)
of Response
Duration
1:1 of
randomisation
improvement in favor
selumetinib in combination
with
2nd line patients
Use of plasma & serum as source
docetaxel
versus
docetaxel
alone.
of CFDNA for analysis of KRAS
KRAS mutant
mutation status
WHO PS 01
Placebo
in
th
Investigate PK of selumetinib
ARRAY press release Sep 30 2011
combination with
docetaxel

Sample size: 87
Study completed accrual; data will be presented at ASCO 2012

Squamous Cell Lung Cancer

A significant minority of NSCLC
No effective targeted therapy
Lack of efficacy or toxicity for
Pemetrexed
Bevacizumab

Some KRAS and PIK3CA mutations

Ongoing systematic genomics efforts
The Cancer Genome Atlas

DDR2 Mutations in Squamous Cell Cancer

"DDR2 mutations are present in 4% of lung

SCCs, and DDR2 mutations are associated
with sensitivity to dasatinib."

Hammerman et al. Cancer Discovery 2011

Phase II Trial of Dasatinib in Squamous

Cell Lung Cancer DF/HCC #11-142
Stage IV
Squamous cell
histology
1 prior systemic
therapy
Tissue available

Dasatinib
100 mg daily
Continuous

Continue until
disease
progression or
development of
toxicity

Primary objective: Response Rate

Secondary objectives: Types/Frequencies of DDR2 Mutations,
Correlation of DDR2 Mutations with RR, PFS, OS and Tox
PI: Hammerman/Johnson

FGFR1 Amplification in a Subset of Squamous Cell Cancers

"Focal FGFR1 amplification is common in

squamous cell lung cancer and associated with
tumor growth and survival, suggesting that FGFR
inhibitors may be a viable therapeutic option in this
cohort of patients."

Weiss J et al. Sci Transl Med 2010

FGFR1 Inhibitor is Effective in FGFR1 Amplified Cells

Phase I trial of BGJ398 (Pan FGFR inhibitor) is currently

underway (NCT01004224)

Weiss J et al. Sci Transl Med 2010

DFCI Thoracic Program Genomics

Initiative
Aim to provide routine genotyping to all
lung cancer patients
EGFR 2004; KRAS 2008
Comprehensive July 2009

Partly supported by philanthropy

EGFR, KRAS, BRAF, PIK3CA, ERBB2 & EML4ALK

> 900 patients genotyped to date

4 dedicated CRCs

DFCI Thoracic Program Genomics

Initiative contd.
Limited to non-squamous cell carcinoma
Squamous cell carcinoma to start 2012

Failure rate ~10%

Insufficient tumor, bad quality DNA
Bone biopsies are bad for genotyping

~50% of the patients with known alterations have

received a molecularly targeted therapy

Systematic Genotyping of Lung Adenocarcinomas

at DFCI
Erlotinib
PF00299804
Lapatinib/Temsirolimus

Second generation EGFR TKI

EGFR
KRAS
EML4-ALK
BRAF
PIK3CA
ERBB2
None

XL147, PKI587
GDC 0980, ZSTK474
AZD6244
GSK2118436
GSK 1120212

Docetaxel +/- AZD6244

GSK 1120212 vs. Docetaxel
GDC 0973/GDC0941
Crizotinib vs. Chemotherapy
Crizotinib, 2nd Generation ALK Inhibitors

Lung Cancer Mutation Consortium

Lung Cancer Mutation Consortium

Patients and Study Plan

1000 patients
Stage IV
ECOG PS 0-2
Lung Adenocarcinoma
Sufficient Tissue (Paraffin)
Informed Consent

Mutational Analysis
CLIA-certified lab at LCMC site:
KRAS, EGFR, EML4-ALK, BRAF,
HER2, PIK3CA, NRAS, MEK1,
AKT1, MET amplification

Kris et al. ASCO 2011

Central
Confirmation of
Adenocarcinoma
Diagnosis
(1 slide)
Report to
LCMC
Virtual
Database

Report to
Physician

Use Data to Select

Therapy
(Erlotinib with EGFR
Mutation)
Recommend
Clinical Trial of
Agent Specific for
Target

Lung Cancer Mutation Consortium

Incidence of Single Driver

Mutations

Kris et al. ASCO 2011

Mutation found in 54% (280/516)

tumors completely tested (CI 50-

Evolution of Lung Cancer Genotyping

Current sequencing based (6 genes)
Currently limited to lung cancer

Mass spec based genotyping (Oncomap)

All cancers; started in 2011

Whole exome sequencing in development

U01 grant

Lung cancer and colorectal cancer

Lung Cancer 2012 Where We Are and

Where Were Heading
One size fits all era of treatment and drug development is
over for lung cancer
Two validated genomic targets
Mutant EGFR and ALK rearrangements
Ongoing - ? use in earlier disease & drug resistance

Rapid pace of pre-clinical discoveries

Goal to find and develop effective therapies for all subsets
of NSCLC patients

Lung Cancer 2012 Where We

Are and Where Were Heading
Pasi A. Jnne, M.D., Ph.D.
Lowe Center for Thoracic Oncology
Dana-Farber Cancer Institute