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Lung Cancer 2012 – Where We
Are and Where We’re Heading
Pasi A. Jänne, 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
Cisplatin 75 mg/m2 day 1 plus
Pemetrexed 500 mg/m2 day 1
Randomization Factors
•
Stage
•
Performance status
•
Gender
•
Histologic vs
cytologic diagnosis
•
History of brain
metastases
R
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
PIK3CA
ERBB2
EML4-ALK
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 10–14 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
1Mok
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*
Secondary: 6- and 12-month OS; OS; ORR*;
DCR; DR; Safety; HRQoL; Lung cancerspecific symptoms; General health status;
Biomarkers; TTD; HCRU
ECOG PS (0/1 vs 2)
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
PIK3CA
ERBB2
EML4-ALK
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
1 Shimamura
Cancer Res 2006
Minami Oncogene 2007
3 Perera PNAS 2009
2
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, 2010
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
Docetaxel
n=40
(75 mg/m2 every 3 wks i.v.)
Trametinib 2 mg QD
PFS2
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
Docetaxel
n=40
(75 mg/m2 every 3 wks i.v.)
Trametinib 2 mg QD
PFS2
Key studyAdditional
design features:
2:1 of
randomization;
cross-over after PD
cohort
25 patients:
Population:•BRAF mutant (both exon 11 and 15)
- KRAS-mutant
•MEK
1 mutant Adenocarcinoma Stage IIIb / IV
nd line population
2
•NRAS mutant
- 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 (IIIB–IV)
2nd line patients
KRAS mutant
WHO PS 0–1
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
NSCLC (IIIB–IV)
•Objective Response Rate
demonstrated with statistical significance, showing
•Duration
of Response
1:1 of
randomisation
2nd line patients
improvement in favor
selumetinib in combination
with
•Use of plasma & serum as source
docetaxel versus docetaxel alone.”
KRAS mutant
of CFDNA for analysis of KRAS
mutation status
WHO PS 0–1
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) of
tumors completely tested (CI 50-59%)
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 We’re 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 We’re Heading
Pasi A. Jänne, M.D., Ph.D.
Lowe Center for Thoracic Oncology
Dana-Farber Cancer Institute