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Please note, these are the actual video-recorded proceedings from the live CME event and may include the use of trade names and other raw,
unedited content. Select slides from the original presentation are omitted where Research To
Practice was unable to obtain permission from the publication source and/or author. Links to view the actual reference materials have been provided for
your use in place of any omitted slides.
Pasi A. Jänne, M.D., Ph.D.Lowe Center for Thoracic Oncology
Dana-Farber Cancer Institute
Lung Cancer 2012 – Where We Are and Where We’re Heading
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
Scagliotti GV, et al. J Clin Oncol. 2008;26(21):3543-3551.
Cisplatin 75 mg/m2 day 1 plus Gemcitabine 1250 mg/m2 days 1 & 8
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
Vitamin B12, folate, and dexamethasone given in both arms
Each cycle repeated q3 weeks up to 6 cycles
Cisplatin/Pemetrexed vs Cisplatin/Gemcitabine for Advanced
NSCLC
Scagliotti GV, et al. J Clin Oncol, 2008;26(21):3543-3551.
Breakdown by Histology: Cis/Pem vs Cis/Gem
Cisplatin/Pemetrexed vs Cisplatin/Gemcitabine for Advanced
NSCLC
Nonsquamous Squamous
Survival Probability
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
PFS Probability
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
Non Small Cell Lung Cancer: From Histology To Genomics
Squamous cell cancer
Adenocarcinoma
EGFR
KRAS
Unknown
EML4-ALKBRAF
PI K3CA
ERBB2MEK1ERBB2
Amplif ication
MET Amplif ication
EGFR
KRAS
Unknown
EML4-ALKBRAF
PI K3CA
ERBB2MEK1ERBB2
Amplif ication
MET Amplif ication
“Druggable” genomic alterations
Kinases Critical to growth &
survival of NSCLC
BRAF
OPTIMAL: Erlotinib vs. Chemotherapy in EGFR Mutant
NSCLC
Zhou et al. Lancet Oncol 2011
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
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
Kwak E et al. N Engl J Med 2010;363(18):1693-703. Copyright © 2012 Massachusetts Medical Society.
Crizotinib is Clinically Effective in EML4-ALK NSCLC
Key Entry Criteria• Positive for ALK gene
translocation• Brain mets allowed• 1 prior chemo
(platinum-based)
RANDOMIZE
N = 318
Crizotinib
Pemetrexed orDocetaxel
N = 159
N = 159
Randomized phase III trial of crizotinib vs chemotherapy in previously treated EML4-ALK
NSCLC
Primary endpoint: PFS
Secondary endpoints: ORR, DR, DCR, OS, Safety, QoL, Biomarkers
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
RANDOMIZE
N=320
Arm A: Crizotinib 250 mg BID administered on a continuous dosing schedule
Arm B: Pemetrexed/cisplatin orpemetrexed/carboplatin Day 1 of a 21-day cycle
N = 160
N = 160
Phase 3 study in previously untreated NSCLC: A8081014
Trial design Endpoints StratificationWorld-wide, multicenter, randomized, open-label, focused screening
Primary: PFS*Secondary: 6- and 12-month OS; OS; ORR*; DCR; DR; Safety; HRQoL; Lung cancer-specific symptoms; General health status; Biomarkers; TTD; HCRU
ECOG PS (0/1 vs 2)Ethnicity (Asian vs non-Asian)Brain metastases
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
*Based on RECIST v 1.1 and confirmed by independent radiology review
www.clinicaltrials.gov (NCT01154140)
Non small cell lung cancer – from histology to genomics
Squamous cell cancer
Adenocarcinoma
EGFR
KRAS
Unknown
EML4-ALKBRAF
PI K3CA
ERBB2MEK1ERBB2
Amplif ication
MET Amplif ication
EGFR
KRAS
Unknown
EML4-ALKBRAF
PI K3CA
ERBB2MEK1ERBB2
Amplif ication
MET Amplif ication
BRAF
Kelly R J et al. JCO 2010
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)
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 20062 Minami Oncogene 20073 Perera PNAS 2009
Leena Gandhi – ASCO 2011
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."
Cohort A: Non- or former light smoker
or EGFR mu(1st line)
Cohort B: HER-2 mu or HER-2 amp*
Ongoing Phase II Trial of Dacomitinib
Dacomitinib45 mg QD
N=80Until
Progression
Serial T790M in blood Cohort A; * [gene]/[centromere of chromosome 17]
ratio >2
Cohort B: no limit on prior number of regimens
V600EG466VG466RG469 delG469AInst TD594GD594N
Summary of BRAF mutations from DFCI NSCLC patients
Exon 11 mutatio
ns
Chapman PB et al. N Engl J Med 2011;364:2507-2516. Copyright © 2012 Massachusetts Medical Society.
Efficacy of Vemurafenib in BRAF V600E Melanoma
With permission from Kopetz et al. ASCO, 2010
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
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
Adopted from Schubber et al, Nature Cancer Review 2007
RAS Signaling
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
Blumenschein. Proc Santa Monica Meeting, 2011
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
MEK114654 Phase II Study in KRAS-Mutant NSCLC
Key study design features: 2:1 randomization; cross-over after PDPopulation:
- KRAS-mutant Adenocarcinoma Stage IIIb / IV- 2nd line population- ECOG 0 or 1
Primary endpoints: PFSSecondary endpoints: OS, ORR, DR, safety, biomarker validation
Trametinib 2 mg QD
Trametinib (2 mg QD)
Docetaxel (75 mg/m2 every 3 wks i.v.)
KRAS- MUTScreen
n=80
n=40PFS2
PFS
MEK114654 Phase II Study in KRAS-Mutant NSCLC
Key study design features: 2:1 randomization; cross-over after PDPopulation:
- KRAS-mutant Adenocarcinoma Stage IIIb / IV- 2nd line population- ECOG 0 or 1
Primary endpoints: PFSSecondary endpoints: OS, ORR, DR, safety, biomarker validation
Trametinib 2 mg QD
Trametinib (2 mg QD)
Docetaxel (75 mg/m2 every 3 wks i.v.)
KRAS- MUTScreen
n=80
n=40PFS2
PFS
Additional cohort of 25 patients:•BRAF mutant (both exon 11 and 15)•MEK 1 mutant•NRAS mutant
Randomized Phase II trial of Selumetinib (AZD6224) vs.
Chemotherapy
Primary•Overall SurvivalSecondary•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
Patients:NSCLC (IIIB–IV)2nd line patientsKRAS mutantWHO PS 0–1
Selumetinib in combination with
docetaxel
1:1 randomisation
Placebo in combination with
docetaxel
Sample size: 87Study completed accrual; data will be presented at ASCO 2012
Randomized Phase II trial of Selumetinib (AZD6224) vs.
Chemotherapy
Primary•Overall SurvivalSecondary•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
Patients:NSCLC (IIIB–IV)2nd line patientsKRAS mutantWHO PS 0–1
Selumetinib in combination with
docetaxel
1:1 randomisation
Placebo in combination with
docetaxel
Sample size: 87Study completed accrual; data will be presented at ASCO 2012
“…progression-free survival, objective response rate, and alive and progression-free at 6 months were all demonstrated with statistical significance, showing improvement in favor of selumetinib in combination with docetaxel versus docetaxel alone.”
ARRAY press release Sep 30th 2011
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
Hammerman et al. Cancer Discovery 2011
"DDR2 mutations are present in 4% of lung SCCs, and DDR2 mutations are associated with sensitivity to dasatinib."
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 dailyContinuous
Continue until disease
progression or development of
toxicity
Primary objective: Response RateSecondary 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
Weiss J et al. Sci Transl Med 2010
"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."
FGFR1 Inhibitor is Effective in FGFR1 Amplified Cells
Weiss J et al. Sci Transl Med 2010
Phase I trial of BGJ398 (Pan FGFR inhibitor) is currently underway (NCT01004224)
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 & EML4-
ALK• > 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
EGFRKRASEML4-ALKBRAFPIK3CAERBB2None
Systematic Genotyping of Lung Adenocarcinomas at DFCI
Erlotinib Second generation EGFR
TKI
Docetaxel +/- AZD6244GSK 1120212 vs. Docetaxel
GDC 0973/GDC0941AZD6244GSK2118436GSK 1120212
XL147, PKI587GDC 0980, ZSTK474
Crizotinib vs. ChemotherapyCrizotinib, 2nd Generation ALK
Inhibitors
PF00299804Lapatinib/
Temsirolimus
Lung Cancer Mutation Consortium
Lung Cancer Mutation Consortium
Patients and Study Plan1000 patients
Stage IVECOG PS 0-2
Lung AdenocarcinomaSufficient Tissue (Paraffin)
Informed Consent
Central Confirmation of
Adenocarcinoma Diagnosis(1 slide)
Mutational Analysis CLIA-certified lab at LCMC site:
KRAS, EGFR, EML4-ALK, BRAF, HER2, PIK3CA, NRAS, MEK1,
AKT1, MET amplification
Use Data to Select Therapy
(Erlotinib with EGFRMutation)
Report to Physician
Report to LCMC Virtual
Database
Recommend Clinical Trial of
Agent Specific for Target
Kris et al. ASCO 2011
Lung Cancer Mutation Consortium
Incidence of Single Driver Mutations
Mutation found in 54% (280/516) oftumors completely tested (CI 50-59%)
Kris et al. ASCO 2011
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
Pasi A. Jänne, M.D., Ph.D.Lowe Center for Thoracic Oncology
Dana-Farber Cancer Institute
Lung Cancer 2012 – Where We Are and Where We’re Heading