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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