1. 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.

2. 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

3. 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

4. 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):

5. Cisplatin/Pemetrexed vs Cisplatin/Gemcitabine for Advanced NSCLC
Breakdown by Histology: Cis/Pem vs Cis/Gem
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
5.3 months 95% CI 4.8, 5.7
4.4 months 95% CI 4.1, 4.0
4.7 months 95% CI 4.4, 5.4
5.5 months 95% CI 4.6, 5.9
0.90; 0.79, 1.02
1.36; 1.12, 1.65
Scagliotti GV, et al. J Clin Oncol, 2008;26(21):

6. Non Small Cell Lung Cancer: From Histology To Genomics
Squamous cell cancer
“Druggable” genomic alterations
Kinases
Critical to growth & survival of NSCLC
Adenocarcinoma
BRAF

7. 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 )
Log-rank p <
Zhou et al. Lancet Oncol 2011

8. 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

9. Soda et al. Nature 2007

10. Crizotinib is Clinically Effective in EML4-ALK NSCLC
Kwak E et al. N Engl J Med 2010;363(18): Copyright © 2012 Massachusetts Medical Society.

11. 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)
N = 159
Pemetrexed or
Docetaxel
N = 318
N = 159
Primary endpoint: PFS
Secondary endpoints: ORR, DR, DCR, OS, Safety, QoL, Biomarkers

12. 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 cancer-specific 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
Arm A: Crizotinib 250 mg BID administered on a continuous dosing schedule
N = 160
Arm B: Pemetrexed/cisplatin or pemetrexed/carboplatin
Day 1 of a 21-day cycle
N = 160
N=320
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
(NCT ) 12 12

13. Non small cell lung cancer – from histology to genomics
Squamous cell cancer
Adenocarcinoma
BRAF

14. 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

15. 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
2 Minami Oncogene 2007
3 Perera PNAS 2009

16. 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

17. 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*
Dacomitinib
45 mg QD
N=80
Until Progression
Serial T790M in blood Cohort A;
* [gene]/[centromere of chromosome 17] ratio >2
Cohort B: no limit on prior number of regimens

18. Summary of BRAF mutations from DFCI NSCLC patients
V600E
G466V
G466R
G469 del
G469A
Inst T
D594G
D594N
Exon 11
mutations

19. Efficacy of Vemurafenib in BRAF V600E Melanoma
Chapman PB et al. N Engl J Med 2011;364: Copyright © 2012 Massachusetts Medical Society.

20. 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

21. Phase II trial of dabrafenib (GSK2118436)
Primary endpoint
Response Rate
Secondary
PFS OS
Toxicity
Dabrafenib
Stage IV NSCLC
Previously treated
BRAF V600E mutant
Sample size: 40 patients
Mutation testing can be done in any CLIA lab
Correlative biomarkers: serum DNA for BRAF V600E

22. Adopted from Schubber et al, Nature Cancer Review 2007
RAS Signaling
Adopted from Schubber et al, Nature Cancer Review 2007

23. 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

24. Trametinib: KRAS-mutant NSCLC
K-ras mutations (n = 22) PFS: Median (95% CI) = 3.8 ( ) months
K-ras wild type (n = 8) PFS: Median (95% CI) = 2.1 ( ) months
Blumenschein. Proc Santa Monica Meeting, 2011

25. MEK114654 Phase II Study in KRAS-Mutant NSCLC
Trametinib
(2 mg QD)
n=80
Docetaxel
(75 mg/m2 every 3 wks i.v.)
Trametinib 2 mg QD
Screen
KRAS- MUT
PFS
PFS2
n=40
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

26. MEK114654 Phase II Study in KRAS-Mutant NSCLC
Trametinib
(2 mg QD)
n=80
Docetaxel
(75 mg/m2 every 3 wks i.v.)
Trametinib 2 mg QD
Screen
KRAS- MUT
PFS
PFS2
n=40
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
Additional cohort of 25 patients:
BRAF mutant (both exon 11 and 15)
MEK 1 mutant
NRAS mutant

27. Randomized Phase II trial of Selumetinib (AZD6224) vs. Chemotherapy
Selumetinib in
combination with
docetaxel
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
Patients:
NSCLC (IIIB–IV)
2nd line patients
KRAS mutant
WHO PS 0–1
1:1 randomisation
Placebo in
combination with
docetaxel
Sample size: 87
Study completed accrual; data will be presented at ASCO 2012 27

28. Randomized Phase II trial of Selumetinib (AZD6224) vs. Chemotherapy
Selumetinib in
combination with
docetaxel
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
Patients:
NSCLC (IIIB–IV)
2nd line patients
KRAS mutant
WHO PS 0–1
“…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
1:1 randomisation
Placebo in
combination with
docetaxel
Sample size: 87
Study completed accrual; data will be presented at ASCO 2012

29. 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

30. 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

31. Continue until disease progression or development of toxicity
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
Continue until disease progression or development of toxicity
100 mg daily
Continuous
Primary objective: Response Rate
Secondary objectives: Types/Frequencies of DDR2 Mutations, Correlation of DDR2 Mutations with RR, PFS, OS and Tox
PI: Hammerman/Johnson

32. 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

33. FGFR1 Inhibitor is Effective in FGFR1 Amplified Cells
Phase I trial of BGJ398 (Pan FGFR inhibitor) is currently underway (NCT )
Weiss J et al. Sci Transl Med 2010

34. 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

35. 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

36. Systematic Genotyping of Lung Adenocarcinomas at DFCI
Erlotinib
Second generation EGFR TKI PF
Lapatinib/Temsirolimus
XL147, PKI587
GDC 0980, ZSTK474
Docetaxel +/- AZD6244
GSK vs. Docetaxel
GDC 0973/GDC0941
AZD6244
GSK
GSK
Crizotinib vs. Chemotherapy
Crizotinib, 2nd Generation ALK Inhibitors

37. Lung Cancer Mutation Consortium

38. Patients and Study Plan
Lung Cancer Mutation Consortium
Patients and Study Plan
1000 patients
Stage IV
ECOG PS 0-2
Lung Adenocarcinoma
Sufficient Tissue (Paraffin)
Informed Consent
Central Confirmation of Adenocarcinoma Diagnosis
(1 slide)
Report to LCMC Virtual Database
Use Data to Select Therapy
(Erlotinib with EGFR
Mutation)
Mutational Analysis
CLIA-certified lab at LCMC site:
KRAS, EGFR, EML4-ALK, BRAF, HER2, PIK3CA, NRAS, MEK1,
AKT1, MET amplification
Report to Physician
Recommend Clinical Trial of Agent Specific for Target
Kris et al. ASCO 2011

39. Incidence of Single Driver Mutations
Lung Cancer Mutation Consortium
Incidence of Single Driver Mutations
Mutation found in 54% (280/516) of
tumors completely tested (CI 50-59%)
Kris et al. ASCO 2011

40. 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

41. 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

42. 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 42