1. New Strategies on Horizon
Tony Mok MD
Dept of Clinical Oncology
The Chinse University of Hong Kong

2. Addressing the difference
TKI is forever
Novel Target

3. TKI is forever

4. 5cm
PR at 2cm
RECIST PD
At 2.6cm 0m 6m
12m
18m

5. 5cm
PR at 2cm
Symptomatic PD at 4cm 0m 6m
12m
18m

6. 5cm
PR at 2cm
RECIST PD
At 2.6cm
Molecular
resistance
Symptomatic PD at 4cm 0m 6m
12m
18m

7. ASPIRATION: To optimize treatment duration
EGFR TKI
EGFR TKI
Advance stage
NSCLC with
EGFR Mutation PD
By RECIST PD
By doctor
Discretion*
PFS 1
PFS 2
*Doctor Discretion: Symptomatic progression, multiple progression
Threat to major organ…etc
PI: K Park

8. TKI Resistance after ASCO 2012
Oncogenic driven cancer with tumor response to TKI
Oligo-Progression
Systemic Progression
Local therapy + continuation of TKI
Systemic therapy
Targeting the resistant gene
Chemotherapy
Chemotherapy + TKI

9. Treatment of TKI Resistance
Oncogenic driven cancer with tumor response to TKI
Oligo-Progression
Systemic Progression
Local therapy + continuation of TKI
Systemic therapy
Targeting the resistant gene
Chemotherapy
Chemotherapy + TKI

10. Local Therapy in Acquired Resistance: MSKCC
18/184 pts/7+ yrs underwent local therapy for extracranial PD
CNS PD excluded
From time of local therapy
Median TTP: 10 months
Median time to new systemic Rx: 22 months
Median OS: 41 months
Yu, ASCO 2012, Abst#7527

11. Local treatment to oligo-progression plus continuation of TKI
Colorado University collection of 65 patients with oncogenic driven cancer (EGFR mutation or ALK positive)
All received EGFR TKI or Crizotinib
PFS 1 defined as <4 sites of progression
Local ablative therapy offered to all sites of involvement and continue TKI
PFS 2 defined as from time of local therapy to second progression
ASCO 2012 Abst 7526

12. PFS of patients treated with LAT and continuation of TKI therapy
Site of first progression
Number of patients
PFS1
(months)(95% CI)
PFS2
Site of 2nd progression
CNS 10
10.9
7.3 – 18.3
7.1
1.7 – 11.3
2 (20%)
no prog
3 (30%)
5 (50%)
eCNS
eCNSϮ 15
9.0
6.5 – 13.8
4.0
4 (27%)
3 (20%)
8 (53%)
All patients 25
9.8
8.8 – 13.8
6.2
3.7 – 8.0
6 (24%)
7 (28%)
12 (48%)
Ϯ Includes 3 patients who progressed systemically (eCNS) and simultaneously within the CNS

13. Future Prospective Study?
Oncogenic driven cancer with tumor response to TKI
PD by RECIST
<4 sites of PD
Randomized
Local therapy + continuation of TKI
Chemotherapy
Primary endpoint: PFS
Secondary endpoint: OS, RR, QOL

14. Treatment of TKI Resistance
Oncogenic driven cancer with tumor response to TKI
Oligo-Progression
Systemic Progression
Local therapy + continuation of TKI
Systemic therapy
Targeting the resistant gene
Chemotherapy
Chemotherapy + TKI

15. Chemo/Erlotinib vs. Chemo Alone at Progression after Acquired Resistance
N = 78 retrospective review of outcomes
chemo alone (N = 44) or
chemo/erlotinib (N = 34)
RR 18% (chemo) vs. 41% with chemo/erlotinib)
No differences in PFS or OS between these two strategies
Goldberg, ASCO 2012, Abst#7524

16. IMPRESS: Chemotherapy with or with gefitinib at progression
Alimta/Platinum
Gefintinib
Advance stage
NSCLC with
EGFR Mutation PD
By RECIST
Primary endpoint: PFS
Alimta/Platinum
Co-PI: Soria J; Mok T

17. Addressing the difference

18. Classic concept of cancer
National Cancer Institute
Understanding Cancer and Related Topics
Understanding Cancer
Normal cell division
Cell Suicide or Apoptosis
Cell damage— no repair
Cancer cell division
Cancer arises from a loss of normal growth control. In normal tissues, the rates of new cell growth and old cell death are kept in balance. In cancer, this balance is disrupted. This disruption can result from uncontrolled cell growth or loss of a cell’s ability to undergo cell suicide by a process called“apoptosis.” Apoptosis, or “cell suicide,” is the mechanism by which old or damaged cells normally self-destruct.
First mutation
Second mutation
Third mutation
Fourth or later mutation
Uncontrolled growth
NCI Web site:

19. What if the cancer is not homogenous?

21. Early finding of intratumor heterogeneity in lung cancer
Twenty-one patients with recurrent EGFR mutation positive lung cancer
Surgical specimens were retrieved from archive
Using laser capture microdissection and analyzed 50–60 areas from each tissue
Fifteen tissues consisted only of cells with EGFR mutations
Six tissues contained both mutated and non-mutated cells.
Taniguchi K, Cancer Sci, 2008 May;99(5):929-35

24. Combination strategy for heterogeneous tumor
Chemotherapy is standard cytotoxic for adenocarcinoma
Adenocarcinoma has a higher incidence of harboring driver oncogene, especially among the non-smoker adenocarcinoma
Cancer patient may have heterogeneous mix of tumor with or without the driver oncogenes
We need a rational approach to “Chemotherapy + Targeted Therapy”

25. Intercalated combination of Chemotherapy + EGFR TKI

26. NVALT-10:Design Primary endpoint: PFS Aerts et al ESMO 2012
Squamous
Erlotinib 150mg p.o. day 2-16
+ Docetaxel 75 mg/m2 day 1 q3 weeks
Patients
Locally advanced or
metastatic NSCLC
(IIIB-IV)
Failed first line
platinum therapy
WHO PS 0-2
Combination
therapy
Primary endpoint: PFS
Non- Squamous
Erlotinib 150mg p.o. day 2-16
+ Pemetrexed 500 mg/m2 day 1 q3 weeks
Squamous and Non Squamous
Erlotinib 150mg p.o. daily
Mono
therapy
Chemotherapy planned 4 cycles
Erlotinib until disease progression
Aerts et al ESMO 2012

27. PFS and OS Improvement in patients with or without EGFR mutation?
Adjusted for stratification factors: p=0.09, HR=0.78 ( )
Adjusted for stratification factors: p=0.02, HR=0.67 (0.50 – 0.93)

28. Improvement limited to non-squamous cell carcinoma
Lack of improvement in squamous cell carcinoma
No improvement in EGFR wild type
Slight improvement in non-squamous cell carcinoma
May imply benefit in a small portion of patients with EGFR mutations
For a population dominated by EGFR wild type, control arm should be Alimta

29. FASTACT-2 (MO22201; CTONG0902) study design
Screening
Study treatment
Maintenance phase
Gemcitabine 1,250mg/m2 (d1, 8) + carboplatin AUC=5 or cisplatin 75mg/m2 (d1) + erlotinib 150mg/day (d15–28); q4wks x 6 cycles
GC-erlotinib (n=226)
Erlotinib 150mg/day PD
Previously untreated stage IIIB/IV NSCLC, PS 0/1
(n=451)
1:1; stratified by stage, histology, smoking status and chemo regimen R
Gemcitabine 1,250mg/m2 (d1, 8) + carboplatin AUC=5 or cisplatin 75mg/m2 (d1) + placebo (d15–28);
q4wks x 6 cycles
GC-placebo (n=225)
Placebo PD
Erlotinib 150mg/day
Primary endpoint: PFS with IRC confirmation
Secondary endpoints: subgroup analyses, OS in all patients and subgroups, ORR, duration of response, TTP, NPR at 16 weeks, safety, QoL
NSCLC = non-small cell lung cancer; PS = performance status; PD = disease progression; AUC = area under the curve; q4wks = every 4 weeks; IRC = independent review committee; OS = overall survival; ORR = objective response rate; TTP = time to progression; NPR = non-progression rate; QoL = quality of life 29 29

30. EGFR mutation status in FASTACT-2
EGFR mutation-positive (Mut+)
EGFR wild-type (WT)
Single resistance mutation
500
300
451
250
400
Erlotinib n=49
200 97
300
241
Placebo n=48
150
200
100
Erlotinib n=69
100
136 50
Placebo
n=67 *
All patients
Tested for EGFR mutation
EGFR mutation status
210 patients in the study had unknown EGFR mutation status
* n=8: one with T790M (received placebo); one with S768I (received placebo); six with exon 20 mutations (two received erlotinib, four received placebo)

31. PFS in ITT population (22 Jun 2012)
1.0
0.8
GC-erlotinib (n=226)
GC-placebo (n=225)
HR=0.57 (95% CI 0.47–0.69)
p<0.0001
0.6
PFS probability
0.4
0.2
6.0
7.6 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38
Time (months) E P
CI = confidence intervals

32. OS in ITT population (22 Jun 2012)
1.0
0.8
GC-erlotinib (n=226)
GC-placebo (n=225)
HR=0.79 (95% CI 0.64–0.99)
p=0.0420
0.6
OS probability
0.4
0.2
15.2
18.3 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38
Time (months)
E P

33. PFS and OS in EGFR WT subgroup (22 Jun 2012)
1.0
0.8
0.6
0.4
0.2
1.0
0.8
0.6
0.4
0.2
12.2
14.9
GC-erlotinib (n=69)
GC-erlotinib (n=69)
GC-placebo (n=67)
GC-placebo (n=67)
HR=0.97 (0.69–1.36)
p=0.8467
RR: 26.1% vs 19.4%
HR=0.77 (0.53–1.11)
p=0.1612
PFS probability
OS probability
5.9
6.7 4 8 12 16 20 24 28 32 36 40 4 8 12 16 20 24 28 32 36 40
Time (months)
Time (months) E P E P

34. PFS and OS in EGFR Mut+ subgroup (22 Jun 2012)
1.0
0.8
0.6
0.4
0.2
1.0
0.8
0.6
0.4
0.2
GC-erlotinib (n=49)
GC-erlotinib (n=49)
GC-placebo (n=48)
GC-placebo (n=48)
HR=0.25 (0.16–0.39)
p<0.0001
RR: 83.7% vs 14.6%
HR=0.48 (0.27–0.84)
p=0.0092
PFS probability
OS probability
6.9
16.8
20.6
31.4 4 8 12 16 20 24 28 32 4 8 12 16 20 24 28 32 36
Time (months)
Time (months) E P E P

35. Novel Target

36. MET Pathways Target Met receptor MetMab Target HGF AMG 102 AVEO299
Target TK
ARQ197, XL184
+ many

37. Phase 2 Study Design: Ficlatuzumab + Gefitinib in NSCLC in the First Line
Stratification:
ECOG PS
Smoking history
Gender
Ficlatuzumab+ gefitinib
(n=94)
Off-study
Early discontinuations, nonresponders, or patients who do not want to participate in crossover
Crossover permitted: gefitinib + ficlatuzumab (progressive disease after initial response, partial response or stable disease >3 months) R
1:1
Key entry criteria:
Stage IIIB/IV NSCLC
Treatment naïve
Adeno histology
Asian, nonsmoker or light former smoker
Gefitinib
Study Endpoints:
Primary: ORR
Secondary: PFS, OS
Enrollment initiated in May 2010 & completed in May 2011
Treatment:
Gefitinib: 250 mg qd Ficlatuzumab: 20 mg/kg q2w in 28-day cycles
Mok et al ESMO 2012 (Poster)

38. Tumor HGF IHC level (n=114)
Biomarker Analyses
188 patients enrolled
May 2010 – May 2011
144 (77%) tissue samples collected
Biomarkers
EGFR mutation (n=125)
c-Met IHC level
(n=123)
Tumor HGF IHC level (n=114)
Stroma HGF level
(n=99)
SM+
SM-
High*
Low
High
S-HGF high
S-HGF low
Definition
TKI sensitive mutation
No or insensitive mutation
Score 2-3+
distribution:
> 75%
Remaining
> 25%
Score: strong moderate
Score: weak negative
n, (% known)
71 (57)
54 (43)
78 (63)
45 (37)
64 (56)
50 (44)
17 (17)
82 (83)
Back-up:
- c-MET score is similar to that used in MetMAb Ph2 study (2-3+, > 50%)
120/123 pts had detectable c-Met, 3/123 were negative. Most c-Met low pt in P06162 trial will be qualified as c-Met positive per AMG102 GEA criteria.
Mok et al ESMO 2012 (Poster)

39. PFS and OS (c-Met Low)
Mok et al ESMO 2012 (Poster)

40. Tivantinib (ARQ 197) 360 mg PO BID
Tivantinib (ARQ 197)/Erlotinib Combination in Non-Small Cell Lung Cancer (Study 209) R A N D O M I Z E
Arm A:
Tivantinib (ARQ 197) 360 mg PO BID
Erlotinib 150 mg PO QD
NSCLC
N =154
Age ≥18 years
Inoperable LA/ metastatic disease
≥1 prior chemo (no prior EGFR TKI) + b
Arm B:
Placebo PO BID
Erlotinib 150 mg PO QD +
Endpoints
1° PFSa
2° ORR, OS
Subset analyses
Crossover: ORR
Accrual complete
Archival tissue evaluated for EGFR / c-MET / K-Ras status in pre-planned subset analyses
a Based on investigator assessment. PFS defined by histology, molecular profile, and other prognostic characteristics. b Patients in the control arm will be allowed to crossover to receive ARQ 197.
Abbreviations: BID, twice daily; EGFR, epidermal growth factor receptor; LA, locally advanced; NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PO, orally; QD, once daily; TKI, tyrosine kinase inhibitor.
Schiller JH, et al. J Clin Oncol. 2010;28(18 suppl II):954s. Abstract LBA7502.
Sequist et al JCO 29:3307, 2011 40

41. PFS and OS (ITT population and Non-squamous cell)

42. Study 302: MET Inhibitor ARQ 197 Plus Erlotinib vs Erlotinib Plus Placebo in Non-Squamous NSCLC (MARQUEE)
RANDOMIZE
Phase 3 in NSCLC
Inoperable locally adv/metastatic disease
Non-squamous histology
1-2 regimens prior chemo (no prior EGFR TKI)
Prior platinum-based doublet therapy required
Early termination at interim analysis (2012)
Arm A:
Tivantinib (ARQ 197) 360 mg PO BID +
Erlotinib 150 mg PO QD
Arm B:
Placebo PO BID
Erlotinib 150 mg PO QD +
Endpoints
1° OS (ITT population)
2°/Exploratory:
- PFS (ITT population)
- OS and PFS in EGFR wt patients
- Safety and toxicity
- QOL/FACT-L
- Biologic sub-group analysis
988 patients
Stratification by EGFR and KRAS mutation status (tissue required)
Interim analysis performed at 50% of events
Abbreviations: BID, twice daily; EGFR, epidermal growth factor receptor; FACT-L, functional assessment of cancer therapy-lung; ITT, intent-to-treat; NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival; PO, orally; QD, once daily; wt, wild type; QOL, quality of life; TKI, tyrosine kinase inhibitor. 42

43. OAM4558g: A Phase II randomized, placebo controlled study testing erlotinib +/- MetMAb in 2nd/3rd line NSCLC
n=69
R A N D O M
I Z A T I O N
1:1
n=137*
Arm A Erlotinib (150 daily) + MetMAb (15 mg/kg IV q3w)
Key eligibility:
Stage IIIB/IV NSCLC
2nd/3rd-line NSCLC
Tissue required
PS 0–2
Stratification factors:
Tobacco history
Performance status
Histology
n=68
Arm B Tarceva (150 daily) + Placebo (IV q3w)
Co-primary objectives:
PFS in ‘Met Diagnostic Positive’ patients (est 50%)
PFS in overall ITT population
Other key objectives:
OS in ‘Met Diagnostic Positive’ patients
OS in overall ITT patients
Overall response rate
Safety/tolerability
Progressive
disease
** Must be eligible and treated with MetMAb
ADD** MetMAb
*128 NSCLC patients enrolled from 3/2009 to 3/2010 plus 9 SCC patients enrolled through 8/2010
n=27
Spiegel et al ASCO 2011

44. MetMAb plus erlotinib leads to a better outcome than erlotinib alone in Met Diagnostic Positive NSCLC patients
PFS: HR=0.53
OS: HR=0.37
Placebo +
erlotinib
1.5 27
MetMAb +
erlotinib
2.9
0.53
(0.28–0.99)
0.042 20
Placebo +
erlotinib
3.8 26
MetMAb +
erlotinib
12.6
0.37
(0.19–0.72)
0.002 16
Median (mo) HR
(95% CI)
Log-rank p-value
No. of events
Median (mo) HR
(95% CI)
Log-rank p-value
No. of events
0.0
0.2
0.4
0.6
0.8
1.0
0.0
0.2
0.4
0.6
0.8
1.0
Probability of progression free
Probability of survival 3 6 9 12 15 18 3 6 9 12 15 18 21
Time to progression (months)
Overall survival (months)
The addition of MetMAb in this population resulted in a 2-fold reduction in the risk of progression and a near 3-fold reduction in the risk of death

45. Development of Met IHC for use as a companion diagnostic
Technical metrics
Tissue was obtained from 100% of patients.
95% of patients had adequate tissue for evaluation of Met by IHC
Intensity of Met IHC staining on NSCLC tumor cells scored in 4 categories
Met Dx Negative
Met Dx Positive
Negative (0)
Weak (1+)
1000
Met Dx Negative
100
MET mRNA (2-Dct) 10
Moderate (2+)
Strong (3+) 1
Met Dx Positive
Methodology
CONFIRM anti-total Met, as per manufacturer’s instructions
Run on Ventana Benchmark instrument at GNE
Negative controls (isotype control) performed on each specimen
Positive controls (cell pellets) included on every run 1 2 3
MET IHC score
Met diagnostic status was assessed after randomization and prior to unblinding
‘Met Diagnostic Positive’ was defined as majority (≥50%) of tumor cells with moderate or strong staining intensity
52% patients enrolled were ‘Met Diagnostic Positive’

46. Phase III study design Registered patients Registered patients
Centralized lab
(Met IHC or T-score)
Centralized lab
(Met IHC or T-score)
Met Diagnostic
Positive
Met Diagnostic
Negative
Met Diagnostic
Positive
Met Diagnostic
Negative excluded
Erl +
MetMab
Erl
Erl +
MetMab
Erl
Erl +
MetMab
Erl
Marker-by-treatment-interaction Design
Marker-based Strategy Design
Mandrekar SJ et al J Biopharm Stat 19:530, 2009

47. Summary TKI is forever Addressing the difference Novel targets
Redefine TKI resistance. RECIST criteria may not be applicable
Addressing the difference
Intercalated combination of chemotherapy and EGFR TKI may potentially improve treatment outcome
Novel targets
C-MET is a promising target but we are still in search of a biomarker

48. Old Strategy
New Strategy