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

Addressing the difference TKI is forever Novel Target

TKI is forever

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

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

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

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

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

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

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

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

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 2.7 -7.4 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

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

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

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

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

Addressing the difference

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: http://cancer.gov/cancertopics/understandingcancer

What if the cancer is not homogenous?

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

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”

Intercalated combination of Chemotherapy + EGFR TKI

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

PFS and OS Improvement in patients with or without EGFR mutation? Adjusted for stratification factors: p=0.09, HR=0.78 (0.59-1.04) Adjusted for stratification factors: p=0.02, HR=0.67 (0.50 – 0.93)

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

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

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)

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 226 192 162 136 102 81 70 59 52 45 39 32 24 17 12 6 1 0 0 0 P 225 185 156 114 57 31 22 15 12 9 7 6 4 3 3 2 1 1 1 0 CI = confidence intervals

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 226 219 202 191 176 165 154 138 129 114 98 85 68 52 39 23 9 6 1 0 P 225 218 206 185 168 156 138 120 103 92 78 68 53 37 24 13 6 4 0 0

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 69 45 15 7 5 3 2 1 0 0 0 P 67 46 16 5 3 2 1 1 1 1 0 E 69 60 49 43 30 19 12 6 4 0 0 P 67 57 43 34 23 15 7 3 2 1 0

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 49 46 42 33 25 19 11 6 0 P 48 35 16 5 4 2 2 1 0 E 49 48 46 45 41 33 24 15 3 0 P 48 48 43 36 26 24 14 6 0 0

Novel Target

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

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)

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)

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

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

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

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. http://clinicaltrials.gov/ct2/show/NCT01244191. 42

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

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

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’

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

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

Old Strategy New Strategy