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New Strategies on Horizon

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.

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New Strategies on Horizon

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  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 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 Gefitinib + 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 Normal cell division Cell Suicide or Apoptosis Cell damage—no repair Cancer cell division First mutation Second mutation Third mutation Fourth orlater mutation Uncontrolled growth

  19. What if the cancer is not homogenous?

  20. 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

  21. 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”

  22. Intercalated combination ofChemotherapy + EGFR TKI

  23. NVALT-10:Design 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

  24. 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)

  25. Improvement limited to non-squamous cell carcinoma For a population dominated by EGFR wild type, control arm should be Alimta • 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

  26. 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

  27. 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 Placebo n=48 241 150 200 Erlotinib n=69 100 136 100 50 Placebo n=67 * 0 0 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)

  28. PFS in ITT population (22 Jun 2012) 1.0 GC-erlotinib (n=226) 0.8 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 0 0 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

  29. OS in ITT population (22 Jun 2012) 1.0 GC-erlotinib (n=226) 0.8 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 0 0 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

  30. PFS and OS in EGFR WT subgroup (22 Jun 2012) PFS OS 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 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 OS probability PFS probability 12.2 14.9 5.9 6.7 0 4 8 12 16 20 24 28 32 36 40 0 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

  31. PFS and OS in EGFR Mut+ subgroup (22 Jun 2012) PFS OS 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 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 OS probability PFS probability 6.9 16.8 20.6 31.4 0 4 8 12 16 20 24 28 32 0 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

  32. Novel Target

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

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

  35. Biomarker Analyses 188 patients enrolled May 2010 – May 2011 144 (77%) tissue samples collected Mok et al ESMO 2012 (Poster)

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

  37. Tivantinib (ARQ 197)/Erlotinib Combination in Non-Small Cell Lung Cancer (Study 209) R A N D O M I Z E Tivantinib(ARQ 197)360 mg PO BID Erlotinib150 mg PO QD Arm A: + • NSCLC • N =154 • Age ≥18 years • Inoperable LA/ metastatic disease • ≥1 prior chemo (no prior EGFR TKI) b Arm B: PlaceboPO BID Erlotinib150 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.bPatients 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

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

  39. Study 302: MET Inhibitor ARQ 197 Plus Erlotinib vs Erlotinib Plus Placebo in Non-Squamous NSCLC (MARQUEE) RANDOMIZE Early termination at interim analysis (2012) Arm A: Tivantinib(ARQ 197)360 mg PO BID + Erlotinib150 mg PO QD • 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 Arm B: PlaceboPO BID Erlotinib150 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

  40. OAM4558g: A Phase II randomized, placebo controlled study testing erlotinib +/- MetMAb in 2nd/3rd line NSCLC 1:1 Arm AErlotinib (150 daily) + MetMAb (15 mg/kg IV q3w) RANDO M IZ A T I O N n=69 n=137* • 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 BTarceva (150 daily) + Placebo (IV q3w) • Co-primary objectives: • PFS in ‘Met DiagnosticPositive’ 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

  41. MetMAb plus erlotinib leads to a better outcome than erlotinib alone in Met Diagnostic Positive NSCLC patients 1.0 1.0 0.8 0.8 0.6 0.6 0.4 0.4 0 3 6 9 12 15 18 0.2 0.2 0 3 6 9 12 15 18 21 0.0 0.0 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 Probability of survival Probability of progression free Time to progression (months) Overall survival (months) The addition of MetMAb in this population resulted in a 2-fold reduction in therisk of progression and a near 3-fold reduction in the risk of death

  42. 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 1000 Negative (0) Weak (1+) Met Dx Negative 100 10 MET mRNA (2-Dct) Moderate (2+) Strong (3+) 1 Met Dx Positive 0 0 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’

  43. 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

  44. Summary • TKI is forever • 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

  45. Old Strategy New Strategy

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