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

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Presentation on theme: "New Strategies on Horizon Tony Mok MD Dept of Clinical Oncology The Chinse University of Hong Kong."— Presentation transcript:

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

2 TKI is forever Addressing the difference Novel Target

3 TKI is forever

4 5cm PR at 2cm RECIST PD At 2.6cm RECIST PD At 2.6cm 6m0m12m18m

5 5cm PR at 2cm Symptomatic PD at 4cm 6m0m12m18m

6 5cm PR at 2cm RECIST PD At 2.6cm RECIST PD At 2.6cm Symptomatic PD at 4cm Molecular resistance Molecular resistance 6m0m12m18m

7 ASPIRATION: To optimize treatment duration Advance stage NSCLC with EGFR Mutation EGFR TKI PD By RECIST PD By doctor Discretion* PFS 1 PFS 2 *Doctor Discretion: Symptomatic progression, multiple progression Threat to major organ…etc EGFR TKI 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 Chemothera py Chemothera py + 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 Chemothera py Chemothera py + 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 Ϯ Includes 3 patients who progressed systemically (eCNS) and simultaneously within the CNS Site of first progression Number of patients PFS1 (months)(95% CI) PFS2 (months)(95% CI) Site of 2 nd progression CNS – – (20%)no prog 3 (30%)CNS 5 (50%)eCNS eCNS Ϯ – (27%)no prog 3 (20%)CNS 8 (53%)eCNS All patients – – (24%)no prog 7 (28%)CNS 12 (48%)eCNS PFS of patients treated with LAT and continuation of TKI therapy

13 Future Prospective Study? Oncogenic driven cancer with tumor response to TKI PD by RECIST <4 sites of PD Local therapy + continuation of TKI Chemotherapy Randomized 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 Chemothera py Chemothera py + 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 Advance stage NSCLC with EGFR Mutation Gefintinib PD By RECIST Gefitinib + Alimta/Platinum Primary endpoint: PFS Co-PI: Soria J; Mok T

17 Addressing the difference

18 Classic concept of cancer Cancer cell division Fourth or later mutation Third mutation Second mutation First mutation Uncontrolled growth Cell Suicide or Apoptosis Cell damage no repair Normal cell division

19 What if the cancer is not homogenous?

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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

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

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

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 Placebo Erlotinib 150mg/day Previously untreated stage IIIB/IV NSCLC, PS 0/1 (n=451) R PD Gemcitabine 1,250mg/m 2 (d1, 8) + carboplatin AUC=5 or cisplatin 75mg/m 2 (d1) + placebo (d15–28); q4wks x 6 cycles GC-placebo (n=225) Gemcitabine 1,250mg/m 2 (d1, 8) + carboplatin AUC=5 or cisplatin 75mg/m 2 (d1) + erlotinib 150mg/day (d15–28); q4wks x 6 cycles GC-erlotinib (n=226) PD Study treatmentMaintenance phaseScreening 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 FASTACT-2 (MO22201; CTONG0902) study design 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 1:1; stratified by stage, histology, smoking status and chemo regimen

30 EGFR mutation status in FASTACT patients in the study had unknown EGFR mutation status 136 Erlotinib n=49 Placebo n=48 Erlotinib n=69 Placebo n= All patientsTested for EGFR mutation EGFR mutation-positive (Mut+) EGFR wild-type (WT) Single resistance mutation 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) PFS probability Time (months) GC-erlotinib (n=226) GC-placebo (n=225) HR=0.57 (95% CI 0.47–0.69) p< E P CI = confidence intervals

32 OS in ITT population (22 Jun 2012) GC-erlotinib (n=226) GC-placebo (n=225) HR=0.79 (95% CI 0.64–0.99) p= OS probability Time (months) E P

33 PFS and OS in EGFR WT subgroup (22 Jun 2012) Time (months) PFS probability Time (months) OS probability GC-erlotinib (n=69) GC-placebo (n=67) HR=0.77 (0.53–1.11) p= GC-erlotinib (n=69) GC-placebo (n=67) HR=0.97 (0.69–1.36) p= RR: 26.1% vs 19.4% PFSOS E P E P

34 PFS and OS in EGFR Mut+ subgroup (22 Jun 2012) Time (months) PFS probability Time (months) OS probability GC-erlotinib (n=49) GC-placebo (n=48) HR=0.48 (0.27–0.84) p= GC-erlotinib (n=49) GC-placebo (n=48) HR=0.25 (0.16–0.39) p< RR: 83.7% vs 14.6% PFSOS E P E P

35 Novel Target

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

37 Phase 2 Study Design: Ficlatuzumab + Gefitinib in NSCLC in the First Line Stratification: ECOG PS Smoking history Gender Stratification: ECOG PS Smoking history Gender Ficlatuzumab+ gefitinib (n=94) 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 R 1:1 Key entry criteria: Stage IIIB/IV NSCLC Treatment naïve Adeno histology Asian, nonsmoker or light former smoker Key entry criteria: Stage IIIB/IV NSCLC Treatment naïve Adeno histology Asian, nonsmoker or light former smoker Gefitinib (n=94) Gefitinib (n=94) 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 Biomarker Analyses 144 (77%) tissue samples collected Biomarker s EGFR mutation (n=125) c-Met IHC level (n=123) Tumor HGF IHC level (n=114) Stroma HGF level (n=99) SM+SM-High*LowHighLow S-HGF high S-HGF low Definition TKI sensitive mutation No or insensitive mutation Score 2-3+ distribution: > 75% Remainin g Score 2-3+ distributio n: > 25% Remaini ng Score: strong moderate Score: weak negative n, (% known) 71 (57)54 (43)78 (63)45 (37)64 (56)50 (44)17 (17)82 (83) 188 patients enrolled May 2010 – May patients enrolled May 2010 – May 2011 Mok et al ESMO 2012 (Poster)

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

40 40 Tivantinib (ARQ 197)/Erlotinib Combination in Non-Small Cell Lung Cancer (Study 209) 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. Endpoints 1° PFS a 2° ORR, OS Subset analyses Crossover: ORR Endpoints 1° PFS a 2° ORR, OS Subset analyses Crossover: ORR Accrual complete Archival tissue evaluated for EGFR / c-MET / K-Ras status in pre-planned subset analyses RANDOMIZERANDOMIZE NSCLC N =154 Age 18 years Inoperable LA/ metastatic disease 1 prior chemo (no prior EGFR TKI) NSCLC N =154 Age 18 years Inoperable LA/ metastatic disease 1 prior chemo (no prior EGFR TKI) b Arm A: Tivantinib (ARQ 197) 360 mg PO BID Erlotinib 150 mg PO QD + Arm B: Erlotinib 150 mg PO QD Placebo PO BID + Sequist et al JCO 29:3307, 2011

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

42 42 Study 302: MET Inhibitor ARQ 197 Plus Erlotinib vs Erlotinib Plus Placebo in Non-Squamous NSCLC (MARQUEE) 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. 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 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 R A N D O M IZ E 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 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 Arm A:Tivantinib (ARQ 197) 360 mg PO BID Erlotinib 150 mg PO QD + Arm B: Erlotinib 150 mg PO QD Placebo PO BID + Early termination at interim analysis (2012)

43 OAM4558g: A Phase II randomized, placebo controlled study testing erlotinib +/- MetMAb in 2nd/3rd line NSCLC *128 NSCLC patients enrolled from 3/2009 to 3/2010 plus 9 SCC patients enrolled through 8/2010 Arm A Erlotinib (150 daily) + MetMAb (15 mg/kg IV q3w) ** Must be eligible and treated with MetMAb Arm B Tarceva (150 daily) + Placebo (IV q3w) RANDOMIZATIONRANDOMIZATION 1:1 Key eligibility: Stage IIIB/IV NSCLC 2nd/3rd-line NSCLC Tissue required PS 0–2 n=137* n=69 n=68 ADD** MetMAb Progressive disease n=27 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 Stratification factors: Tobacco history Performance status Histology Spiegel et al ASCO 2011

44 MetMAb plus erlotinib leads to a better outcome than erlotinib alone in Met Diagnostic Positive NSCLC patients Time to progression (months) Probability of progression free Placebo + erlotinib MetMAb + erlotinib (0.19–0.72) Median (mo) HR (95% CI) Log-rank p-value No. of events Overall survival (months) Probability of survival Placebo + erlotinib MetMAb + erlotinib (0.28–0.99) Median (mo) HR (95% CI) Log-rank p-value No. of events 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 PFS: HR=0.53OS: HR=0.37

45 Met Dx Negative 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 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 Negative (0)Weak (1+) Moderate (2+)Strong (3+) Met Dx Negative Met Dx Positive MET IHC score Met Dx Positive MET mRNA (2 - ct )

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

47 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

48 Old Strategy New Strategy


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