New experimental targets for gastric cancer Andrés Cervantes

Transcription

1 New experimental targets for gastric cancer Andrés Cervantes Professor of Medicine

2 Outline Acquired capabilities of Cancer IGFR pathway PI3K-AKT-m-TOR pathway MET pathway FGFR pathway Check point inhibitors

3 Acquired Capabilities of Cancer 1. Self-Sufficiency in Growth Signals a. Receptors: EGFR-family, IGF1R, MET, FGFR b. Downstream effectors: PI3K, mtor, AKT 2. Insensitivity to Antigrowth Signals 3. Evading Apoptosis 4. Limitless Replicative Potential 5. Sustained Angiogenesis 6. Tissue Invasion and Metastasis Cancer cells Immune cells Fibroblasts Endothelial cells Hanahan & Weinberg, Cell 100, 2000

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5 ADQUIRED CAPABILITIES OF CANCER: SELF SUFFICIENCY IN GROWTH SIGNALS RECEPTORS: EGFR FAMILY MET FGFR DOWNSTREAM EFFECTORS: PI3K AKT m-tor

6 Rationale for Targeting Other Receptors & Downstream Signaling Proteins Met receptor Hepatocyte growth factor (HGF) & c-met highly expressed in GC specimens: 73% and 77% (Chen, 2007) MET gene amplification in 10-15% GC (Bechletner, 2008) Estimulation of c-met with HGF induces signal transduction, that is abrogated with c-met TKIs (Catenacci, 2008) Met inhibitors in the clinic in GC: Foretinib - GSK089 (Jhawer, 2009) and XL880 (Jhawer, 2008)

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8 Targeted therapies in First-line treatment for Advanced Gastric Cancer: Summary of Phase III Trials TRIAL CHEMOTHERAPY BIOLOGICAL HR OS P value Increase in median survival ToGA 1 AVAGAST 2 EXPAND 3 REAL-3 4 RILOMET-1 5 N: 609 METGASTRIC 6 N: 562 Cisplatin+5FU/ca pecitabine Cisplatin+ capecitabine Cisplatin+ capecitabine Oxaliplatin+ epirubicin + capecitabine Cisplatin+ epirubiicin+ capecitabine Trastuzumab months Bevacizumab months Cetuximab months Panitumumab months Rilotumumab ,9 months Stopped in futility analysis FOLFOX6 Onartuzumab months 1.Bang YJ, Lancet Van Cutsem E, J Clin Oncol Lordick F, Lancet Oncol Waddell T, Lancet Oncol Lancet Oncology Shah M, JAMA Oncology,

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10 Rilotumumab versus placebo plus ECX as first line treatment in MET-positive gastric or esophagogastric junctional cancer Catenacci DVT, et al. Lancet Oncol 2017; 5:

11 Rilotumumab versus placebo plus ECX as first line treatment in MET-positive gastric or esophagogastric junctional cancer Catenacci DVT, et al. Lancet Oncol 2017; 5:

12 Molecular Heterogeneity and Receptor Coamplification Drive Resistance to Targeted Therapy in MET-Amplified Esophagogastric Cancer Kwak EL, et al. Cancer discov 2015; 5:

13 Molecular Heterogeneity and Receptor Coamplification Drive Resistance to Targeted Therapy in MET-Amplified Esophagogastric Cancer Kwak EL, et al. Cancer Discov 2015; 5:

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16 Dienstmann R,et al. Ann Oncol 2014; 25:

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18 Dienstmann R,et al. Ann Oncol 2014; 25:

19 High-level clonal FGFR amplification and response to FGFR Inhibition in a translational clinical trial Pearson A, et al. Cancer Discovery 2016,

20 ADQUIRED CAPABILITIES OF CANCER: SELF SUFFICIENCY IN GROWTH SIGNALS RECEPTORS: EGFR FAMILY IGFR1 c-met DOWNSTREAM EFFECTORS: PI3K AKT m-tor

21 Rationale for Targeting Other Receptors & Downstream Signaling Proteins PI3K-mTOR inhibitors RAD001 (everolimus) is a derivative of rapamycin which act as a signal transduction inhibitor of mtor RAD001 attenuates production of HIF-1α and VEGF in GC in vitro and markedly inhibits NCI-N87 GC xenografts growth (Cejka, 2008) Preliminary results showed that RAD001 monotherapy is generally well tolerated with promising activity in pts with previously treated advanced GC 1 1 Muro et al. J Clin Oncol 2008 (ASCO)

22 THE PHOSPHATIDYLINOSITOL 3 KINASE (PI3K) SIGNALING PATHWAY

23 Comprehensive Molecular Characterization of Gastric Adenocarcinoma: Molecular platforms The Cancer Genome Atlas Research Network. Nature 2014; 513:

24 Comprehensive Molecular Characterization of Gastric Comprehensive Adenocarcinoma: Molecular Molecular Characterization platforms of Gastric Adenocarcinoma: Molecular platforms Array-based somatic copy number analysis Whole exome sequencing Array-based DNA methylation profiling Messenger RNA sequencing microrna sequencing Reverse Phase Protein Array (RPPA) The Cancer Genome Atlas Research Network. Nature 2014; 513:

25 50% 9% 20% 22% The Cancer Genome Atlas Research Network. Nature 2014; 513:

26 Comprehensive Molecular Characterization of Gastric Adenocarcinoma: PI3KCA mutations by subtype The Cancer Genome Atlas Research Network. Nature 2014; 513:

27 MTOR AND PHOSPORILATED MTOR IN GASTRIC CANCER NEGATIVE NEGATIVE POSITIVE POSITIVE 1072 samples from gastric cancer patients after surgery Immunohystochemical assessment of mtor and pmtor Yu G, et al. Clin Cancer Res 2009; 15:1821

28 Yamada, et al. Proc ASCO GI 2009 Everolimus in gastric cancer EVEROLIMUS IN GASTRIC CANCER Phase I: 2 PRs out of 4 patients with metastatic, heavily pretreated cancer of the stomach or gastroesophageal junction Phase II: No OR, DCR was 55% (29/53pts), mpfs was 83 days (95%CI: days) Baseline 2 months after RAD mg

29 Gastric Cancer: Second Line Chemotherapy Trials Comparing BSC versus Active Treatment Trial Author Thuss- Patience et al. 1 Year :1 Park et al :1 Ford et al :1 Otshu et al :1 Fuchs et al :1 Patients Random (n) Treatment 1. Eur J Cancer 2011; 47: J Clin Oncol 2012; 30: Lancet Oncol 2014; 15: J Clin Oncol 2013; 31: Lancet 2014; 383: HR OS P value Gain in Median Survival Irinotecan ,4 months Irinotecan Docetaxel ,3 months Docetaxel ,6 months Everolimus months Ramucirumab months

30 Phase II Study of weekly Paclitaxel +/- Olaparib for second line in advanced gastric cancer Stratification: ATM Low A: weekly Paclitaxel R B: weekly Paclitaxel plus Olaparib 100 mg bid Primary end point: PFS Co-Primary end point: PFS in ATM Low Secondary end points: OS, OS in ATM Low, Toxicity Bang JY, et al. J Clin Oncol 2015;33:

31 Bang JY, et al. J Clin Oncol 2015;33: Phase II Study of weekly Paclitaxel +/- Olaparib for second line in advanced gastric cancer

32 Bang JY, et al. J Clin Oncol 2015;33: Phase II Study of weekly Paclitaxel +/- Olaparib for second line in advanced gastric cancer

33 Challenges Target discovery has resulted in numerous novel drugs in clinical development Signal transduction inhibition does not guarantee tumor response: Target presence and dependence Redundancy Cross-talk Molecular-based population enrichment needed Combinations: mechanistic interactions Phase III trials are warranted

34 PD-1 Pathway and Immune Surveillance PD-1 is a negative co-stimulatory receptor expressed primarily on activated T cells 1 Binding of PD-1 to its ligands PD-L1 and PD-L2 inhibits effector T-cell function 1 Expression of PD-L1 on tumor cells and macrophages can suppress immune surveillance and permit neoplastic growth 2 1.Keir ME et al. Annu Rev Immunol. 2008;26: Pardoll DM. Nat Rev Cancer. 2012;12:

35 Pembrolizumab (MK-3475) Is a Humanized IgG4, High-Affinity, Anti-PD-1 Antibody Dual blockade of PD-L1 and PD-L2 No cytotoxic (ADCC/CDC) activity Pharmacokinetics support dosing every 2 weeks (Q2W) or every 3 weeks (Q3W) Low occurrence of anti-drug antibodies, which have no impact on pharmacokinetics Demonstrated clinical activity in multiple tumor types 1-7 Recently approved in the United States for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor 1. Ribas A et al. J Clin Oncol. 2014;32(suppl 5):abstr LBA9000; 2. Rizvi N et al. J Clin Oncol. 2014;32(suppl 5): abstr 8007; 3. Garon EB et al. J Clin Oncol. 2014;32(suppl 5):abstr 8020; 4. Seiwert TY et al. J Clin Oncol. 2014;32(suppl 5):abstr Plimack E et al. Abstr. LBA23. Presented at 2014 by: ESMO Kei Congress, Muro September 26-30, Madrid, Spain. 6. Moskowitz CH et al. Bood. 2014;124(21):abstr 290; 7. Nanda R et al. Abstract 1349 (S1-09) presented at SABCS 2014, Dec 9-13, San Antonio, TX.

36 KEYNOTE-012: Gastric Cancer Cohort Complete Response Discontinuation Permitted c Recurrent or metastatic adenocarcinoma of the stomach or GEJ ECOG PS 0-1 PD-L1-positive tumor a No systemic steroid therapy No autoimmune disease (active or history of) No active brain metastases Pembrolizumab 10 mg/kg Q2W Partial Response or Stable Disease Treat for 24 months or until progression or intolerable toxicity Confirmed Progressive Disease b Discontinue Screening: 65 of 162 (40%) patients assessed for PD-L1 expression had PD-L1-positive tumors Patients: 19 patients from Asia and 20 patients from the rest of the world Treatment: 10 mg/kg IV Q2W Response assessment: Performed every 8 weeks per RECIST v1.1 : Muro K, et al. ASCO GI 2015; Abstract nr.03

37 PD-L1 Expression in Gastric Cancer Samples PD-L1 Negative PD-L1 Positive: Stromal and Tumor Staining PD-L1 Positive: Tumor Staining PD-L1 Positive: Tumor Staining PD-L1 expression was assessed in archival tumor samples using a prototype IHC assay and the 22C3 antibody Positivity was defined as staining in the stroma or in 1% of tumor cells Muro K, et al. ASCO GI 2015; Abstract nr.03

38 PD-L1 Expression in Gastric Cancer Samples Topalian S, et al. Nature Rev Cancer 2016; 16:

39 Pembrolizumab induces Responses in Chemorefractory Gastric Cancer. Muro K, et al. Lancet Oncol 2016; 17:

40 Maximum Percentage Change From Baseline in Tumor Size a Keynote-012 (RECIST v1.1, Central Review) Muro K, et al. Lancet Oncol 2016; 17:

41 64-Year-Old Male With Recurrent Gastric Cancer Treated with Pembrolizumab March 22, 2014 May 8, 2014 July 3, 2014 August 28, 2014 September 26, 2014 November 6, 2014

42 Multifactorial Biomarkers of Clinical Response to PDL-1 Blockade Topalian S, et al. Nature Rev Cancer 2016; 16:

43 KEYNOTE-059 Cohort 1: Efficacy and Safety of Pembrolizumab Monotherapy in Patients With Previously Treated Advanced Gastric Cancer Presented By Charles Fuchs at 2017 ASCO Annual Meeting

44 KEYNOTE-059 (NCT ): Phase 2 Multicohort Study of Pembrolizumab for G/GEJ Adenocarcinoma<br /> Presented By Charles Fuchs at 2017 ASCO Annual Meeting

45 Response in All Patients Presented By Charles Fuchs at 2017 ASCO Annual Meeting

46 Response by PD-L1 Expression Presented By Charles Fuchs at 2017 ASCO Annual Meeting

47 Maximum Percentage Change From Baseline in<br />Target Lesion Sizea Presented By Charles Fuchs at 2017 ASCO Annual Meeting

48 Nivolumab (ONO-4538/BMS ) as Salvage Treatment After Second- or Later-Line Chemotherapy for Advanced Gastric or Gastroesophageal Junction Cancer (AGC): A Double-Blinded, Randomized, Phase 3 Trial Key eligibility criteria: Age 20 years Unresectable advanced or recurrent gastric or gastroesophageal junction cancer Histologically confirmed adenocarcinoma Prior treatment with 2 regimens and refractory to/intolerant of standard therapy ECOG PS of 0 or 1 R 2:1 Stratification based on: Nivolumab 3 mg/kg IV Q2W Country (Japan vs Korea vs Taiwan) ECOG PS (0 vs 1) Number of organs with metastases (< 2 vs 2) Placebo Primary endpoint: OS Secondary endpoints: Efficacy (PFS, BOR, ORR, TTR, DOR, DCR) Safety Exploratory endpoint: Biomarkers Patients were permitted to continue treatment beyond initial RECIST v1.1 defined disease progression, as assessed by the investigator, if receiving clinical benefit and tolerating study drug Kang YK et al. ASCO GI 2017

49 Probability of Survival (%) Overall Survival Patients, n Events, n Median OS [95% CI], months 12-Month OS Rate [95% CI], % Nivolumab [ ] 26.6 [ ] Placebo [ ] 10.9 [ ] Hazard ratio, 0.63 (95% CI, ) P < At risk: Nivolumab Placebo Time (months) Kang YK et al. ASCO GI 2017

50 RECIST Response and Disease Control ORR, n (%) [95% CI] P value BOR, n (%) Complete response Partial response Stable disease Progressive disease DCR, n (%) [95% CI] P value Nivolumab 3 mg/kg (n = 268) 30 (11.2) [ ] < (11.2) 78 (29.1) 124 (46.3) 108 (40.3) [ ] Placebo (n = 131) 0 [0 2.8] (25.2) 79 (60.3) 33 (25.2) [ ] Median TTR (range), months 1.61 ( ) Median DOR, months [95% CI] 9.53 [ ] Kang YK et al. ASCO GI 2017

51 Maximum Reduction From Baseline in Target Lesions (%) Maximum Reduction in Tumor Burden From Baseline a Nivolumab a Placebo Patients with Tumor reduction: 37.3% 40 Patients with Tumor reduction: 12.4% Kang YK et al. ASCO GI 2017

52 Adverse Event Summary Patients, n (%) AEs Any Serious AEs AEs leading to discontinuation AEs leading to dose delay Nivolumab 3 mg/kg (n = 330) Placebo (n = 161) Any Grade Grade 3/4 Any Grade Grade 3/4 300 (90.9) 131 (39.7) 23 ( 7.0) 63 (19.1) 137 (41.5) 91 (27.6) 13 ( 3.9) 40 (12.1) 135 (83.9) 75 (46.6) 12 ( 7.5) 27 (16.8) AEs leading to death 35 (10.6) 25 (15.5) 63 (39.1) 47 (29.2) 9 ( 5.6) 17 (10.6) TRAEs Any Serious TRAEs TRAEs leading to discontinuation TRAEs leading to dose delay 141 (42.7) 33 (10.0) 9 ( 2.7) 25 ( 7.6) 34 (10.3) 21 ( 6.4) 4 ( 1.2) 14 ( 4.2) 43 (26.7) 8 ( 5.0) 4 ( 2.5) 2 ( 1.2) TRAEs leading to death 5 (1.5) 2 (1.2) 7 (4.3) 4 (2.5) 3 (1.9) 1 (0.6) Kang YK et al. ASCO GI 2017

53 Nivolumab ± Ipilimumab in Patients With Advanced/Metastatic Chemotherapy-Refractory Gastric, Esophageal, or Gastroesophageal Junction Cancer: CheckMate 032 Study Presented By Yelena Janjigian at 2017 ASCO Annual Meeting

54 Checkmate 032 EG Cohort Presented By Yelena Janjigian at 2017 ASCO Annual Meeting

55 Objective Response Presented By Yelena Janjigian at 2017 ASCO Annual Meeting

56 Best Reduction in Target Lesions Presented By Yelena Janjigian at 2017 ASCO Annual Meeting

57 50% 9% 20% 22% The Cancer Genome Atlas Research Network. Nature 2014; 513: