Novel Targets and Therapies for GI Malignancies: What does the future hold? David H. Ilson, M.D., Ph.D. GI Oncology Service Memorial Sloan-Kettering Cancer Center New York, NY

GI Cancers: US Incidence in 2013 292,200 new cases and 144,570 deaths (49%) Case Fatality Rate: Colorectal: 48% Esophagogastric: 66% Pancreatic: 85% HCC: 70% Male > Female Ongoing rise in Esophageal and GEJ Adenocarcinoma, HCC Siegel et al, CA 63: 11-30; 2013

Gene Amplification more Common in Esophagogastric Cancer 296 Esophageal / Gastric Cancers, 190 CRC Amplified genes in 37% Gas / Eso tumors FGFR1-2 HER2 EGFR MET Targetable Receptors and Receptor Tyrosine Kinases KRAS also amplified Similar data for a Chinese series Dulak AM et al Can Res 72: 4383; 2012

Molecular Targets: Esophageal and Gastric Cancer KRAS mutation: <5% BRAF mutation: <5% EGFr mutation: <5% HER2 over expression / amplification: 10% to 25% Trastuzumab + chemo improves OS in HER2+ disease CMET amplification: 10% IHC over expression 40% Dulak AM, et al. Cancer Res. 2012;72(17):4383-4393. Dulak AM, et al. Nat Genet. 2013;45(5):478-486. Lordick F, et al. Lancet Oncol. 2013;14(6):490-499. Bang YJ, et al. Lancet. 2010;376(9742):687-697.

ToGA Trial Design Phase III, randomized, open-label, international, multicenter study 5FU or capecitabine + cisplatin (n = 290) 3807 patients screened 810 HER2-positive (22.1%) HER2-positive advanced GC (n = 584) R 5FU or capecitabine + cisplatin + trastuzumab (n = 294) Stratification factors Advanced vs metastatic GC vs GEJ Measurable vs nonmeasurable ECOG PS 0-1 vs 2 Capecitabine vs 5-FU Eligibility criteria for the ToGA trial include: >18 years of age, HER2-positive histologically confirmed gastric cancer or gastro-oesophageal adenocarcinoma, with inoperable, locally advanced or recurrent and/or metastatic disease. The ToGA trial planned to recruit 584 patients. An additional 10 patients, who had already signed the informed consent form when the screening cut-off was reached, were allowed to enter the trial, resulting in a total of 594 patients recruited. The primary end point is overall survival in the two treatment arms. Secondary end points include progression-free survival, overall response rate, clinical benefit rate, duration of response and safety profile. Bang Y, et al. Lancet. 2010;376(9742):687-697

ToGA: Efficacy Outcome Chemotherapy + Trastuzumab (n = 294) Chemotherapy Alone (n = 290) HR (95% CI) P Value Primary endpoint Median OS, months 13.8 11.1 0.74 (0.60-0.91) .0046 Secondary endpoints Median PFS, months 6.7 5.5 0.71 (0.59-0.85) .0002 ORR, % 47.3 34.6 - .0017 CR 5.4 2.4 .0599 PR 41.8 32.1 .0145 Preplanned subgroup analysis indicated improved OS benefit with increasing HER2 expression by IHC Exploratory analysis of IHC 2+/FISH+ and IHC 3+ cohort demonstrated a 4-month increase in OS with trastuzumab HR: 0.65 (95% CI: 0.51-0.83) ORR, overall response rate Bang Y, et al. Lancet. 2010;376(9742):687-697.

Targeted Agents Phase III: HER2: Met Disease LOGIC: Cape-Ox + / - Lapatinib (HER2+) First line Negative trial for OS Benefit in Asian pts TYTAN: Paclitaxel + / - Lapatinib (HER2+) Second Line: Negative Trial PFS and Survival Benefit in subset of patients IHC 3+ for lapatinib Hecht JR, et al. J Clin Oncol. 2013;31(Suppl):Abstract LBA4001 Bang et al GI Cancers Symposium 2013 Abstract 11

RTOG 1010: Phase III Study of Neoadjuvant Trastuzumab and Chemoradiation for Esophageal Adenocarcinoma (Siewert I, II) ‘ CHEMORADIATION SURGERY HER-2 (+) (FISH) TRASTUZUMAB + CHEMORADIATION SURGERY + TRASTUZUMAB (1 YR) HER-2 (-) (FISH) ALTERNATIVE STUDIES Chemoradiation: Carboplatin, Paclitaxel + RT 5040 cGy  Surgery Maintenance trastuzumab post op OS Primary Endpoint

HER2-Directed Therapy Trials Ongoing HER2 Trials First-line JACOB: Cape-Cis-Trastuzumab + / - Pertuzumab, 780 patients HELOISE: Cape-Cis + 2 dose levels of Trastuzumab, 400 patients Second-line: GATSBY: Paclitaxel vs TDM-1

Large molecule VEGF inhibitors VEGF-A VEGF-R1 (Flt-1) Migration Invasion Survival VEGF-R3 (Flt-4) Lymphangio- genesis VEGF-R2 (KDR/Flk-1) Proliferation Permeability PlGF VEGF-B VEGF-C, VEGF-D Functions Y Bevacizumab Y Ramucirumab Aflibercept (VEGF Trap)

Targeted Agents Phase III: Negative Trials for VEGF, mTOR, and EGFr AVAGAST: Cape-Cisplatin + / - Bevacizumab Negative trial for OS mTOR GRANITE: BSC vs Everolimus REAL 3: ECX + / - Panitumumab (U.K.) Negative: Panitumumab had inferior outcomes EXPAND: Cape-Cis + / Cetuximab (E.U.) Negative: Cetuximab trended inferior COG: BSC vs Gefitinib (U.K.): Negative Ohtsu A, et al. J Clin Oncol. 2011;29(30):3968-3976 Ohtsu A, et al. J Clin Oncol. 2013;31(31):3935-3943 Waddell T Lance Oncol 14: 481; 2013 Lordick F et al Lancet 14:490; 2013 Sutton JCO 30: 2012 (suppl 34 abstr 6)

EGFr: Definitive Cetuximab + Chemo RT SCOPE-1 Cape-Cis  Cape-Cis- RT + / - RT 258 pts (65 AC,188 SCC) RTOG 0436 Pac-Cis-RT + / - Cetuximab 328 pts (203 AC,125 SCC) Crosby Lancet 14: 627; 2013 Suntha JCO 32: 2014 (suppl 3; abstr LBA6

VEGF Revisited? Apatinib Phase III Trial Planned Small-molecule multitargeted TKI with activity against VEGFR China 144 patients, placebo vs 850 mg/d or 425 mg BID OS 2.5 months  4.0 months, 4.5 months RR 10% Phase III Trial Planned Ramucirumab: Humanized moAb Targeting VEGr2 receptor TKI, tyrosine kinase inhibitor; VEGFR, VEGF receptor Li J, et al. J Clin Oncol. 2013;31(26):3219-3225. Fuchs CS, et al. Lancet. 2014;383(9911):31-39.

VEGFr: Ramucirumab in Gastric Cancer: REGARD Trial Gastric/GEJ Cancer with POD on FU or Platinum Based Chemo RANDOMIZATION, 355 patients Patients with advanced gastric cancer refractory to prior FP were randomly assigned into weekly paclitaxel or irinotecan group. Stratification factors were institution, performance status and target lesion. Paclitaxel 80mg/m2 was administered weekly for consecutive three weeks with one-week rest. And irinotecan 150mg/m2 was administered bi-weekly. BSC + Placebo BSC + Ramucirumab 8 mg/kg q 2 weeks Fuchs CS, et al. Lancet. 2014;383(9911):31-39

VEGF Revisited? Ramucirumab: REGARD Trial PFS improved 2.1 months  3.8 months (HR 0.483, P<.0001) OS improved 3.8 months  5.2 months (HR 0.776, P = .047) Disease control improved from 23% to 49% (P<.0001) Essentially no toxicity (rare grade ≥3 hypertension 8%) Fuchs CS, et al. Lancet. 2014;383(9911):31-39.

Time Since Randomization, Months Time Since Randomization, Months REGARD Trial: Results OS PFS 20 HR (95% CI) = 0.483 (0.376-0.620) Log-rank P value (stratified) <.0001 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 40 60 80 100 PFS, % 238 117 Number at risk Ramucirumab Placebo 213 92 113 27 65 61 45 30 18 Time Since Randomization, Months Ramucirumab (n = 238) Placebo (n = 117) Censored 27 HR (95% CI) = 0.776 (0.603-0.998) Log-rank P value (stratified) =.047 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 26 28 40 60 80 100 OS, % 238 117 Number at risk Ramucirumab Placebo 154 66 92 34 49 Ramucirumab (n = 238) Placebo (n = 117) Censored Time Since Randomization, Months Fuchs CS, et al. Lancet. 2014;383(9911):31-39.

VEGFr: RAINBOW: Study Design 1:1 Ramucirumab 8 mg/kg day 1&15 + Paclitaxel 80 mg/m2 day 1,8 &15 of a 28-day cycle N = 330 R A N D O M I Z E Treat until disease progression or intolerable toxicity Survival and safety follow-up S C R E EN Placebo day 1&15 + Paclitaxel 80 mg/m2 day 1,8 &15 N = 335 Important inclusion criteria: - Metastatic or loc. adv. unresectable gastric or GEJ* adenocarcinoma - Progression after 1st line platinum/fluoropyrimidine based chemotherapy Stratification factors: - Geographic region, - Measurable vs non-measurable disease, - Time to progression on 1st line therapy (< 6 mos vs. ≥ 6 mos) Wilke GI Symposium 2014 LBA 7

RAINBOW: Ramucirumab + Paclitaxel for Metastatic Gastric Cancer 665 pts with POD on fluorinated pyrimidine + platinum Weekly paclitaxel 80 mg/m2 + /- Ram 8 mg/kg PFS improved 2.9 months  4.4 months (HR 0.635, P<.0001) OS improved 7.4 months  9.6 months (HR 0.807, P = .0169) RR improved from 16% to 28% (p = 0.0010 (P<.0001) Increased toxicity neutropenia and hypertension Wilke GI Symposium 2014 LBA 7

Ramucirumab First-line: FOLFOX + / - Ramucirumab Other VEGF agents Randomized phase II Other VEGF agents FOLFOX + / - Pazopanib (TKI)

VEGF Adjuvant Trials Gastric Cancer MAGIC 2 Trial: EOX + / - Bevacizumab Amended for HER2 + patients Randomized to + / - Lapatinib (HER1-2 TKI)

CMET Pathway Goyal L, et al. Clin Cancer Res. 2013;19(9):2310-2318.

CMET: Rilotumumab: Gastric Cancer First Line Phase II ARM A Rilotumumab (15 mg/kg) + ECX Q3W (n = 40) RANDOM I ZE ARM B Rilotumumab (7.5 mg/kg) + ECX Q3W (n = 40) ARM C Placebo + ECX Q3W (n = 40) Stratification factors: ECOG PS 0 vs 1 LA vs Metastatic E: Epirubicin: 50 mg/m2 IV, day 1 C: Cisplatin: 60 mg/m2 IV, day 1 X: Capecitabine: 625 mg/m2 BID orally, days 1-2 Rilotumumab: IV over 60 ± 10 minutes prior to chemotherapy ClinicalTrials.gov identifier: NCT00719550 Zhu M, et al. J Clin Oncol. 2012;30(Suppl): Abstract 2535.

PFS and OS in c-MetHigh Patients Median Months (80% CI) HR (80% CI) 6.9 (5.1, 7.5) 0.53 (0.25, 1.13) 4.6 (3.7, 5.2) Median Months (80% CI) HR (80% CI) 11.1 (9.2, 13.3) 0.29 (0.11, 0.76) 5.7 (4.5, 10.4) Zhu M, et al. J Clin Oncol. 2012;30(Suppl): Abstract 2535.

Ongoing Trials: Met Inhibitors Targeting CMET, + IHC RILOMET-1 ECX + / - Rilotumumab (targeting ligand HGF) MetGastric FOLFOX + / - MetMab (targeting receptor) Tyrosine Kinase Inhibitors Promising phase I activity in CMET amplified

Fibroblast growth factor receptor Ligand activated trans membrane growth factor receptor Signals via RAS  Map kinase and PI3K-AKT but also via Hedgehog and Notch pathways, and WNT Phase II Trials Dovitinib (TKI) in FGFR gene amplified gastric cancer Dovitinib + Docetaxel in gastric cancer

PARP Inhibitors: Olaparib in Gastric Cancer Gastric/GEJ Cancer with POD on FP RANDOMIZATION: Paclitaxel Paclitaxel + Olaparinib Bang YJ, et al. J Clin Oncol. 2013;31(suppl): Abstract 4013

PARP Inhibition in Gastric Cancer: Olaparib Patients randomized to Paclitaxel + / Olaparib Tissue testing for ATM protein Negative in13% = In vitro sensitivity to olaparib 124 patients randomized, ATM + / - OS benefit in ATM + / -, Greater in ATM – Phase III Trial planned Bang YJ, et al. J Clin Oncol. 2013;31(suppl): Abstract 4013

Trials of Targeted Agents 1st Line Target Agent Trial Regimen Number Status HER2 Pertuzumab JACOB XP + T +/- Pertuzumab 780 Ongoing Trastuzumab HELOISE XP + T (2 doses) 400 CMET Rilotumumab Rilomet-1 ECX + / - Rilo 650 Onartuzumab MetGastric FOLFOX + /- O 800 EGFr Panitumumab NCT01627379 5-FU-Cis + / - Pan 300 VEGFr Pazopanib PaFLO FLO + / - Pazop 75 2nd Line mTOR Everolimus AIOST00111 Pac + / - Evero 665 TDM-1 GATSBY Pac vs TDM-1 412 Nimotuzumab NCT01813253 Irino + / - Nimo PARP Olaparib Pac + / - Olap Planned

Esophagogastric Cancer: Immunotherapies Agents that deregulate immune suppression Anti PD-1 phase I: PD-1: T cell programmed cell death receptor, blockade may enhance immune responses Active in NSCLC, RCC 7 gastric cancers, no activity Anti PDL-1 phase I MPDL3280A: Blocks ligand PR in 1/1 Gastric Cancer, 26/29 responses ongoing Enhanced activity in PDL-1 + patients Ipilimumab Anti CTLA-4 antibody Phase II FOLFOX  capecitabine maintenance vs ipilumimab Ribas A, et al. N Eng J Med. 2012;366:2443 Herbst R et al. JCO 31 (supp): Abstract 3000

HCC: Sorafenib is the Standard for Advanced Disease SHARP TRIAL ASIA PACIFIC TRIAL OS 7.9  10.7 months, HR 0.69 OS 4.5  6.2 months, HR 0.68 Llovet NEJM 359: 378; 2008 Chang Lancet Oncol 10:25; 2009

Sorafenib in HCC Modest single agent activity in Child’s A pts with HCC Toxicity monitoring and dose reduction are key Outcomes vary depending on geographic region, etiology and severity of cirrhosis No biomarker has been identified

Failed Phase III Trials Agent Target Number Overall Survival First Line Sunitinib vs Sorafenib VEGFr, PDGFr, C-KIT, FLT3 1074 8.1 vs 10 months, HR 1.31 Brivanib vs Sorafenib VEGFr, FGFr 1155 9.5 vs 9.9 months, HR 1.07 Erlotinib/Placebo vs E/Sorafenib EGFR 720 9.5 vs 8.5 months, HR 0.929 Linifanib vs Sorafenib VEGFr, PDGFr 1035 9.1 vs 9.8 months, HR 1.046 Second Line Brivanib vs BSC 395 9.4 vs 8.2 months, HR 0.89 Sorafenib OS consistently 8.5-10 months

Ongoing Single Agent Studies Angiogenesis: Ramucirumab, TSU-68, Cedirinab, Pazopanib, lenvatinib, Axitinib CMET: Tivantinib, cabozantinib, foretinib, METmab, IMC-280, LY2875358 EGFR: Lapatinib, cetuximab mTOR: Everolimus, temsirolimus, sirolimus, CC-23

Ongoing Single Agent Studies MEK Selumetinib, rafametinib HDAC Belinostat, resminostat HSP-90 Genetespib Oncolytic viruses JX-594 Immunotherapy Tremelimumab, PD-1, PD-L1

CMET Targeted Therapy in HCC Tivantinib vs Placebo in HCC CMET TKI 107 pts, Child’s Pugh A, PS 0-1, most failed sorafenib 160 mg tivantinib vs placebo Cross over permitted at POD TTP HR 0.64, p = 0.04 OS not different, given cross over (6.2- 6.6 months) CMET IHC low, better prognosis, no benefit from tivantinib CMET IHC high, OS 3.8 to 7.2 months (HR 0.38, p = 0.01) with tivantinib Phase III Trial planned in CMET high pts OS CMET High Santoro Lancet Oncol 14: 55; 2013

CMET Targeted Therapy in HCC Cabozantinib vs Placebo in HCC (4007) CMET and VEGR2 TKI, most patients failed sorafenib 107 pts, Child’s Pugh A, PS 0-1, most failed sorafenib 100 mg cabozantinib, stable disease randomized to placebo or continuation Cross over permitted at POD 41 treated PFS 4.4 mos, OS 15 mos in all pts RR 5%, Stable disease 78% Larger phase II trial planned Verslype et alJ Clin Oncol 30: 2012 (suppl Abst 4007)

Promising Signals Ramucirumab Lenvatinib Immunotherapy Anti VEGFr2 RR 10%, PFS 4 months, OS 12 months Lenvatinib VEGFr1-3, FGFr1-4, RET, KIT, PDGFrβ TKI 37% modified RECIST response rate TTP 12.8 months, OS 18.7 months Immunotherapy Anti CTLA-4 RR 17%, PFS 6 months

Ongoing Trials First Line Sorafenib vs Sorafenib + Doxorubicin (CALGB 80802) Lenvantinib vs Sorafenib Sorafenib + Local Regional Therapy Sorafenib + / - SBRT (RTOG 1112) Sorafenib + / - TACE (ECOG) Sorafenib vs Y90 Second Line Ramucirumab vs BSC ADI-PEG 20 vs BSC Tivantinib and Cabozantinib vs BSC Regorafenib vs BSC

Pancreatic Cancer Improvements in Chemotherapy Gemcitabine  G + Nab-Paclitaxel  FOLFIRINOX OS 6 months  8.5 months  11.1 months Response: 6%  23%  32% Targeted Agents Only approved agent is EGFr TKI Erlotinib

NCI PA.3 Phase III Trial Untreated Advanced Pancreas Ca Gemcitabine + Placebo R A N D O M I Z E Erlotinib Stratify N= 569 LA vs M1 Center PS 0-1 vs 2 Primary Enpoint OS 80% power, 33% increase Moore, et al. J Clin Oncol, 2007

Survival Distribution Function PA.3 Overall Survival Months Survival Distribution Function 1.00 0.75 0.50 0.25 6 12 18 24 G + Erlotinib (N= 261) G + Placebo (N= 260) Med. Survival (mths) 6.24 mths 5.9 mths 1-Year Survival 23% 17% CR + PR 8.6% 8% CR + PR + SD 57% 49% HR= 0.82 (0.69-0.99) p= 0.038 *Adjusted for PS and extent of disease at baseline † From Cox regression model ‡ From 2-sided log-rank test Moore, et al. J Clin Oncol, 2007

Molecular Correlates Gemcitabine +/- Erlotinib PA.3 N= 569 pts – 117 samples (21%) EGFR (+) or (–) no correlation with outcome Post-hoc K-ras mutational status analysis Trend to OS benefit in the pts with wild-type K-ras Gem Gem + E HR P-value K-ras mutant 7.4 mths 6.0 mths 1.07 0.78 K-ras WT 4.5 mths 6.1 mths 0.66 0.34 Moore, et al. ASCO, 2007 (Abst #4521)

Genetic Alterations in Pancreatic Ca Gene Mutation/ Deletion p16 80% K-ras (B-raf) 90%+ p53 70% SMAD4/ TGFβR1+2 55% BRCA 1, 2, PALB2 5-8% Mismatch repair genes 4% STK11 (Peutz-Jeghers) 5% MKK4 5-13% FANCC/ FANCG 5% Amplification/ Overexpression PI3K/ Akt, c-myc, Shh/ Gli, Notch, etc (10-30%) Other Genetic Changes Telomere shortening Widespread allelic loss Infiltrating pancreatic ca Courtesy, M. Goggins (JHCC)

NegativePhase III Anti-Vascular Trials in PC Drug N RR Med OS Reference Gemcitabine + Bevacizumab 590 13% 5.8 mths Kindler CALGB 80303 Gemcitabine + Placebo 10% 6.1 mths Gemcitabine + Erlotinib + Bevaciz. 607 13.5% 7.1 mths Van Cutsem AViTA Gemcitabine + Erlotinib 8.6% 6 mths Gemcitabine + Axitinib 593 NR 8.5 mths 8.3 mths Gemcitabine + Aflibercept 594 7.7 mths Rougier 6.5 mths Kindler, HJ. J Clin Oncol, 2010. Van Cutsem, E. J Clin Oncol, 2009. Kindler, HJ. Lancet Oncology, 2011. Rougier, P. ESMO, GI, 2010

New Targets, New Drugs Target Class of Drug Example of Drug IGF-1R Antibody to IGF-1R Tyrosine kinase inhibitor AMG 479, MK-0646, IMC-A12 OSI-906 RAS Farnesyl transf. inhibitor Oncolytic viral agents Tipifarnib, Salarasib Reovirus mTOR/ P13K/ AKT/MEK mTOR inhibitor AKT, P13K Everolimus, temsirolimus MK-2206, XL-765, BKM-120, Selumetinib Hedgehog (Hh) Notch Small molecule Hh inhibitor Gamma-secretase inhibitor GDC-0449, IPI-926, LDE-225 R04929097 PMSCA Antibody to PSCA AGS-1C4D4 SRC SRC, bcr-abl inhibitor Dasatinib, AZD 0530 TRAIL Antibody to DR4, DR5 Mapatumumab AMG 655 Integrin Antibody to α5β1 integrin Volociximab PARP PARP inhibitor AZD 2281, ABT-888, BSI-201 Vaccines/ Immunotherapy Checkpoint inhibitors, vaccines Ipilumimab, nivolumab, GVAX/CRS207

Phase II: GVAX + / - CRS-207 GVAX: Irradiated, GM-CSF secreting allogeneic pancreatic cancer cell lines given intradermally, preceded by Cytoxan to reduce T regs CRS-207: Live-attenuated Listeria monocytogenes which expresses mesothelin  immune stimulant 90 pts previous treated randomized 2: 1 to C/GVAX + CRS-207 or C/GVAX alone OS 6.1 vs 3.9 months (HR 0.54, p = 0.011) More CA 19-9 stabilization with combination Le J Clin Oncol 32: 2014 (suppl 3; abstr 177)

Recent Negative Phase II-III Targeted Therapy Drug Trial Med PFS or OS Reference Gem + AMG-479 (IGF-1R) Phase III GAMMA No Change Press Release Gem + Placebo Gem + Sorafenib Phase III BAYPAN PFS 5.7 mos Goncalves Ann Oncol 2012 3.8 mos Gem Phase II LEAP OS 6.0 mos Poplin ASCO 2013 CO-1.01 (hENT1) 6.0 mos Gem + Masitinib (CKIT, PDGF, FGF) Phase III 7.7 mos Deplanqa GI Symposium 2013 Gem + IPI-926 (Shh) Phase II 5.9 mos Gem + Vismodegib 6.3 mos Catenacci ASCO 2012 Gem (Shh) 5.4 mos

Novel Targets Stroma and Microenvironment PEGPH20: degrades hyaluronic acic, may increase drug delivery Onoing phase II: Nab-P + / - PEGPH20 FOLFIRINOX + / - PEGPH20 BRCA mutant pancreatic cancers (5%) Deficient homologous DS DNA repair Results in genomic instability, chromosomal deletion and exchange PARP inhibition Cis-Gem + / Veliparib, randomized phase II

Ongoing Randomized Phase II-III Trials Number Target Phase III Gem + / - TH302 (alkylating agent) 660 Hypoxic Environment Phase II Gem-Nab-P + / - PEGPH20 M402 OMP59R5 OGX-427 132 148 140 Hyaluronic acid Stroma Notch HSP27 Gem + / - MSC193698 Afatinib TL-118 174 117 80 MEK EGFR, HER2 Angiogenesis Gem-Cis + / - Veliparib 70 PARP

Approved Targeted Agents in CRC Growth factor receptor inhibitors: VEGFr/ VEGF Anti VEGF A ligand antibody: Bevacizumab Soluble VEGF receptor: Aflibercept VEGFr TKI: Regorafenib EGFr: Anti EGFr antibodies: Cetuximab Panitumumab

Integration of VEGF Targeted Agents into Chemotherapy Bevacizumab can be used with first line FOLFIRI, 5-FU/capecitabine, FOLFOX Bevacizumab can be continued into second line chemotherapy, with FOLFOX or FOLFIRI Alfibercept can be used second line with FOLFIRI after POD on FOLFOX/Bev Regorafenib: Late line therapy after POD on all conventional lines of therapy

HER1/EGFR Signaling Pathways Extracellular Intracellular P P Src PLC GAP Grb2 Shc Nck Vav Grb7 Crk Ras Abl PKC PI3K MAPK JNK Survival, Growth, Proliferation, Adhesion, Migration, Angiogenesis, Metastasis Data from Sedlacek. Drugs. 2000;59:435. Sedlacek Drugs. 2000;59:435.

Integration of EGFR Agents in Colorectal Cancer: KRAS WT tumors First Line: Cetuximab, Panitumumab approved to combine with FOLFIRI or FOLFOX Capecitabine based trials with Cetuximab failed  toxicity Second, Third Line Cetuximab, Panitumumab approved as monotherapy Suggested added benefit when combined with irinotecan or FOLFIRI second line BRAF mutant patients are eligible for EGFR therapy

All KRAS Mutant Patients Should Not Get Cetuximab Current testing looks at KRAS exon 2 mutations Trial of FOLFOX + / - Cetuximab An additional 17% had KRAS exon 3/4, NRAS exon 2/3/4 Douillard NEJM 369:11;2013

CALGB 80405: Bevacizumab vs Cetuximab in First-line KRAS WT mCRC Untreated KRAS WT mCRC (n=1500) Bevacizumab + FOLFOX or FOLFIRI Cetuximab + FOLFOX or FOLFIRI PD R Primary endpoint: OS Secondary endpoints: ORR, PFS, TTF, DOR, and safety NCT identifier: NCT00265850. 57

Phase III study design FOLFIRI + Cetuximab FOLFIRI + Bevacizumab Cetuximab: 400 mg/m2 i.v. 120min initial dose 250 mg/m2 i.v. 60min q 1w mCRC 1st-line therapy KRAS wild-type N= 592 Randomize 1:1 FOLFIRI + Bevacizumab Bevacizumab: 5 mg/kg i.v. 30-90min q 2w FOLFIRI: 5-FU: 400 mg/m2 (i.v. bolus); folinic acid: 400mg/m2 irinotecan: 180 mg/m2 5-FU: 2,400 mg/m2 (i.v. 46h) Key inclusion criteria Patients ≥18 years with histologically confirmed diagnosis of mCRC ECOG PS 0-2 prior adjuvant chemotherapy allowed if completed >6 month before inclusion Amendment in October 2008 to include only KRAS wildtype patients 150 active centers in Germany and Austria 58 58

Assessable for response Evaluation of ORR FOLFIRI + Cetuximab FOLFIRI + Bevacizumab Odds ratio p ORR % 95%-CI ITT population (N= 592) 62.0 56.2 – 67.5 58.0 52.1 – 63.7 1.18 0.85-1.64 0.183 Assessable for response (N= 526) 72.2 66.2 – 77.6 63.1 57.1 – 68.9 1.52 1.05-2.19 0.017 p = Fisher´s exact test (one-sided)

Probability of survival months since start of treatment Progression-free survival Events n/N (%) Median (months) 95% CI ― FOLFIRI + Cetuximab 250/297 (84.2%) 10.0 8.8 – 10.8 ― FOLFIRI + Bevacizumab 242/295 (82.0%) 10.3 9.8 – 11.3 HR 1.06 (95% CI 0.88 – 1.26) Log-rank p= 0.547 1.0 0.75 Probability of survival 0.50 0.25 0.0 12 24 36 48 60 72 months since start of treatment numbers at risk 297 295 100 99 19 15 10 6 5 4 3

Probability of survival months since start of treatment Overall survival Events n/N (%) Median (months) 95% CI ― FOLFIRI + Cetuximab 158/297 (53.2%) 28.7 24.0 – 36.6 ― FOLFIRI + Bevacizumab 185/295 (62.7%) 25.0 22.7 – 27.6 HR 0.77 (95% CI: 0.62 – 0.96) Log-rank p= 0.017 1.0 0.75 Probability of survival 0.50 0.25 0.0 0.0 12 24 36 48 60 72 months since start of treatment numbers at risk 297 295 218 214 111 60 47 29 18 9 2

I4T-MC-JVBBPhase III Trial 2nd Line FOLFIRI +/- Ramucirumab (RAISE) 62 I4T-MC-JVBBPhase III Trial 2nd Line FOLFIRI +/- Ramucirumab (RAISE) Ramucirumab IV + FOLFIRI q 2 weeks 525 pts mCRC after failure FP/oxaliplatin + BEV regimen R 1:1 Placebo + FOLFIRI q 2 weeks 525 pts Stratification factors: Region KRAS status First-line TTP (<>6 mos) Primary EP: OS Accrual completed PIs: Tabernero 62

Anti-CTLA4 in CRC 1/45 crc: PR (response duration 15m) Median PFS 2.3m 45% alive >6months Chung et al. JCO 2010

Anti-PDL1 Anti-PD1 BMS-936559 BMS-936558 MPDL3280A RESPONSE RATE 0/18 crc 1/14 crc: CR MPDL3280A RESPONSE RATE RESPONSE RATE 1/4 crc 0/19 crc Net N =55 CRC patients

Study Design (CA209-142 trial) to open January 2014: anti PD-1

BRAF V600E Inhibitor: PLX4032 (Vemurafenib) Refractory Melanoma Refractory Colorectal 100 100 78% Response Rate 5% Response Rate 75 75 50 50 25 25 Low AKT activation Minimal hypermethylation High AKT activation Extensive hypermethylation %Change From Baseline (Sum of Lesion Size) %Change From Baseline (Sum of Lesion Size) -25 -25 -50 -50 -75 -75 Flaherty et al NEJM ‘10 Kopetz et al ASCO ‘10 -100 -100 Oncogene mutation does not imply oncogene dependence Understand the biological context in which particular mutations occur Kopetz, CTPM Jan 2011

Randomized Phase II of Dual BRAF + EGFR Inhibition in BRAFmut mCRC Primary endpoint: PFS Arm B design pending outcomes from ongoing Phase 1 studies N=42 ~800 screened Courtesy: Scott Kopetz

Prominent cMET / HGF Inhibitors Agent Structure Target Rilotumumab Human monoclonal antibody HGF Onartuzumab (metMab) Humanized monovalent antibody c-MET Tivantinib (ARQ 197) Small molecule c-MET kinase Cabozantinib (XL184)

Phase 2 Study Design + + Eligibility Age ≥ 18 years Inoperable, locally advanced or metastatic disease KRAS WT 1 line of prior systemic Tx ECOG PS 0-1 No prior anti-EGFR therapy RANDOMIZE DOUBLE BLIND Cetuximab 500 mg/m2 IV q14 days Tivantinib (ARQ 197) 360 mg PO BID + Irinotecan 180 mg/m2 IV q14 days Cetuximab 500 mg/m2 IV q14 days Placebo PO BID + Irinotecan 180 mg/m2 IV q14 days N = 150 1:1 Primary Endpoint: PFS Stratification Factors: 1) ECOG PS (0 vs 1) 2) Best response to 1st-line therapy (CR/PR/SD vs PD) Secondary Endpoints: OS, ORR, safety Eng et al., ASCO 2013

Progression-Free Survival, % Time Since Randomization, mo Progression-Free Survival Full Analysis Set (median follow-up: 15.9 mo) HR = 0.85 (95% CI, 0.55 - 1.33) Stratified log-rank P = 0.38 Progression-Free Survival, % 3 9 15 6 12 18 21 Time Since Randomization, mo 100 75 50 25 Placebo (n = 57) Tivantinib (n = 60) Events Median, mo 95% CI T 44 8.3 5.6 - 10.8 P 37 7.3 5.3 - 9.0 Eng et al., ASCO 2013

PFS and OS by MET Expression MET-High MET-Low PFS ORR: T = 54.2%; P = 30.0% ORR: T = 27.3%; P = 41.7% 100 100 HR = 0.74 (95% CI, 0.36 - 1.52) Log-rank P = 0.41 HR = 0.22 (95% CI, 0.06 - 0.80) Log-rank P = 0.01 75 75 Progression-Free Survival, % 50 Progression-Free Survival, % 50 Tivantinib (n = 24) Tivantinib (n = 11) 25 25 Placebo (n = 20) Placebo (n = 12) OS 3 6 9 12 15 18 21 3 6 9 12 15 18 21 100 HR = 0.58 (95% CI, 0.25 - 1.36) Log-rank P = 0.20 100 HR = 0.78 (95% CI, 0.24 - 2.47) Log-rank P = 0.67 75 75 Overall Survival, % 50 Overall Survival, % 50 25 25 4 8 12 16 20 24 28 32 4 8 12 16 20 24 28 32 Time Since Randomization, mo Time Since Randomization, mo Eng et al., ASCO 2013