Translational Research in Upper GI Cancers: Gastroesophageal Cancer Cholangiocarcinoma

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1 Translational Research in Upper GI Cancers: Gastroesophageal Cancer Cholangiocarcinoma Daniel Catenacci, MD Developmental Therapeutics Symposium April 20, 2018

2 Disclosure Information 23 rd Annual Developmental Therapeutics Symposium Daniel Catenacci, MD I have the following financial relationships to disclose: Consultant for: Merck, BMS, Five Prime, Lilly, Taiho, Genentech/Roche, Amgen, Insys, Aduro, Heron, Tocagen, Gritstone, Astellas, Genmab, Seattle Genetics, Foundation Medicine, Nantomics Guardant Health, Human Longevity I will discuss non-approved therapies and investigational uses of therapies in my presentation. 2

3 Overview Metastatic Gastroesophageal Adenocarcinoma Standard of care Molecular Heterogeneity (inter and intrapatient) ctdna,study designs & treatment strategies Metastatic Cholangiocarcinoma (intrahepatic) Standard of care Molecular Heterogeneity (interpatient) 3

4 Gastroesophageal Cancer Diaphragm Esophagus Esophagogastric Junction (EGJ) Cardia Lesser curvature Angular notch (incisura angularis) Pylorus Duodenum TYPE I Pyloric Antrum TYPE II TYPE III Gastric Bodyor Stomach Cancer Esophageal (SCC) EGJ AC Type I, II, III Seiwert Fundus Gastric (non-cardia) AC Greater curvature Esophageal vs. Gastric Adenocarcinoma 7 th edition 2010 AJCC/UICC Staging Sehdev A, Catenacci DVT. Gastroesophageal Adenocarcinoma: Focus on Epidemiology, Classification and Staging. Discov Med 2013

5 BSC 1 FAMTX 2 SP 3 FP 4 IF 5 EOF 6 DCF 4 ECF 6 ECX 6 EOX 6 XP 7 FOLFIRI 8 FOLFOX 9 +T X/FP+/-T 10 X/FP+/-T 10 HER2 (+) HER2 IHC3+ or IHC2+/FISH+ +T X/FP+/-T 10 HER2 IHC3+/FISH+ +T mos Months Murad, et al. Cancer Vanhoefer, et al. JCO Ajani, et al. ASCO Van Cutsem, et al. JCO Dank, et al. Ann Oncol Cunningham, et al. NEJM Kang, et al. Ann Oncol Guimbaud, et al. JCO Shah et al. JAMA Oncol Bang et al. Lancet 2010.

6 Anti-HER2 Therapy for EGA IV Lin e Trial N Treatment 1 0 Endpt mos HR Δ mpfs HR Δ RR Δ 1L 1. Bang et al Lancet 2010 TOGA 584 Cis/FP Cis/FP tras OS 11.8* 16* * P<0.05* * P< % 47% +12 1L 2. Hecht et al J Clin Oncol 2015 LOGiC 545 (487) Cis/FP Cis/FP - lapat OS p=n.s. (0.86, N.S.) P= % 53% +14 1L 3. Tabernero et al ESMO 2017 JACOB 504 Cis/FP - tras Cis/FP tras/pert OS p=n.s % 57% +9 2L 4. Satoh et al J Clin Oncol 2014 TYTAN 261 Paclitaxel Paclitaxel-lapat OS p=n.s p< % 27% +18 TOGA *mos and HR and Δ: For IHC2+/3+ & FISH+ subset 2L 5. Kang et al GI ASCO 2016 GATSBY 345 (1:2) Pac38%, D62% T-DM1 OS p=n.s p=n.s % 21% +1

7 Antiangiogenesis for EGA Line Trial N Treatment 1 0 Endpt mos HR Δ mpfs HR Δ RR Δ 2L Fuchs et al Lancet 2013 REGARD 335 Placebo Ramucirumab OS p= % 3% 0 2L Wilke et al Lancet Oncol 2014 RAINBOW 665 Paclitaxel-Plbo Paclitaxel-Ram OS p= % 27% +11 3L Li et al J Clin Oncol Placebo Apatinib OS/PFS p= % +3 1L - AVAGAST - negative OS positive PFS (bevacizumab), Ohtsu et al. JCO RAINFALL negative OS positive PFS (ramucirumab), Fuchs et al. GI ASCO 2018

8 N= 86 MSI-H pts 12 different tumor types GEA: TCGA 23% Stage IV <3% Le et al. Mismatch repair deficiency predicts response of solid tumors to -1 blockade. Science 2017

9 Response in All Patients All patients (N = 259) Response* % 95% CI ORR (CR+PR) DCR CR PR SD Median (range) follow-up: 5.8 months ( ) Data cutoff: Jan16, 2017 *Only confirmed responses were included CR+PR+SD 2 months

10 Response by -L1 Expression Response* -L1 positive ( n= 148) -L1 negative (n = 109) % 95% CI % 95% CI ORR DCR CR PR FDA grants accelerated approval to pembrolizumab for advanced L1+ gastric cancer September 22, 2017 Data cutoff: Jan16, 2017 *Only confirmed responses were included CR+PR+SD 2 months

11 -L1 Expression IHC * -L1 expression in gastric cancer is determined by Combined Positive Score (CPS) # -L1 staining cells (tumor cells, lymphocytes, macrophages) CPS = X 100 Total # viable tumor cells A specimen is considered to have positive -L1 expression if CPS 1 -L1-negative -L1-positive Immune Cells Tumor Cells Immune Cells Tumor Cells *22C3 pharmdx IHC DAKO, Carpinteria, CA

12 PFS by -L1 Expression Progression-free Survival (%) Numbers at risk -L1 Positive -L1 Negative Time (months) Median (95% CI) -L1 positive 2.1 mo ( ) -L1 negative 2.0 mo ( ) Data cutoff: Jan16, 2017

13 OS by -L1 Expression Overall Survival (%) Numbers at risk -L1 Positive -L1 Negative Time (months) Median OS (95% CI) -L1 positive 5.8 mo ( ) -L1 negative 4.9 mo ( ) Data cutoff: Jan16, 2017

14 Nivolumab (ONO-4538/BMS ) as salvage treatment after second or later-line chemotherapy for advanced gastric or gastro-esophageal junction cancer (AGC): A double-blinded, randomized, phase III trial. Progression-Free Survival Presented By Yoon-Koo Kang at 2017 Gastrointestinal Cancers Symposium

15 Nivolumab (ONO-4538/BMS ) as salvage treatment after second or later-line chemotherapy for advanced gastric or gastro-esophageal junction cancer (AGC): A double-blinded, randomized, phase III trial. Overall Survival Presented By Yoon-Koo Kang at 2017 Gastrointestinal Cancers Symposium

16 Pembrolizumab vs SOC 2L Phase III KEYNOTE-061 N=592 Second line gastric/gej adenocarcinoma Paclitaxel vs Pembrolizumab NEGATIVE mos Primary Endpoint L1+ tumors All comers Merck Provides Update on KEYNOTE-061, a Phase 3 Study of KEYTRUDA (pembrolizumab) in Previously Treated Patients with Gastric or Gastroesophageal Junction Adenocarcinoma. KEYTRUDA-pembrolizumab-in-Previously-Treated-Patients-with-Gastric-or-Gastroesophageal-Junction-Adenocarcinoma/default.aspx December 14, 2017

17 Avelumab vs SOC 3L Phase III Javelin-300 N=371 Third line gastric/gej adenocarcinoma Paclitaxel/irinotecan vs Avelumab NEGATIVE mos All comers Merck Provides Update on KEYNOTE-061, a Phase 3 Study of KEYTRUDA (pembrolizumab) in Previously Treated Patients with Gastric or Gastroesophageal Junction Adenocarcinoma. KEYTRUDA-pembrolizumab-in-Previously-Treated-Patients-with-Gastric-or-Gastroesophageal-Junction-Adenocarcinoma/default.aspx December 14, 2017

18 Median OS ~9-12 months ~14-16 months for HER2++ trastuzumab 1L 5FU, platinum, irinotecan, taxane First line 2 and 3 drug regimens (2 preferred) (trastuzumab) Improve QOL Treat & prevent symptoms Improve survival time Second line 1-2 drug regimens (2 preferred), (ramucirumab) Cougar -02, REGARD, RAINBOW etc (pembro not better than chemo KN061) Improve QOL Treat & prevent symptoms Improve survival time Third line cytotoxics, (pembro) Summary: Stage IV Keynote 059 Cohort 1, Attraction 02 (but Avelumab not better than chemo Javelin300) Other Investigational Biomarkers & Targeted therapies: One size fits all approach negative or not impressive: Biology Matters! Immunotherapy -1/CTLA4/IDO/LAG3 inhibitors MSI-H/TMB/L1+ Vaccines, CAR-T Targeted therapies to HER2++, EGFR++, MET++, FGFR2++ INTER- and INTRA-Patient Molecular HETEROGENEITY How do we move forward?

19 Spatial Heterogeneity Revealed by Multi-site NGS Sequencing: PANGEA Cohort 4: PANGEA 28 patients Divergent primary tumor and metastatic or cfdna profiling led to treatment reassignment in 32% (9/28) of patients cfdna and metastatic disease concordant in 90% of cases Pectasides et al. Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma. Cancer Discov Jan;8(1): doi: / CD Epub 2017 Oct 4. 19

20 Temporal Heterogeneity: Tumors Evolve Over Time to Develop Treatment Resistance Response Progression Sensitive Clone Resistant Clones Misale et al. Cancer Discovery (2014)

21 The PANGEA -IMBBP Trial Personalized ANtibodies for Gastro-Esophageal Adenocarcinoma: A Pilot 1 st Metastatic Trial of Biologics Beyond Progression Historical Control (Arm A) FOLFOX FOLFOX-T PFS 1 FOLFIRI PFS 2 FOLTAX PFS 3 6m 60% 4m 30% 2m Biomarker Evaluation in all samples to allow for treatment assignment Patient Case: HER2 and EGFR amplified Diagnosis: metastatic cancer Anticipated Incidence 20% HER2 amplified Arm B1 FOLFOX -Trastuzumab PFS 1 FOLFIRI + T PFS 2 FOLTAX + T PFS 3 7% MET amplified/hi Arm B2 FOLFOX -METab FOLFIRI + M FOLTAX + M ARM B: Therapy based on molecular profile 8% FGFR2 amplified Arm B3 FOLFOX 7/18% EGFR amplified/hi KRAS wild type Nl HER2,FGFR2,RON,MET Arm B4 -FGFR2ab FOLFOX -EGFRab FOLFIRI + F FOLFIRI + EGFRab FOLTAX + F FOLTAX + EGFRab primary mos Endpoint (N~68) 15/10% KRAS/BRAF/ PIK3CA/AKT/PTENdel mt/amplified Nl HER2,FGFR2,RON,MET Arm B5 15% MSI-H, High TMB, EBV+ Arm B6 FOLFOX -VEGFR2ab FOLFOX -1ab FOLFIRI + V FOLFIRI + 1 FOLTAX + V FOLTAX + 1

22 Case 3: Using Molecular Testing in the Clinic 45 y/o M 4/ months of back pain CBC WBC 1.1, Hb 5, Plts 5 CT bone, liver, lung, LN metastases PET uptake in stomach EGD confirmed gastric cancer - HER2 positive by FISH and IHC (heterogeneous 50% IHC3+, 50% IHC0), NGS 37 copies - Clinically should be treated as HER2+ - Two prior opinions hospice, b/c transfusion dependent plts and PRBCs - U of C Admitted, next am bone marrow biopsy confirmed tumor infiltration - started FOLFOX and transfusion support (1 wk) - Platelets started to recover - Enrolled in PANGEA clinical trial and add anti-egfr antibody per protocol: - Molecular testing EGFR amp in metastases and ctdna, no HER2 amp - Metastatic sites biopsied (LN and bone marrow): HER2-, EGFR amplified - (NGS EGFR++ 67 copies primary, EGFR copies LN) - EGFR FISH ratio 11.1 primary, 9.4 bone marrow

23 Primary gastric body tumor IHC HER2 Moderately Differentiated Tumor (positive)

24 Primary gastric body tumor IHC HER2 Poorly Differentiated Tumor (negative) IHC HER2 Moderately Differentiated Tumor (positive) Tumor Spatial Heterogeneity ~ 50:50

25 Primary gastric body tumor IHC EGFR Poorly Differentiated Tumor (positive) IHC EGFR Moderately Differentiated Tumor (Negative) Tumor Spatial Heterogeneity ~ 50:50

26 Metastatic Bone Marrow Biopsy IHC EGFR Poorly Differentiated Tumor (positive)

27 Primary tumor Gastric Body EGFR FISH Metastatic Site Bone Marrow EGFR FISH: EGFR/CEP7 Ratio: 11.1 HER2 FISH: The HER2:D17Z1 ratio is 6.9 EGFR amplification Copy Number= 67 ERBB2 amplification Copy Number= 31 EGFR FISH: EGFR/CEP7 Ratio:9.4 ERBB2 not amplified

28 PET pre/post FOLFOX-ABT-806 R hepatic tumor Primary tumor Complete Response R hepatic tumor Complete response Primary tumor PET 4/22/16 PET 8/31/16

29 GM tumor markers

30 Case GM PANGEA13: ctdna NGS FOLFOX6 1 month Enrolled in PANGEA FOLFOX6- ABT806 1 month FOLFOX6- ABT806 2 months 5FU- ABT806 2 months NED on CT 10/26/16 5FU- ABT806 2 months EGFR copy

31 Heterogeneity over time NED on CT 1/5/17 - bilateral hydronephrosis ~8 months PFS January 2017 Peritoneum Biopsied 1 Peritoneal Biopsy: HER2 negative EGFR negative KRAS amplified 37 copies

32 Diagnosis: metastatic cancer The PANGEA -IMBBP Trial Personalized ANtibodies for Gastro-Esophageal Adenocarcinoma: A Pilot 1 st Metastatic Trial of Biologics Beyond Progression Historical Control (Arm A) Biomarker Evaluation in all samples to allow for treatment assignment FOLFOX FOLFOX-T PFS 1 FOLFIRI PFS 2 FOLTAX PFS 3 6m 60% 4m 30% 2m Anticipated Incidence 20% HER2 amplified Arm B1 FOLFOX -Trastuzumab PFS 1 1 FOLFIRI + T PFS 2 2 FOLTAX + T PFS 3 7% MET amplified/hi Arm B2 FOLFOX -METab 1 FOLFIRI + M 2 FOLTAX + M ARM B: Therapy based on molecular profile 8% FGFR2 amplified Arm B3 FOLFOX 5/20% EGFR amplified/hi KRAS wild type Nl HER2,FGFR2,RON,MET Arm B4 -FGFR2ab FOLFOX -EGFRab 1 1 FOLFIRI + F FOLFIRI + EGFRab 2 2 FOLTAX + F FOLTAX + EGFRab primary mos Endpoint (N~68) 15/10% KRAS/BRAF/ PIK3CA/AKT/PTENdel mt/amplified Nl HER2,FGFR2,RON,MET Arm B5 15% MSI-H, High TMB, EBV+ Arm B6 FOLFOX -VEGFR2ab FOLFOX -1ab 1 1 FOLFIRI + V FOLFIRI FOLTAX + V FOLTAX + 1

33 Baseline Intra-patient Heterogeneity 9/28 = 32% Inter-patient Heterogeneity - prioritized algorithm 12 (23%) 5 (10%) 3 (6%) 4 (8%) 0 14 (28%) 9 (18%) 4 (8%)

34 PANGEA BIOMARKER INCIDENCES 23% 5% 15% 6% HER2 MET 18% 8% 23% 33% 4% 7% 7% FGFR2 EGFR++ MSI-High RAS/PIK3CA EGFR+ 28% 8% 6% 10% All Neg Estimated Actual to Date N= 51 Joshi et al. Personalized antibodies for gastroesophageal adenocarcinoma (PANGEA): A phase II precision medicine trial (NCT ) J Clin Oncol 36, 2018 (suppl 4S; abstr TPS198).

35 Enrollment Target N=68 ITT n= 51, 43 ITT Joshi et al. Personalized antibodies for gastroesophageal adenocarcinoma (PANGEA): A phase II precision medicine trial (NCT ) J Clin Oncol 36, 2018 (suppl 4S; abstr TPS198).

36 Primary Endpoint OS PANGEA-IMBBP.63.5 In a phase IIa pilot study 80% power, one-sided alpha 0.1, HR 0.67 (mos 18 months) Assuming historical mos is 12 months (it isn t) H 0 : 50% of patients alive at 12 months with SOC H 1 : 63% of patients alive at 12 months with PANGEA Sample size needed: 68 patients (43 alive at 12 months)

37 Primary Endpoint OS In a phase IIa pilot study 80% power, one-sided alpha 0.1, HR 0.67 (mos 18 months) Assuming historical mos is 12 months (it isn t) H 0 : 50% of patients alive at 12 months H 1 : 63% of patients alive at 12 months Sample size needed: 68 patients (43 alive at 12 months) 23/33 (70%) alive >12 months. HER2+ patients 8/9 (89%) alive >12 months. 4/6 (66.7%) HER2+ patients alive at >24 months 2 retained HER2+positive, 4 became HER2-negative MET/FGFR2+ 1/5 (20%) alive >12 months Joshi et al. Personalized antibodies for gastroesophageal adenocarcinoma (PANGEA): A phase II precision medicine trial (NCT ) J Clin Oncol 36, 2018 (suppl 4S; abstr TPS198).

38 ARM A: Standard Chemotherapy + Placebo Diagnosis: metastatic cancer The PANGEA -2MBBP Trial Personalized ANtibodies for Gastro-Esophageal Adenocarcinoma: Phase II Metastatic Biologic Beyond Progression Trial (R 2:1) Anticipated Incidence 18% Biomarker Evaluation in all samples prior to randomization R 2:1 HER2 amplified Standard care: Control Arm Stratify: i) Stage ii) PS iii) Biomarker iv) GEJ v distal stomach vi) Site of metastases Arm B1 FOLFOX + placebo Arm A1: HER2 amplified FOLFOX-Traztuzumab Arm A2: MET amplified/hi Arm A3: FGFR2 amplified Arm A4: KRAS/PI3K wild type Arm A5: KRAS/BRAF/PIK3CA mt/amp Arm A6: MSI-H, High TMB, EBV+, L1+ FOLFOX -Trastuzumab PFS 1 FOLFIRI PFS 2 FOLTAX PFS 3 + Ram + placebo PFS 1 Primary Endpoint: OS (HR 0.67) i) Arm A v B (N=192, 128-B:64-A ) ii)arm A x v B x FOLFIRI + T PFS 2 FOLTAX + T PFS 3 ARM B: Therapy based on molecular profile 7% 7% 7% 33% 28% MET amplified/hi FGFR2 amplified EGFR/HER3 amplified/hi KRAS wild type Nl HER2,FGFR2,RON,MET KRAS/BRAF/ PIK3CA/AKT/PTENdel mt/amplified Nl HER2,FGFR2,RON,MET MSI-H, High TMB, EBV+, L1+ Arm B2 Arm B3 Arm B4 Arm B5 Arm B6 FOLFOX -METab FOLFOX -FGFR2ab FOLFOX -EGFRab FOLFOX -VEGFR2ab FOLFOX --1ab FOLFIRI + M FOLFIRI + F FOLFIRI + E FOLFIRI + V FOLFIRI + 1 FOLTAX + M FOLTAX + F FOLTAX + E FOLTAX + V FOLTAX + 1 primary mos Endpoint (N~192 68:128)

39 Current trials for Intrahepatic Cholangio previously treated (2L or 3L) Phase 3: AG-120/placebo for IDH1 mutated IHCC (20-25%) Phase 2a: INCB for FGFR2 fusion (15%) Geynisman, Catenacci. Towards Personalized Therapy for Advanced Biliary Cancer. Discov Med 2011 Ross et al. New Routes to Targeted Therapy of IHCC Revealed by NGS. The Oncologist

40 A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of AG-120 in Previously Treated Subjects with Nonresectable or Metastatic Cholangiocarcinoma with an IDH1 Mutation Gain of Function Mts Glioma Chondosarcoma AML IHCC 40

41 A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of AG-120 in Previously Treated Subjects with Nonresectable or Metastatic Cholangiocarcinoma with an IDH1 Mutation PI: Daniel Catenacci, MD N = 186 patients Eligibility: Metastatic IHCC or unresectable IHCC 2L or 3L therapy IDH1 mutation Screen for IDH1 mutation centrally confirmed R A N D O M I Z E 2:1 AG mg PO BID Primary endpoint: PFS Target HR 0.5 Placebo (Crossover)

42 FGFR2 Fusions DNA NGS ok, but RNA NGS more sensitive Geynisman, Catenacci. Towards Personalized Therapy for Advanced Biliary Cancer. Discov Med 2011 Ross et al. New Routes to Targeted Therapy of IHCC Revealed by NGS. The Oncologist 2014

43 A Phase 2, Open-Label, Single-Arm, Multicenter Study to Evaluate the Efficacy and Safety of INCB in Subjects With Advanced/Metastatic or Surgically Unresectable Cholangiocarcinoma Including FGFR2 Translocations Who Failed Previous Therapy PI: Daniel Catenacci, MD Expansion to n=100 Randomized Phase III 1L R 1:1 vs Gem/Cis N=434 PFS primary endpoint n=60 n=20 n=20

44 BGJ398 in Patients With FGFR-Altered Advanced Cholangiocarcinoma N=61 Javle et al. Phase II Study of BGJ398 in Patients With FGFR-Altered Advanced Cholangiocarcinoma. JCO 2017

45 Acknowledgments GI Oncology Manish Sharma, MD Hedy Kindler, MD Blase Polite, MD Chih-Yi (Andy) Liao, MD Personalized Cancer Care Consortium Walter Stadler, MD Mary Sherrell, MA Steven Maron, MD 45