Addressing Tumor Molecular Heterogeneity using A Novel Clinical Trial Design - PANGEA

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1 Addressing Tumor Molecular Heterogeneity using A Novel Clinical Trial Design - PANGEA Daniel Catenacci, MD Assistant Professor of Medicine Associate Director GI Oncology Program May 12, 2017

2 Addressing Molecular Heterogeneity Gastroesophageal Cancer Next-Generation Companion Diagnostics & Next-Generation Trials Molecular Drivers Oncogene Addiction Inter-patient Heterogeneity Intra-patient Heterogeneity Classic Companion Diagnostics Classic Biomarker-Driven Trials Next-Gen Companion Diagnostics Next-Gen Clinical Trial Designs

3 Addressing Molecular Heterogeneity Gastroesophageal Cancer Next-Generation Companion Diagnostics & Next-Generation Trials Molecular Drivers Oncogene Addiction Inter-patient Heterogeneity Intra-patient Heterogeneity Classic Companion Diagnostics Classic Biomarker-Driven Trials Next-Gen Companion Diagnostics Next-Gen Clinical Trial Designs

4 The Gastroesophageal Nomenclature Diaphragm Esophagus Esophagogastric Junction (EGJ) Cardia Lesser curvature Angular notch (incisura angularis) Pylorus Duodenum TYPE I Pyloric Antrum TYPE II TYPE III Gastric Body or 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 D. Discov Med 2013

5 Gastroesophageal Adenocarcinoma Epidemiology US 2010 Gastric Cancer 26,370 new cases/year 10,730 deaths/year Esophageal Cancer (70% EGJ Adenocarcinoma) 16,940 new cases/year EGJ 400% increase in the last decades 15,690 deaths/year Kris et al. J Clin Oncol. Dec, 2010; Worldwide Gastroesophageal Cancer 2012: >1,000,000 deaths/year 3 rd cancer incidence 2 nd cancer death Ferlay et al. Int J Can. 2014;

6 First Line Management of Advanced Gastroesophageal Cancer 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 mos Months BSC = best supportive care; MTX = methotrexate; S = S-1; A = doxorubicin F = 5-FU; C/P = cisplatin; I = irinotecan; E = epirubicin; O = oxaliplatin; D = docetaxel 1. 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 ONC 2016 FOLFOX FOLFIRI FOLTAX

7 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 X/FP+/-T 10 HER2 (+) HER2 IHC3+ or IHC2+/FISH+ HER2 IHC3+/FISH+ +T +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. JCO Abstr 4012 ASCO Bang et al. Lancet 2010.

8 Molecular Phenotyping- Solid Tumors Next-Generation Companion Diagnostics & Next-Generation Trials Molecular Drivers Oncogene Addiction Inter-patient Heterogeneity Intra-patient Heterogeneity Classic Companion Diagnostics Classic Biomarker-Driven Trials Next-Gen Companion Diagnostics Next-Gen Clinical Trial Designs

9 Addressing Molecular Heterogeneity Next-Generation Companion Diagnostics & Next-Generation Trials Molecular Drivers Oncogene Addiction Inter-patient Heterogeneity Intra-patient Heterogeneity Classic Companion Diagnostics Classic Biomarker-Driven Trials Next-Gen Companion Diagnostics Next-Gen Clinical Trial Designs

10 How Gene Alterations Can Cause Cancer DNA Transcription RNA Translation protein ALTERED GENES ALTERED PROTEINS ALTERED PATHWAYS RAS Code for RAF CDKN2a RAS PTEN MAPK Resulting in RAF mtor AKT MAPK CANCER 11

11 Addressing Molecular Heterogeneity Next-Generation Companion Diagnostics & Next-Generation Trials Molecular Drivers Oncogene Addiction Inter-patient Heterogeneity Intra-patient Heterogeneity Classic Companion Diagnostics Classic Biomarker-Driven Trials Next-Gen Companion Diagnostics Next-Gen Clinical Trial Designs

12 Inter-Patient Tumor Heterogeneity Catenacci D. Next-generation clinical trials: Novel strategies to address the challenge of tumor molecular heterogeneity. Molecular Oncology 2014

13 Mutation Profile: Targeted Multiplex Inter-patient Heterogeneity 1. TP53 mt, ARID1A mt 2. TP53 mt, APC mt 3. MET amp+, TP53 mt, NOTCH1 mt 4. FGFR2 amp+, TP53 mt, E-cadherin mt 5. KRAS amp+, TP53 mt, CDKN2A/B mt 6. PI3KCA mt, PTCH1 mt, MLH1 mt, MSH1 mt 7. HER2 amp+, SRC amp+, TOP1 amp+ 8. HER2 amp+, KRAS amp+, AKT amp+, CCNE1 amp+, CCND1 amp+, MCL1 amp+ 9. TP53 mt, PIK3CA mt, CTNNB1 mt, SMAD4 mt 10. IGF1R amp+ 11. CEBPA mt 12. MET amp+ 13. HER2 amp+, PIK3CAmt, PTEN mt, CDK6 amp, TP53 mt 14. MDM2 amp+ 15. CDH1 mt 16. Src amp+, AURKA amp+, CCND1 amp+, CDK4 amp+, RICTOR amp+, CDKN2A/B loss, ATM mt

14 Mutation Profile: Targeted Multiplex Inter-patient Heterogeneity 1. TP53 mt, ARID1A mt 2. TP53 mt, APC mt 3. MET amp+, TP53 mt, NOTCH1 mt 4. FGFR2 amp+, TP53 mt, E-cadherin mt 5. KRAS amp+, TP53 mt, CDKN2A/B mt 6. PI3KCA mt, PTCH1 mt, MLH1 mt, MSH1 mt 7. HER2 amp+, SRC amp+, TOP1 amp+ 8. HER2 amp+, KRAS amp+, AKT amp+, CCNE1 amp+, CCND1 amp+, MCL1 amp+ 9. TP53 mt, PIK3CA mt, CTNNB1 mt, SMAD4 mt 10. IGF1R amp+ 11. EGFR amp+, CEBPA mt 12. MET amp+ 13. HER2 amp+, PIK3CAmt, PTEN mt, CDK6 amp, TP53 mt 14. MDM2 amp+ 15. CDH1 mt 16. Src amp+, AURKA amp+, CCND1 amp+, CDK4 amp+, RICTOR amp+, CDKN2A/B loss, ATM mt

15 Addressing Molecular Heterogeneity Next-Generation Companion Diagnostics & Next-Generation Trials Molecular Drivers Oncogene Addiction Inter-patient Heterogeneity Intra-patient Heterogeneity Classic Companion Diagnostics Classic Biomarker-Driven Trials Next-Gen Companion Diagnostics Next-Gen Clinical Trial Designs

16 Baseline Spatial Heterogeneity Revealed by Multi-site NGS Sequencing Pectasides Catenacci. Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma in review

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

18 Addressing Molecular Heterogeneity Next-Generation Companion Diagnostics & Next-Generation Trials Molecular Drivers Oncogene Addiction Inter-patient Heterogeneity Intra-patient Heterogeneity Classic Companion Diagnostics Classic Biomarker-Driven Trials Next-Gen Companion Diagnostics Next-Gen Clinical Trial Designs

19 Tumor Heterogeneity: Inter-patient!! How to characterize economically? Stricker, Catenacci, Seiwert. Semin Oncol 2011

20 Addressing Molecular Heterogeneity Next-Generation Companion Diagnostics & Next-Generation Trials Molecular Drivers Oncogene Addiction Inter-patient Heterogeneity Intra-patient Heterogeneity Classic Companion Diagnostics Classic Biomarker-Driven Trials Next-Gen Companion Diagnostics Next-Gen Clinical Trial Designs

21 Classic Biomarker-Driven Clinical Trial Designs Retrospective - prospective Biomarker-stratified Biomarker population enriched Catenacci D. Next-generation clinical trials: Novel strategies to address the challenge of tumor molecular heterogeneity. Molecular Oncology 2014

22 Predictive Prognostic Catenacci D. Next-generation clinical trials: Novel strategies to address the challenge of tumor molecular heterogeneity. Molecular Oncology 2014

23 Biomarker-stratified Predictive Prognostic Catenacci D. Next-generation clinical trials: Novel strategies to address the challenge of tumor molecular heterogeneity. Molecular Oncology 2014

24 Biomarker population enriched Catenacci D. Next-generation clinical trials: Novel strategies to address the challenge of tumor molecular heterogeneity. Molecular Oncology 2014

25 Biomarker population enriched eg. TOGA trial HER2 amp+ Screened 4000 patients To get 584 (~20% positive rate) (and this had ~130 HER2- pts) Catenacci D. Next-generation clinical trials: Novel strategies to address the challenge of tumor molecular heterogeneity. Molecular Oncology 2014

26 Biomarker population enriched eg. Phase I expansions PIK3CA mt Catenacci D. Next-generation clinical trials: Novel strategies to address the challenge of tumor molecular heterogeneity. Molecular Oncology 2014

27 Addressing Molecular Heterogeneity Next-Generation Companion Diagnostics & Next-Generation Trials Molecular Drivers Oncogene Addiction Inter-patient Heterogeneity Intra-patient Heterogeneity Classic Companion Diagnostics Classic Biomarker-Driven Trials Next-Gen Companion Diagnostics Next-Gen Clinical Trial Designs

28 How do we molecularly profile? Now NGS (DNA/RNA), MS Stricker, Catenacci, Seiwert. Semin Oncol 2011

29 Next-Generation Diagnostics: NGS for Inter-Patient Tumor Heterogeneity NGS can also provide: MSI status Mutations/Mb >19mt/Mb Implications for immunotherapy Khoury, Catenacci. Next-Generation Companion Diagnostics: Promises, Challenges, and Solutions. Arch Pathol Lab Med 2015.

30 Next-Generation Diagnostics: Liquid Biopsy ctdna NGS for Intra-Patient Tumor Heterogeneity Khoury, Catenacci. Next-Generation Companion Diagnostics: Promises, Challenges, and Solutions. Arch Pathol Lab Med 2015.

31 Next-Generation Diagnostics: Mass Spec for Inter-Patient Tumor Heterogeneity Khoury, Catenacci. Next-Generation Companion Diagnostics: Promises, Challenges, and Solutions. Arch Pathol Lab Med 2015.

32 Addressing Molecular Heterogeneity Next-Generation Companion Diagnostics & Next-Generation Trials Molecular Drivers Oncogene Addiction Inter-patient Heterogeneity Intra-patient Heterogeneity Classic Companion Diagnostics Classic Biomarker-Driven Trials Next-Gen Companion Diagnostics Next-Gen Clinical Trial Designs

33 Next-Generation Clinical Trial Designs Exploratory Platform Expansion Platform Type IA Global /Compartmentalized Histology Dependent Expansion Platform Type IB Global /Compartmentalized Histology Agnostic Expansion Platform Type IIA Grass-roots /Holistic Expansion Platform Type IIB Grass-roots Histology Dependent Without Biologic Beyond Progression With Biologic Beyond Progression Histology Agnostic Catenacci D. Next-generation clinical trials: Novel strategies to address the challenge of tumor molecular heterogeneity. Molecular Oncology 2014

34 Exploratory Platform Eg. I-SPY, BATTLE Umbrella: Biomarker Stratified (if control included) Catenacci D. Molecular Oncology 2014

35 Expansion Platform Type IA Global/Compartmentalized eg. FOCUS - Colon Umbrella: Population Enriched Catenacci D. Next-generation clinical trials: Novel strategies to address the challenge of tumor molecular heterogeneity. Molecular Oncology 2014

36 Expansion Platform Type IB Global/Compartmentalized Histology Agnostic eg ( NCI-MATCH, Signature ) How? With different tumor types? Umbrella: Population Enriched Catenacci D. Next-generation clinical trials: Novel strategies to address the challenge of tumor molecular heterogeneity. Molecular Oncology 2014

37 Expansion Platform Type IIA Grass-Roots/Holistic eg. PANGEA - GEC IIA Catenacci D. Molecular Oncology 2014

38 Expansion Platform Type IIA with biologic beyond progression (BBP) eg. PANGEA - BBP IIA- INTER-PATIENT HETEROGENIETY Intrapatient - space 1 0 v Met - over time Regulatory Challenge -because multiple : Biomarkers Assays Drugs Lines NEW/Different INTRA-PATIENT HETEROGENIETY Catenacci D. Next Generation Clinical Trials: Strategies to Address Tumor Molecular Heterogeneity. Molecular Oncology 2014 Catenacci D. Expansion Platform Design Type II: Testing a Treatment Strategy. Lancet Oncol 2015.

39 Catenacci D. Expansion Platform Design Type II: Testing a Treatment Strategy. Lancet Oncol Expansion Platform Type IIB Grass-Roots/Holistic eg. SHIVA IIB- Agnostic SHIVA: 10 treatment groups No placebo MD choice N= (67%) profiled 195 (26%) fit Randomized 99 vs 96 NEGATIVE for PFS! Le Tourneau et al. Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA). Lancet Oncol 2015.

40 Catenacci D. Molecular Oncology 2014

41 One size fits all PANGEA N of 1 Individualized therapy

42 Inter-patient Heterogeneity - prioritized algorithm Intra-patient Heterogeneity - through space 1 0 vs Metastases - over time (resistance)

43 van Hagen P et al. N Engl J Med 2012;366: Hazard Ratios for Death. Forrest Plot

44 Subgroup Expansion Platform Type II Treatment All Patients (ITT) Personalized Z Tx A B C Z Y X Z Z Z D E Biomarker groups W Z V Z F G H U T S Z Z Z Personalized New Tx Z Tx Better Standard Tx Better

45 Subgroup All Patients (ITT) HER2++ MET++ FGFR2++ EGFR++ MSI-H/EBV+ KRAS++ MET+ PANGEA Treatment Personalized Tx HER2-Ab MET-Ab FGFR2-Ab EGFR-Ab PD1-Ab VEGFR2-Ab MET-Ab EGFR+ EGFR-Ab VEGFR2+ Personalized Tx Better Standard Tx Better VEGFR2-Ab

46 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 PFS 1 FOLFIRI PFS 2 FOLTAX PFS 3 6m 60% 4m 30% 2m Diagnosis: metastatic cancer Biomarker Evaluation in all samples to allow for treatment assignment Dose finding phase Ib lead in Anticipated Incidence 20% HER2 amplified Arm B1 FOLFOX -Trastuzumab PFS 1 PD1 FOLFIRI + T PFS 2 PD2 FOLTAX + T PFS 3 7% MET amplified/hi Arm B2 FOLFOX -METab PD1 FOLFIRI + M PD2 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 PD1 PD1 FOLFIRI + F FOLFIRI + EGFRab PD2 PD2 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 -PD1ab PD1 PD1 FOLFIRI + V FOLFIRI + PD1 PD2 PD2 FOLTAX + V FOLTAX + PD1

47 Inter-patient Heterogeneity - prioritized algorithm Baseline Intra-patient Heterogeneity 9/28 = 32%

48 Enrollment

49 ORR ITT (excluding MET++/FGFR2++) Biomarker group N=15 HER /15 87% ORR EGFR++ 2 MSI-H 1 16/16 100% DCR VEGFR2++ 3 EGFR+ 1 VEGFR2+ 1 (not eval-->peritoneal dz not measurable) 15

50 ORR 1 and DCR 1 ITT plan 68 patients (all treated with biologic therapy) Interim analysis at 30% of enrolled patients ORR All pts evaluable for ORR ORR = 16/20 80% Historic ORR = 30-45% Of those treated with ORR = 13/15 87% biologic therapy: Of those NOT treated ORR = 3/5 60% with biologic therapy (ie MET/FGFR2+): Historic ORR by HER2 + vs - ORR by HER2 HER2+ pts per PANGEA ORR HER2+ 8/8 100% HER2+ = 47% (TOGA), vs 35% chemo alone) HER2- pts per PANGEA ORR HER2-8/ % HER2- = 30-40% (METGASTRIC, FOLFOX-placebo 40% in HEr2- pts) Of those treated with ORR HER2-5/7 71% biologic therapy: Of those NOT treated ORR HER2-3/5 60% with biologic therapy: (ie MET/FGFR2+) DCR Of those treated with DCR 16/16 DCR = 100% Historic DCR = 60-70% biologic therapy: Of those NOT treated DCR 5/5 100% with biologic therapy: (ie MET/FGFR2+)

51 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) 10/13 (77%) alive 12 months.

52 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 15% Biomarker Evaluation in all samples prior to randomization R 2:1 HER2 amplified Standard care: Control Arm 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+ Stratify: i) Stage ii) PS iii) Biomarker iv) GEJ v distal stomach vi) Site of metastases Arm B1 FOLFOX -Trastuzumab PFS 1 FOLFIRI PFS 2 FOLTAX PFS 3 + placebo + placebo PFS 1 PD Primary Endpoint: OS (HR 0.67) i) Arm A v B (N=192, 128-B:64-A ) ii)arm A x v B x Secondary Endpoints: PFS 1,2,3, PFS 1+2+3, 2 nd /3 rd line rates RR, toxicity, Arm A 1 v A 2, B 1 v B 2 etc Tissue correlates FOLFIRI + T PFS 2 PD FOLTAX + T PFS 3 20% MET amplified/hi Arm B2 FOLFOX -METab PD FOLFIRI + M PD FOLTAX + M ARM B: Therapy based on molecular profile 5% 20% FGFR2 amplified EGFR/HER3 amplified/hi KRAS wild type Nl HER2,FGFR2,RON,MET Arm B3 Arm B4 FOLFOX -FGFR2ab FOLFOX -EGFRab PD PD FOLFIRI + F FOLFIRI + E PD PD FOLTAX + F FOLTAX + E primary mos Endpoint (N~192) 25% 15% KRAS/BRAF/ PIK3CA/AKT/PTENdel mt/amplified Nl HER2,FGFR2,RON,MET MSI-H, High TMB, EBV+ Arm B5 Arm B6 FOLFOX -VEGFR2ab FOLFOX -PD-1ab PD PD FOLFIRI + V FOLFIRI + PD1 PD PD FOLTAX + V FOLTAX + PD1

53 Addressing Molecular Heterogeneity Gastroesophageal Cancer Next-Generation Companion Diagnostics & Next-Generation Trials Molecular Drivers Oncogene Addiction Inter-patient Heterogeneity Intra-patient Heterogeneity Classic Companion Diagnostics Classic Biomarker-Driven Trials Next-Gen Companion Diagnostics Next-Gen Clinical Trial Designs

54 Thank you!