1 / 48

Daniel Catenacci , MD Assocaite Professor of Medicine Director GI Oncology Program

Daniel Catenacci , MD Assocaite Professor of Medicine Director GI Oncology Program. April 26, 2018. Next-generation precision oncology trials. Next-generation precision oncology trials. Gastroesophageal Adenocarcinoma. Molecular Heterogeneity,

doane
Download Presentation

Daniel Catenacci , MD Assocaite Professor of Medicine Director GI Oncology Program

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Daniel Catenacci, MD AssocaiteProfessor of Medicine Director GI Oncology Program April 26, 2018 Next-generation precision oncology trials

  2. Next-generation precision oncology trials Gastroesophageal Adenocarcinoma Molecular Heterogeneity, Molecular Evolution, & Implications in the Clinic Testing A Treatment Strategy - PANGEA Inter-patient Heterogeneity Intra-patient Heterogeneity PANGEA Updates & Clinical Vignettes

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

  4. Gastroesophageal Adenocarcinoma (GEA)Epidemiology US 2015 Gastric Cancer 24,590 new cases/year 10,720 deaths/year Esophageal Cancer(70% EGJ Adenocarcinoma) 16,980 new cases/year EGJ 400% increase in last decades 15,590 deaths/year Seigelet al. Ca Cancer J Clin 2015; www.cancer.org. Worldwide Gastroesophageal Cancer 2018: • All Cancer: 18,078,957 incidence; 9,555,027 deaths • GEC: 1,605,735 incidence; 1,292270 deaths • (13% of all cancer deaths) • 3rd cancer incidence • 2nd cancer death Bray et al. Ca Cancer J Clin 2018; Fitzmaurice et al. JAMA ONC. 2018; www.cancer.org

  5. First Line Management of Advanced Gastroesophageal Cancer BSC 1 mOS = ~10-11m 1yr OS = ~40% 2yr OS = ~15-20% 5yr OS < ~2% 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 0 2 4 6 8 10 12 • Murad, et al. Cancer 1993 2. Vanhoefer, et al. JCO 20003. Ajani, et al. ASCO 2009 4. Van Cutsem, et al. JCO 2006 • 5. Dank, et al. Ann Oncol 2008 • 6. Cunningham, et al. NEJM 2008 7. Kang, et al. Ann Oncol 2009 • 8. Guimbaud, et al. JCO 2014 • 9. Shah, et al. JAMA ONC 2016 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

  6. EGA:Molecular Heterogeneity N=100 50% 9% TCGA MSI-H EBV+ CIN GS Interpatient 22% 20% Intrapatient baseline temporal Catenacci DVT. Next-generation clinical trials: Novel strategies to address the challenge of tumor molecular heterogeneity. Molecular Oncology 2014

  7. Mutation Profile: Targeted MultiplexInter-patient Heterogeneity • TP53 mt, ARID1A mt • TP53 mt, APC mt • MET amp+, TP53 mt, NOTCH1 mt • FGFR2 amp+, TP53 mt, E-cadherin mt • KRAS amp+, TP53 mt, CDKN2A/B mt • PI3KCA mt, PTCH1 mt, MLH1 mt, MSH1 mt • HER2 amp+, SRC amp+, TOP1 amp+ • HER2 amp+, KRAS amp+, AKT amp+, CCNE1 amp+, CCND1 amp+, MCL1 amp+ • TP53 mt, PIK3CA mt, CTNNB1 mt, SMAD4 mt • IGF1R amp+ • EGFR amp+, CEBPA mt • MET amp+ • HER2 amp+, MET amp+, PIK3CAmt, PTEN mt, CDK6 amp, TP53 mt • MDM2 amp+ • CDH1 mt • Src amp+, AURKA amp+, CCND1 amp+, CDK4 amp+, RICTOR amp+, CDKN2A/B loss, ATM mt

  8. Mutation Profile: Targeted MultiplexInter-patient Heterogeneity • TP53 mt, ARID1A mt • TP53 mt, APC mt • MET amp+, TP53 mt, NOTCH1 mt • FGFR2 amp+, TP53 mt, E-cadherin mt • KRAS amp+, TP53 mt, CDKN2A/B mt • PI3KCA mt, PTCH1 mt, MLH1 mt, MSH1 mt • HER2 amp+, SRC amp+, TOP1 amp+ • HER2 amp+, KRAS amp+, AKT amp+, CCNE1 amp+, CCND1 amp+, MCL1 amp+ • TP53 mt, PIK3CA mt, CTNNB1 mt, SMAD4 mt • IGF1R amp+ • EGFR amp+, CEBPA mt • MET amp+ • HER2 amp+, MET amp+, PIK3CAmt, PTEN mt, CDK6 amp, TP53 mt • MDM2 amp+ • CDH1 mt • Src amp+, AURKA amp+, CCND1 amp+, CDK4 amp+, RICTOR amp+, CDKN2A/B loss, ATM mt

  9. 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+/-T10 HER2 (+) +T X/FP+/-T10 HER2 IHC3+ or IHC2+/FISH+ HER2 IHC3+/FISH+ +T X/FP+/-T10 mOS Months 16 0 2 4 6 8 10 12 14 18 • Murad, et al. Cancer 1993 2. Vanhoefer, et al. JCO 2000 3. Ajani, et al. ASCO 2009 4. Van Cutsem, et al. JCO 2006 5. Dank, et al. Ann Oncol 2008 6. Cunningham, et al. NEJM 2008 7. Kang, et al. Ann Oncol 2009 8. Guimbaud, et al. JCO 2014 9. Shah et al. JAMA Oncol 2016. 10. Bang et al. Lancet 2010.

  10. GEA Clinical Summary • Many Molecular Targets • HER2, EGFR, FGFR2, MET, PD1/L1 (PDL1: MSI-H, TMB, EBV, ?) • others…claudin, lag3, etc • Small subsets within GEA • Inter and Intrapatient Heterogeneity

  11. GEA Standard Therapy • Cytotoxics: 5FU, platinum, irinotecan, taxane, TAS102 1L (FOLFOX)  2L (FOLFIRI)  3L (FOLTAX) 4L (TAS102) • Few targeted therapies incorporated into routine care: Marker Incidence Treatment Therapy Line Approval Benefit HER2++ ~15% Chemo+Trastuzumab 1L 2010 HR 0.65 none 100% Chemo+Ramucirumab 2L 2014/15 HR 0.8 MSI-High ~2-3% Pembrolizumab 2L+ 2017*HR? (great) PDL1+ >1% ~50-60% Pembrolizumab 3L+ 2017 * HR? (marginal) * Conditional approvals MANY NEGATIVE ‘TARGETED/IO’ STUDIES!!

  12. Quantifying & Addressing Tumor Molecular Heterogeneity To Improve Clinical Outcomes2008-13: Designing the PANGEA clinical trial ADCC & Specific Less Molecular Chaos Preserved PS • Optimize chemotherapy & targeted therapy • “OPTIMOX/OPTIMIRI/OPTITAX” Cytotoxic plus: • Introduce targeted monoclonal antibody therapies into early care • Optimally molecularly profile & group patients • Inter-Patient Heterogeneity (NGS) • Match a targeted biologic to predefined biomarker groups by prioritized algorithm • Intra-Patient Baseline Spatial Heterogeneity • Group by metastatic disease site if discordant • ctDNA? • Intra-Patient Temporal Heterogeneity • Re-profiling growing/resistant tumors and re-assign therapy • ctDNA? • Test a Personalized Treatment Strategy Compared to Control Personalized ANtibodies for GastroEsophagealAdenocarcinoma: PANGEA Address Small Subsets & multiple concurrent events Address Optimal Target: Baseline Address Optimal Target:Serially

  13. IIA- Expansion Platform Type IIA – with biologic beyond progression (BBP)eg. ‘PANGEA - BBP’ INTER-PATIENT HETEROGENIETY Baseline Intrapatient Heterogeneity - space 10 v Met - over time Temporal INTRA-PATIENT HETEROGENIETY • Regulatory Challenge • -because multiple : • Biomarkers • Assays • Lines • Drugs • NEW/Different 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.

  14. Hazard Ratios for Death. van Hagen P et al. N Engl J Med 2012;366:2074-2084. Forrest Plot

  15. Classic Clinical Trial Design Expansion Platform Type II Subgroup Treatment All Patients (ITT) Z Personalized Tx A Z Z Z B Y C X Z D Z W Biomarker groups E Z V F U Z One Histology Multiple Genetic events Multiple Drugs One Treatment Strategy One Histology Multiple Genetic Events One Drug G T Z H S Z Personalized Tx Better New Tx “Z” Better Standard Tx Better Catenacci D. Expansion Platform Design Type II: Testing a Treatment Strategy. Lancet Oncol 2015.

  16. PANGEA Subgroup Treatment Standard Stats Apply Phase IIa Phase IIb Phase III All Patients (ITT) Personalized Tx HER2++ HER2-Ab MET++ MET-Ab FGFR2++ FGFR2-Ab EGFR++ EGFR-Ab MSI-H/EBV+/TMB-H/PDL1++ PD1-Ab KRAS++ VEGFR2-Ab MET+ MET-Ab EGFR+ EGFR-Ab VEGFR2+ VEGFR2-Ab Personalized Tx Better Standard Tx Better Etc… Etc…

  17. Phase IIa Multiple Histologies One Genetic event: MSI-H One Drug MSI-H 5/2017 Presented by: Le et al. Science 2017

  18. Primary Endpoint OS PANGEA-IMBBP • 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 = ~10-11m) • H0: 50% of patients alive at 12 months with SOC • H1: 63% of patients alive at 12 months with PANGEA • Sample size needed: 68 patients (43 alive at 12 months) .63 .5 0 12 18 6

  19. Inter-PatientTumorHeterogeneity PANGEA concept groundwork 2008-2013 Catenacci et al.

  20. Bioinformatics/AI N of 1 Individualized therapy One size fits all PANGEA 

  21. A Compromise Between Number of Potential Treatment Groups and Feasibility Treatment assignment % Anticipated Incidence

  22. Spatial Heterogeneity Revealedby 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. 2018 Jan;8(1):37-48. doi: 10.1158/2159-8290.CD-17-0395. Epub 2017 Oct 4.

  23. PANGEA Case 3: Applying Molecular Testing in the Clinic • 45 y/o M – • 4/2016 2 months of back pain  CBC WBC 1.1, Hb 5, Plts 5 • CT – bone, liver, lung, peritoneum, 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

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

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

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

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

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

  29. The PANGEA -IMBBP TrialPersonalized ANtibodies for Gastro-Esophageal Adenocarcinoma: A Pilot 1stMetastatic Trial of Biologics Beyond Progression Historical Control (Arm A) FOLFOX FOLFOX-T PFS1 FOLFIRI PFS2 PFS3 FOLTAX 60% 30% 6m 2m 4m Biomarker Evaluation in all samples to allow for treatment assignment Patient Case 3 EGFR amplified Diagnosis: metastatic cancer PFS3 PFS2 Anticipated Incidence PFS1 FOLFOX -Trastuzumab FOLFIRI + T FOLTAX + T Arm B1 PD PD 20% HER2 amplified FOLFIRI + M FOLFOX -METab FOLTAX + M Arm B2 MET amplified/Hi 7% PD PD FOLFOX -FGFR2ab Arm B3 FOLFIRI + F FOLTAX + F FGFR2 amplified 8% PD PD ARM B: Therapy based on molecular profile primary mOS Endpoint (N~68) EGFR amplified/Hi KRAS wild type Nl HER2,FGFR2,RON,MET FOLFIRI + EGFRab FOLFOX -EGFRab Arm B4 PD PD FOLTAX + EGFRab 7/18% KRAS/BRAF/ PIK3CA/AKT/PTENdel mt/amplified Nl HER2,FGFR2,RON,MET FOLFOX -VEGFR2ab FOLFIRI + V FOLTAX + V PD PD 15/10% Arm B5 FOLFOX -PD1ab FOLFIRI + PD1 FOLTAX + PD1 PD PD 15% MSI-H, High TMB, EBV+ Arm B6

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

  31. GM tumor markers

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

  33. NED on CT 10/26/16 Enrolled in PANGEA Case GM PANGEA13: ctDNA NGS 5FU- ABT806 2 months FOLFOX6 1 month 5FU- ABT806 2 months FOLFOX6- ABT806 1 month FOLFOX6- ABT806 2 months EGFR copy +++ 40.94 0 0 ++ 2.63

  34. Heterogeneity over time NED on CT 1/5/17 - bilateral hydronephrosis PD1 Primary Tumor Biopsy: HER2 positive EGFR negative KRAS negative PD1 Peritoneal Biopsy: HER2 negative EGFR negative KRAS amplified 37 copies ~8 months PFS January 2017 Peritoneum PD Biopsied…

  35. The PANGEA -IMBBP TrialPersonalized ANtibodies for Gastro-Esophageal Adenocarcinoma: A Pilot 1stMetastatic Trial of Biologics Beyond Progression Historical Control (Arm A) FOLFOX FOLFOX-T PFS1 FOLFIRI PFS2 PFS3 FOLTAX 60% 30% 6m 4m 2m Biomarker Evaluation in all samples to allow for treatment assignment Diagnosis: metastatic cancer PFS3 PFS2 Anticipated Incidence PFS1 FOLFOX -Trastuzumab FOLFIRI + T FOLTAX + T Arm B1 PD1 PD2 20% HER2 amplified FOLFIRI + M FOLFOX -METab FOLTAX + M Arm B2 MET amplified/Hi 7% PD1 PD2 FOLFOX -FGFR2ab Arm B3 FOLFIRI + F FOLTAX + F FGFR2 amplified 8% PD1 PD2 ARM B: Therapy based on molecular profile primary mOS Endpoint (N~68) EGFR amplified/Hi KRAS wild type Nl HER2,FGFR2,RON,MET FOLFIRI + EGFRab FOLFOX -EGFRab Arm B4 FOLTAX + EGFRab 5/20% PD1 PD2 KRAS/BRAF/ PIK3CA/AKT/PTENdel mt/amplified Nl HER2,FGFR2,RON,MET FOLFOX -VEGFR2ab FOLFIRI + V FOLTAX + V PD1 PD2 15/10% Arm B5 FOLFOX -PD1ab FOLFIRI + PD1 FOLTAX + PD1 PD1 PD2 15% MSI-H, High TMB, EBV+ Arm B6

  36. The PANGEA -IMBBP TrialPersonalized ANtibodies for Gastro-Esophageal Adenocarcinoma: A Pilot 1stMetastatic Trial of Biologics Beyond Progression Historical Control (Arm A) FOLFOX FOLFOX-T PFS1 FOLFIRI PFS2 PFS3 FOLTAX 60% 30% 6m 4m 2m Biomarker Evaluation in all samples to allow for treatment assignment PANGEA Patient Example EGFR++FGFR2++KRASmt Diagnosis: metastatic cancer PFS3 PFS2 Anticipated Incidence PFS1 FOLFOX -Trastuzumab FOLFIRI + T FOLTAX + T Arm B1 PD1 PD2 20% HER2 amplified FOLFIRI + M FOLFOX -METab FOLTAX + M Arm B2 MET amplified/Hi 7% PD1 PD2 FOLFOX -FGFR2ab Arm B3 FOLFIRI + F FOLTAX + F FGFR2 amplified 8% PD1 PD2 ARM B: Therapy based on molecular profile EGFR amplified/Hi KRAS wild type Nl HER2,FGFR2,RON,MET FOLFIRI + E FOLFOX -EGFRab Arm B4 FOLTAX + E 5/20% PD1 PD2 KRAS/BRAF/ PIK3CA/AKT/PTENdel mt/amplified Nl HER2,FGFR2,RON,MET FOLFOX -VEGFR2ab FOLFIRI + V FOLTAX + V PD1 PD2 15/10% Arm B5 FOLFOX -PD1ab FOLFIRI + P FOLTAX + P PD1 PD2 15% MSI-H, High TMB, EBV+ Arm B6

  37. The PANGEA -IMBBP TrialPersonalized ANtibodies for Gastro-Esophageal Adenocarcinoma: A Pilot 1stMetastatic Trial of Biologics Beyond Progression Historical Control (Arm A) FOLFOX FOLFOX-T PFS1 FOLFIRI PFS2 PFS3 FOLTAX 60% 30% 6m 4m 2m Biomarker Evaluation in all samples to allow for treatment assignment PANGEA60 Patient Example EGFR++HER2++ Diagnosis: metastatic cancer PFS3 PFS2 Anticipated Incidence PFS1 FOLFOX -Trastuzumab FOLFIRI + T FOLTAX + T Arm B1 PD1 PD2 20% HER2 amplified FOLFIRI + M FOLFOX -METab FOLTAX + M Arm B2 MET amplified/Hi 7% PD1 PD2 FOLFOX -FGFR2ab Arm B3 FOLFIRI + F FOLTAX + F FGFR2 amplified 8% PD1 PD2 ARM B: Therapy based on molecular profile EGFR amplified/Hi KRAS wild type Nl HER2,FGFR2,RON,MET FOLFIRI + E FOLFOX -EGFRab Arm B4 FOLTAX + E 5/20% PD1 PD2 KRAS/BRAF/ PIK3CA/AKT/PTENdel mt/amplified Nl HER2,FGFR2,RON,MET FOLFOX -VEGFR2ab FOLFIRI + V FOLTAX + V PD1 PD2 15/10% Arm B5 FOLFOX -PD1ab FOLFIRI + P FOLTAX + P PD1 PD2 15% MSI-H, High TMB, EBV+ Arm B6

  38. The PANGEA -IMBBP TrialPersonalized ANtibodies for Gastro-Esophageal Adenocarcinoma: A Pilot 1stMetastatic Trial of Biologics Beyond Progression Historical Control (Arm A) FOLFOX FOLFOX-T PFS1 FOLFIRI PFS2 PFS3 FOLTAX 60% 30% 6m 4m 2m Biomarker Evaluation in all samples to allow for treatment assignment PANGEA Patient Example FGFR2++PDL1++KRASmt Diagnosis: metastatic cancer PFS3 PFS2 Anticipated Incidence PFS1 FOLFOX -Trastuzumab FOLFIRI + T FOLTAX + T Arm B1 PD1 PD2 20% HER2 amplified FOLFIRI + M FOLFOX -METab FOLTAX + M Arm B2 MET amplified/Hi 7% PD1 PD2 FOLFOX -FGFR2ab Arm B3 FOLFIRI + F FOLTAX + F FGFR2 amplified 8% PD1 PD2 ARM B: Therapy based on molecular profile EGFR amplified/Hi KRAS wild type Nl HER2,FGFR2,RON,MET FOLFIRI + E FOLFOX -EGFRab Arm B4 FOLTAX + E 5/20% PD1 PD2 KRAS/BRAF/ PIK3CA/AKT/PTENdel mt/amplified Nl HER2,FGFR2,RON,MET FOLFOX -VEGFR2ab FOLFIRI + V FOLTAX + V PD1 PD2 15/10% Arm B5 FOLFOX -PD1ab FOLFIRI + P FOLTAX + P PD1 PD2 15% MSI-H, High TMB, EBV+ Arm B6

  39. Baseline Intra-patient Heterogeneity 9/28 = 32% Pectisideset al. *update 24/62 = 39% Inter-patient Heterogeneity - prioritized algorithm 15 (19%) 9(11%) 4 (5%) Target N=68 ITT Enrolled 80; n= 68 ITT 8 (10%) 1 (1%) 5 (6%) 20 (25%) 9(11%) 9 (11%)

  40. PANGEA BIOMARKER INCIDENCES 11% 19% 11% 11% 5% 25% 10% 7% Actual to Date N= 80 Estimated Joshi et al. Personalized antibodies for gastroesophageal adenocarcinoma (PANGEA): A phase II precision medicine trial (NCT02213289) J ClinOncol 36, 2018 (suppl 4S; abstr TPS198).

  41. Enrollment Target N=68 ITT n= 80, 68 ITT Joshi et al. Personalized antibodies for gastroesophageal adenocarcinoma (PANGEA): A phase II precision medicine trial (NCT02213289) J ClinOncol 36, 2018 (suppl 4S; abstr TPS198).

  42. Expansion Platform Type II Subgroup Treatment All Patients (ITT) Personalized Vaccine 1 Z 2 Y 3 X 4 W Individual patients 5 V One (or more) Histology ‘Nof1’ 20-peptide vaccine One Treatment Strategy 6 U 7 T 8 S Personalized Vaccine Better New Tx “Z” Better Standard Tx Better

  43. “Expansion Platform Type IIB – Grass-Roots/Holistic”eg. ‘SHIVA’ IIB- Agnostic • SHIVA: • 10 treatment groups • No placebo – MD choice • N=741 • 496 (67%) profiled • 195 (26%) fit • Randomized • 99 vs 96 • NEGATIVE for PFS! But what if such a study was positive? Le Tourneau et al. Molecularly targeted therapy based on tumourmolecular profiling versus conventional therapy for advanced cancer (SHIVA). Lancet Oncol2015. Catenacci D. Expansion Platform Design Type II: Testing a Treatment Strategy. Lancet Oncol2015.

  44. FDA Pharma Patient-centered personalized treatment strategy Biotech/Molecular Profiling Academia/ Cooperative Groups

  45. Summary and Future Directions • GEA is a very molecularly heterogeneous cancer • Baseline primary tumor to metastatic site • Over time, particularly after targeted therapy • Targets and their drugs exist at relatively low frequencies • incorporating into standard practice remains elusive • PANGEA phase IIa pilot study NCT02213289: • Accruing well, biomarker incidences are similar to expected • Translational correlatives consistent with hypotheses • Baseline intrapatient heterogeneity- ~30-40% discordance 10 Met • Resulting in altered therapy assignment • ctDNA NGS well representative of metastatic sites • Temporal heterogeneity and ‘keeping up with the tumor’ • ctDNA NGS well representative • Early efficacy data ORR, PFS, and most importantly OS are promising • Enrollment completed for this pilot to n=68 (ITT) • Randomized phase II (II/III?) study planned, N=192 • Compared to placebo? Compared to physician’s choice? – “do what you do” • Need Regulatory and Pharma buy in

  46. The PANGEA -2MBBP TrialPersonalized ANtibodies for Gastro-Esophageal Adenocarcinoma: Phase IIMetastatic Biologic Beyond Progression Trial (R 2:1) Standard care: Control Arm FOLFOX + placebo PFS1 FOLFIRI + Ram PFS2 FOLTAX + placebo PFS3 ARM A: Standard Chemotherapy + Placebo Biomarker Evaluation in all samples prior to randomization Arm A1: HER2 amplified FOLFOX-Traztuzumab Arm A2: MET amplified/Hi Arm A3: FGFR2 amplified Arm A4: KRAS/PI3K wild type • Primary Endpoint: OS (HR 0.67) • i) Arm A v B (N=192, 128-B:64-A ) • ii)Arm Ax v Bx Arm A5: KRAS/BRAF/PIK3CA mt/amp Arm A6: MSI-H, High TMB, EBV+, PDL1+ Diagnosis: metastatic cancer Stratify: i) Stage ii) PS iii) Biomarker iv) GEJ v distal stomach vi) Site of metastases R 2:1 Anticipated Incidence PFS1 PFS2 PFS3 FOLFOX -Trastuzumab FOLFIRI + T FOLTAX + T Arm B1 PD PD 18% HER2 amplified FOLFOX -METab FOLFIRI + M FOLTAX + M PD PD Arm B2 7% MET amplified/Hi FOLFOX -FGFR2ab PD FOLFIRI + F PD FOLTAX + F Arm B3 7% FGFR2 amplified ARM B: Therapy based on molecular profile primary mOS Endpoint (N~192 68:128) EGFR/HER3 amplified/Hi KRAS wild type Nl HER2,FGFR2,RON,MET FOLFOX -EGFRab PD PD 7% FOLFIRI + E FOLTAX + E Arm B4 KRAS/BRAF/ PIK3CA/AKT/PTENdel mt/amplified Nl HER2,FGFR2,RON,MET FOLFIRI + V FOLTAX + V FOLFOX -VEGFR2ab PD PD Arm B5 33% FOLFOX -PD-1ab FOLFIRI + PD1 FOLTAX + PD1 Arm B6 PD PD MSI-H, High TMB, EBV+, PDL1+ 28%

  47. GI Medical Oncology Hedy Kindler, MD Blase Polite, MD Andy Liao, MD Manish Sharma, MD Christine Racette, APN Kenisha Allen, APN Sara Covert, RN Mellissa Arangoa, RN Erika Pemberton ZabdiEk-Vazquez, CRA Leah Chase, CRA Tamika Harris Grant Support: NIH K12/K23 CRF YIA ALLIANCE Foundation YIA UCCCC Pilot Award for Precision Oncology Genentech/Amgen/ OncoplexDx Collaborations LLK Foundation Sal Ferrara II (SF2) Foundation Ullman Foundation Award Castle Foundation Award ACKNOWLEDGEMENTS Biostatistics Yuan Ji, PhD Theodore Karrison, PhD James Dignam, PhD Pathology & Tissue Banking EpiCore and TRIDOM John Hart, MD Shu-Yuan Xiao, MD NamrataSetia, MD Lei Zhao, MD Emma Whitcomb, MD Lindsay Alpert, MD Surgery and Interventional GI Mitchell Posner, MD Kevin Roggin, MD Kiran Turaga, MD Mark Ferguson, MD Irving Waxman, MD Uzma Siddiqui, MD Christopher Chapman, MD Interventional Radiology & Pulm Paul Chang, MD Abraham Dachman, MD Kyle Hogarth, MD DOM/Section: Everett Vokes, MD Walter Stadler, MD FunmiOlopade, MD Harvey Golomb, MD Ravi Salgia, MD/PhD CATENACCI LAB: RajaniKanteti, PhD (Steven Maron, MD) Yan Wang Leah Chase Kelly Moore Peng Xu, PhD Les Henderson Samantha Lomnicki Emily O’Day Brittany Rambo Rachel Rendak SamsungBass Lab JeeyunLee, MD Gabby Wong, Phd Eirini Pectisides, MD University of Urbino: Francesco Graziano, MD Annamaria Ruzzo, MD Abbvie/Roche/Amgen Foundation Medicine: Jeffrey Ross, MD Siraj Ali, PhD Alexa Shrock, PhD Guardant Health: Becky Nagy, MS Richard Lanman, MD Lesli Kiedrowski, Phd OncoPlexDx/Nantworks: Todd Hembrough, PhD Fabiola Cecchi, PhD

  48. Thank You!

More Related