The Multi-Modality Clinical Model for SBRT/SABR (Pancreatic Cancer)

Stereotactic Body Radiation Therapy (SBRT) for Pancreatic Cancer December 9, 2016 If you experience technical difficulty during the presentation: Contact WebEx Technical Support directly at: US Toll Free: 1-866-229-3239 Toll Only: 1-408-435-7088 or Submit a question to the Event Producer via the Q&A Panel The Multi-Modality Clinical Model for SBRT/SABR (Pancreatic Cancer) Pancreatic Cancer: Stereotactic Body Radiation Therapy (SBRT) & Translational Paradigms Joseph Herman, MD, MSc Professor Director, Clinical Research Department of Radiation Oncology MD Anderson Cancer Center 1

Disclosure Relevant Financial Relationship(s) AbbVie, Oncosil, and BTG: Consulting Viragh Family Foundation: Funding for trial Gonzalez and McKnight Family Foundations: Translational Studies Off Label Usage Aduro: GVAX Merck: Pembro Overview In 2015, approximately 48,960 people were diagnosed with PCA Nearly 40% of PCA patients present with non-metastatic localized disease 2

What stage am I? Resectable Borderline Resectable Unresectable or Locally Advanced Metastatic (tumor spread beyond the pancreas and to another location) Pancreatic MDC: Case Review Present Cases using outline Review Pathology Review Images CT/PET/MRI/ EUS Discuss Case and reach consensus See patients and discuss options Enroll in trials/studies Dictate note and cc to referring physician Nutrition, Pain, Enzymes 3

Where is my pancreas? Where is my tumor? Resectability: Contact with Veins Less than 180º More than 180º Deformity Slide(s) courtesy of Dr. Mahmoud Al-Hawary ** Veins can be reconstructed 4

Resectability: Contact with Arteries Assessment based on: Degree of tumor contact with the vessel circumference Whether vessel caliber narrowing or contour deformity is present Less than 180º More than 180º Deformity Difficult to resect arteries Slide(s) courtesy of Dr. Mahmoud Al-Hawary Prospective Identification of Anatomically Resectable Pancreatic Cancer by CT Scan 1. Absence of disease outside of the pancreas 2. Tissue plane between tumor and SMA/CA 3 V A T 2 3. Open SMV-PV confluence 1 Use of these criteria yield high rates of microscopically complete (R0) resection 5

Borderline Resectable and Locally Advanced Pancreatic Cancer Borderline Resectable Locally Advanced (Unresectable) SMA Patient Selection? SMA Tumor abuts a major blood vessel(s) Deemed resectable Neoadjuvant therapy recommended Tumor encases a major blood vessel(s) Deemed unresectable or LAPC New role for definitive therapy Resection Determined by Vessel Involvement Resectable Borderline Locally advanced SMV/PV AHPBA/SSO/SSAT/NCCN Resectable No contact Borderline Abut, encase or occlude Locally Advanced Not reconstructable SMA No contact Abut Encased CHA No contact Abut or shortsegment encase Long-segment encase Celiac Trunk No contact <180 >180 6

We need better systemic therapy AND radiation therapy! Medical Oncology Radiation Oncology Locally Advanced and Borderline Resectable PCA Treatment focus is on performance status rather than stage: ECOG 0-1, young FFX ECOG >1 or elderly GEM or GEM/NAB-P Maximize chemotherapy 4-6 months then reevaluate for local therapy (radiation +/- surgery) 7

Chemotherapy: Systemic Therapy Gemcitabine Gemcitabine + X Gemcitabine + Abraxane FOLFIRINOX (5-FU, Irinotecan, Oxaliplatin) Immunotherapy Targeted therapy NCCN Guidelines Rationale for More Intense Local Treatment in LAPC 30% Local only disease JHU Autopsy Series 60% Local progression - MDACC phase II trial Patients die of biliary, gastric, SMV/portal obstruction Iacobuzio-Donahue et al, JCO, 2009 Crane et al, JCO, 2011 8

Potential Effects of Radiation SBRT CRT Tumor SMV SMA Positive Surgical Margin Well-vascularized rim, hypoxic core Outline of Tumor Mass on CT Slide courtesy of Chris Crane, MD Stereotactic RT: Modern Treatment Devices CYBER-KNIFE TRILOGY SYNERGY 9

007: Stereotactic Body Radiation Therapy (SBRT)? Goldfinger (1964) Evolution of Radiation Therapy 3-D CRT IMRT IMRT Plan ABC IGRT SBRT Plan 10

What Are Fiducials? Civco Knurled Gold Fiducials Gold Anchor Core Oncology Visicoil Civco Coupled Markers Placed via endoscopic ultrasound (similar to biopsy) SBRT Planning & Delivery (videos) Respiratory Control Plan Quality Assurance 11

GI Atlas Intensity Modulated RT Planning & Delivery PTV Treatment Plan (1.75 Gy x 30 fractions) IMRT Dose Volume Histogram 12

MDACC Dose Escalation - LAPC IMRT 63-70 Gy/Image guided + breath hold 2006-2014 N=49 63Gy-70Gy / 28 fx ms-22.6 mo N=177 50.4Gy / 28fx ms- 17.9mo Krishnan and Crane IJROBP 2016 Stereotactic Body Radiation Therapy (SBRT) Planning & Delivery (fiducials and breath hold) Tumor Treatment Plan (5-6.6 Gy x 5 fractions) SBRT Dose Volume Histogram 13

JHU SBRT: Overall Survival Median OS from diagnosis = 20.1 mos (95% CI: 15.6 23.5) Data with standard chemoradiation for pancreas cancer 14

Patient with BLR PDAC (Intergroup Definition) P R E- R E GI S T E R E N R O L L m FOLFIRINOX 2 months R E S T A G E 50.4g EBRT + CAPE R E S T A G E SURGERY R E S T A G E GEM 2 months F O L L O W Centralized radiographic review of pretreatment and restaging studies Prospective QC of all modalities Protocol-mandated operative indications and procedures Analysis and reporting of survival rates and objective response metrics What did we learn from A021101? FOLFIRINOX and Radiation is Acceptable in Borderline (non-metastatic disease) R0 operations possible in 64% patients but vascular resection 80% 33% resections <5% viable cells, 13% pcr (no tumor) 1/3 resected patients did not start postop chemo, emphasizing need for more preoperative Rx Median OS of all enrolled patients: 22 months Katz, JAMA Surg 2016 15

Role of Radiation Therapy in Locally Advanced Disease (LAPC)? GERCOR LAP-07 Trial Unresectable PCA 1st Gemcitabine x 4 months Gemcitabine plus erlotinib x 4 months 2nd Gemcitabine x 2 months RT (5400 cgy) + capecitabine Gemcitabine plus erlotinib x 2 months RT (5400 cgy) + capecitabine None None Erlotinib Erlotinib Hummel et al, JAMA 2016 Role of Radiation Therapy in Locally Advanced Disease (LAPC)? No survival benefit with RT Only 60% included in 2 nd randomization Local control benefit with RT With better chemotherapy, perhaps RT would have a larger impact Hummel et al, JAMA 2016 16

What Is The Role of Neoadjuvant Therapy in LAPC? - LAP 07 Study 449 patients (4%) underwent a curative-intent resection Eleven patients (2.5%) had an R0 resection Median OS was 30.9 months Can we increase the proportion of patients getting surgery with improved systemic therapy and IMRT or SBRT? Hammel et al 2016, JAMA Benefits of SBRT vs. Standard Chemoradiation Shorter duration of radiation (3-5 days vs. 30 days) Improved quality of life Limit delay of chemotherapy and time to surgery Easily combined with other modalities Higher resection rates?? Less acute GI toxicity 17

Treatment Volumes and Dosimetry: SBRT vs. IMRT A B C D E F Pancreas SBRT Studies Study N Dose Local Control at 1 Year OS (mos) Toxicity Schellenberg (2008) 16 25Gy x1 100% 11.4 47% G2-4 Didolkar (2010) 85 5-10Gy x3 92% 18.6 22.3% G3+ Mahadevan (2010) 36 8-12Gy x3 78% 14.3 33% G1-2, 8% G3 Polistina (2010) 23 10Gy x3 50% 10.6 20% G1 Mahadevan (2011) 39 8-12Gy x3 85% 20 41% G1-2, 9% G3 Rwigema (2011) 71 24Gy x1* 49% 10.3 39.5% G1-2, 4.2% G3 Schellenberg (2011) 20 25Gy x1 94% 11.8 15% G1-2, 5% G3 Goyal (2012) 19 20-25Gy x1* 81% 14.4 11% G1-2, 16% G3 Lominska (2012) 28 4-8Gy x3-5 86% 5.9 7% G3 Gurka (2013) 10 5Gy x5 40% 12.2 0% Chuong (2013) 73 5-10Gy x5 81% 15-16 5% G3 18

Phase II Multi-institutional Trial: Gemcitabine + SBRT (n=49) Johns Hopkins, Stanford, Memorial Sloan Kettering (Gem, up to 1 Cycle allowed) 1 week break F-SBRT 6.6 Gy x 5 Mon-Fri 1 week break Gem (3 wks on, 1 wk off) until toxicity or progression Primary endpoint: Late GI Toxicity > 4 months (40% to 20%) Secondary endpoints: Tumor Progression Free Survival, pre-tx biopsy, PET/CT, QOL, biomarkers Key features: Central review, dose constraints, RT quality assurance Herman JM et al. Cancer 2015 Median OS: 13.9 mos Median PFS: 7.9 mos Herman JM et al. Cancer 2015 19

Phase II Multi-institutional Trial: SBRT Toxicity and QOL Toxicity Acute GI Grade 2: 0% Grade 3: 12.2% Late GI Grade 2: 2.1% Enteritis Grade 3: 8.5% Fistula (1) Ulcer (3) Quality of Life (EORTC) Mean global QOL: Scores unchanged pre/post SBRT Surgery 5 (10%) were deemed resectable after therapy 1 (2%) denied surgery The remaining 4 (8%) patients underwent margin- and node-negative resection LAPC patients may successfully be resected?! Herman JM et al. Cancer 2015 Simultaneous Integrated Boost (SIB)- Based SBRT Dose Escalation SIB delivers high doses to the tumor/ vessel interface Tuli et al. Rad Res. 2014 20

Current Approach Appropriate Staging Maximize chemo (4-6 months) Maximize chemo ( 6 months) Radiation therapy ULTIMATE GOAL Surgery +/- IRE Radiation therapy Maintenance chemotherapy?? LAPC: Neoadjuvant Multi-agent Chemotherapy +/- Radiation Therapy Study Surgery N Neodjuvant Chemo Radiation Type R0 Resection Med OS or Path Reponse Moffitt N=159 BR: 51 LAPC: 5 GTX 81% BR FFX 43% LA SBRT: All 30-50 Gy/5 Fx BR: 96% LAPC: 100% 34.2 mos Hopkins N=88 BR: 4 LAPC: 15 Mixed SBRT: All 33 Gy/5 Fx 84% 22 mos MSKCC N=101 LAPC: 31 FFX 6 mos CRT: 50%* Chemo: 79% **CRT: 33% PR: >50% (75 vs. 22) # MGH N=188 BR: 14 LAPC: 26 FFX CRT: 14 CRT/IORT: 10 Proton: 6 92% ~32 mos *75% Gem based, **Vasc resection rate 47 vs. 7, # favor of CRT Mellon; Moningi; Sadot; Ferrone et al. 21

Which Patients Should Be Taken to Surgery Following Neoadjuvant Therapy? Most tumors do not shrink after neoadjuvant therapy There is a treatment effect Chemo SBRT Surgery 22

Hopkins: Neoadjuvant Chemo vs. Chemo + SBRT (N=177) 2008 2016: Median Follow-up 17.0 mos Characteristic Chemo group, n (%) Chemo/SBRT group, n (%) No. patients 67 110 Age 65 29 (43%) 45 (41%) Male gender 39 (58%) 56 (51%) Caucasian race 60 (90%) 98 (89%) Head of pancreas lesion 50 (75%) 77 (70%) Locally advanced disease 16 (24%) 56 (51%) FOLFIRINOX-based chemotherapy Chemotherapy duration 4 months 34 (51%) 79 (72%) 20 (30%) 63 (57%) Hopkins: Neoadjuvant Chemo vs. Chemo + SBRT (N=177) 100 90 80 70 60 50 40 30 20 10 0 % Margin Negativity 83% 57% Chemo SBRT 100 90 80 70 60 50 40 30 20 10 0 % Node Negativity 60% 40% Chemo SBRT 23

Pathologic Complete Response or Near Pathologic Complete Response Pathologic complete response (pcr) No residual tumor can be identified or measured Near pcr Scattered microscopic foci of single cells or groups of single cells Typically within a dense area of fibrosis Demonstrating marked treatment effect Hopkins: Neoadjuvant Chemo vs. Chemo + SBRT (N=177) % pcr % Near pcr 30 40 25 20 15 10 8% 35 30 25 20 15 10 18% 30% 5 0 0% Chemo SBRT 5 0 Chemo SBRT SBRT does improve pathologic response but higher doses are needed for ablation 24

Proposed Alliance A021501: Preoperative Extended Chemotherapy Vs. Chemotherapy Plus Hypofractionated Radiation Therapy for BRPC of the Head of The Pancreas Arm A P R E - R E G I S T R A T I O N E N R O L L R A N D O MI Z E mffx x 4 cycles Arm B mffx x 4 cycles mffx x 4 cycles mffx x 3 cycles SBRT Surgery Surgery FOLFOX x 4 cycles F O L L O W FOLFOX x 4 cycles F O L L O W Central review of baseline imaging Central review of radiation QI Central review of preoperative imaging Central review of pathology Know Your Tumor KYT at enrollment = Re-staging Surgical Exploration in LAPC Radiographic evidence of tumor downstaging is not required for surgical evaluation Under multidisciplinary review, consider the following: 1. 4 months of chemotherapy and no distant metastases 2. Good performance status/no limiting comorbidities 3. Stable or improved CA 19-9, technically resectable 4. Ideally, <12 weeks after SBRT Katz MH, et al. Cancer. 2012;118(23):5749-5756 Dholakia AS, et al.. J Radiat Oncol. 2013 Dec;2(4):413-25 25

Does multi-agent chemotherapy combined with SBRT lead to improved survival and improve the likelihood that patients with LAPC undergo surgery? Results: Patient & Tumor Characteristics July 2010 to April 2015, 117 patients with LAPC received definitive Chemo + SBRT Patient or tumor characteristic N=117 Median age at diagnosis, years (range) 65 (36-88) Caucasian race 84% Male gender 52% Median baseline KPS (range) 90 (80-100) Head of pancreas tumor 58% Rosati and Herman et al. 26

Results: Treatment Characteristics Induction chemotherapy agent(s) None Gemcitabine-based (alone*, gem+nab-p, GTX, gem/cis) FOLFIRINOX-based Combination of both Induction chemotherapy duration (months) Median (range) 4 months SBRT dose (Gy) Median (range) 33 Gy Time in months, median (range) From diagnosis to SBRT From SBRT to the end of follow-up From diagnosis to the end of follow-up N=117 8% 49% 33% 10% 2.8 (0-22.3) 38% 33.0 (25.0-33.0) 73% 4.0 (0.4-25.8) 13.6 (1.1-62.4) 19.4 (4.0-68.5) *31% of patients received gemcitabine alone on a clinical trial or due to poor performance status Results: Overall Survival Median OS from diagnosis = 20.1 mos (95% CI: 15.6 23.5) Median OS from SBRT = 14.5 mos (95% CI: 12.2 18.6) 27

Overall Survival By Induction Chemotherapy Type / Duration No chemo Single-agent GEM Multi-agent chemo Gem-based chemo FFX-based chemo <4 months chemo 4 months chemo Results: Surgical Implications LAPC (n=117) Surgery (n=42) No Surgery (n=75) Successful resection* (n=33) Aborted (n=3) IRE (n=6) Distant Mets (n=46) R0 Resection (91%) Vessel Involvement (n=17) N0 Resection (82%) Performance Status (n=10) Path CR (15%) Other (n=2) 28

Results: Surgical Implications LAPC (n=117) Surgery (n=42) No Surgery (n=75) Successful resection* (n=33) Aborted (n=3) IRE (n=6) Distant Mets (n=46) R0 Resection (91%) Vessel Involvement (n=17) N0 Resection (82%) Performance Status (n=10) Path CR (15%) Other (n=2) *Three patients went to surgery + IRE Results: Surgical Implications LAPC (n=117) Surgery (n=42) No Surgery (n=75) Successful resection* (n=33) Aborted (n=3) IRE (n=6) Distant Mets (n=46) 39% R0 Resection (91%) Vessel Involvement (n=17) 15% N0 Resection (82%) Performance Status (n=10) 9% Other (n=2) 2% *Three patients went to surgery + IRE 29

Results: Surgical Implications LAPC (n=117) Surgery (n=42) No Surgery (n=75) Successful resection* (n=33) Aborted (n=3) IRE (n=6) Distant Mets (n=46) 39% R0 Resection (91%) Vessel Involvement (n=17) 15% N0 Resection (82%) Performance Status (n=10) 9% Other (n=2) 2% *Three patients went to surgery + IRE Results: Surgical Resection and Overall Survival Median OS (mos) P-value Surgery vs. no surgery 29.7 vs. 17.0 0.0001 R0 resection vs. R1/R2 resection 34.7 vs. 23.1 0.170 30

Current Study: Pancreatic Cancer Research Study (PanCRS) Induction Chemotherapy: mfolfirinox x 4 cycles Restage Stable or Better Disease Progression Arm 1 mfolfirinox Randomize Arm 2 SBRT+mFOLFIRINOX 8 Gy x 5 Off Study Participating Institutions: Stanford, UCSF, UCLA, Loyola, BC Cancer Agency, Duke, UTSW Pancreas SBRT: Patient selection for surgery Clinical stage is determined by imaging Can biomarkers determine a local vs. systemic profile at diagnosis and guide management Imaging (PET, CT) Tumor Sequencing Immunohistochemistry (core/cell block) ctdna (tumor/plasma) 31

Association of stroma and delta measurement High delta tumors have lower stroma content. (A) (B) Test set (12 cases) (C) Validation set (37 cases) Courtesy of Eugene Koay Clinical associations for low and high delta tumors Patient cohort: 101 patients who underwent upfront surgery for resectable PDAC Proportions of patients having metastasis within 6 months Overall survival Patients with high delta tumor showed poor prognosis (early distant metastasis, shorter overall survival ). The delta classification is an independent predictor of distant metastasis-free survival and overall survival. Courtesy of Eugene Koay 32

After Before 12/12/2016 SBRT Tumor Response by PET Mean SUVmax 5.14 3.13 (p<0.001) Mean SUVpeak 4.01 2.40 (p<0.001) On MVA, PET avidity at baseline predicted for poor survival Herman et al. Cancer 2015 Total Lesion Glycolysis Predicts Path Response to Neoadj Therapy 33

Patient Selection Smad4 (Dpc4) Status Dpc4/Smad4 Wild-Type (Local) Dpc4/Smad4 Mutant (Systemic) Gross tumor pathology comparison. A) Pancreas specimen from pt with locally advanced disease. B) Liver specimen from pt with extensive metastatic disease. Iacobuzio-Donahue et al, JCO, 2009 34

How can we enhance the effects of RT or use RT to enhance immunotherapy? 35

Small Animal Radiation Research Platform: Bioluminescent Imaging (BLI) and Targeted Radiation in Small Animals Mouse SBRT SARRP Research Platform. http://www.xstrahl.com/sarrp.htm. PARP Inh In Vivo C Tuli et al, Trans Onc 2015 Tuli, et al, Rad Res 2013 Tuli, et al, Trans Onc 2012 36

Phase I study: ABT-888 in combination with gemcitabine and IMRT for LAPC (VelGemRad) Gemcitabine: IV infusion of 1000 mg/m 2 on days 1, 8, 15 of the cycle IMRT: 36 Gy in 15 fractions (2.4 Gy/day, M-F) Veliparib: administered per dose escalation schema, 60 mg BID 1 Objective: to determine the MTD, safety and toxicity profile 2 Objectives: Measure the clinical activity of the treatment (RECIST 1.1) Evaluate tumor/blood pre/during/post treatment for DNA damage/repair proteins Assess pre-tx germline/somatic/epigenetic mutations in BRCA1/2, PALB2, PTEN Tuli et al, in preparation 73 SBRT: Immune Modulation Kamrava M., Hodge JW., et al. Mol. BioSyst., 2009 - Adapted with Permission (Andrew Sharabi) 37

SBRT Treatment Response Gross: 3.8 cm (Extensive Treatment Effects) Future Directions: Pancreas Vaccine GVAX: GM-CSF Secreting, Allogeneic, Whole Tumor Cell Vaccine GVAX GM-CSF Dendritic Cell Tumor Cell Destruction Mesothelin Tumor antigen Antigen uptake & Activation May Inhibit recurrence Limited toxicity Combined with other therapies T Cell Activation & Proliferation T Cell 38

Blocking CTLA-4 and PD-1 Tumor Microenvironment Activation (cytokines, lysis, proliferation, migration to tumor) Dendritic cell MHC B7 TCR CD28 +++ B7 CTLA-4 - - - anti-ctla-4 CTLA-4 Blockade +++ T cell T cell +++ - - - - - - TCR MHC PD-1 PD-L1 anti-pd-1 PD-1 PD-L2 anti-pd-1 PD-1 Blockade Tumor cell FFX +SBRT + GVAX + Anti-PD-1 in Patients with LAPC Anti-PD-1 39

Proton Beam Therapy Ling TC et al. Transl Cancer Res 2012;1(3):150-158 Conclusions: Multi-agent chemotherapy improves survival (>4 months) FFX > Gem/Abx SBRT improves R0 resections and path response with limited toxicity or delay Select LAPC patients can have surgery with favorable OS Local and distant progression still common Need better maintenance therapies Support clinical trials P s: Pain, Panc Enzymes, PANCAN, PMDC 40

Johns Hopkins MD Anderson 41

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