Neoadjuvant Therapy for Pancreatic Cancer Mark M. Zalupski, M.D. University of Michigan Ascension Michigan GI Conference Multidisciplinary Management of the GI Cancer Patient March 30, 2019

Disclosures – None Off Label Use - Yes

Definition of neoadjuvant treatment Pancreas Cancer – Background, Multi-modality and Adjuvant Therapy Neoadjuvant Trials Ongoing Efforts and Conclusions

What is neoadjuvant treatment? “Treatment given as a first step to shrink a tumor before the main treatment, which is usually surgery” 1st treatment sometime called induction Can be chemotherapy and/or radiation Use often has defined value in post-op setting Main treatment = curative intent = surgery No need to “shrink” tumor in operable disease Target of systemic Tx includes micrometastatic dz

Pancreatic Cancer - Scope of the Problem 56,440 cases expected 20181 5 year survival 7.7% By 2030, pancreas Ca expected to surpass breast, prostate and CRC to become 2nd leading cause of cancer death2 Small minority (~15%) with operable dz (includes resectable and borderline resectable disease) Older patient population with co-morbidities and disease associated complications 1CA Cancer J Clin. 2018;68(1):7-30 2Can Res 2014:74;2913

CT Criteria for Resection No extra pancreatic disease No extension to celiac/SMA Patent SMV/PV Encasement / reconstructable SMV/PV Contact on SMA / celiac (<=180o) Resectable

Resectable adenocarcinoma of the pancreatic head Kitts 527268 Resectable tumor, RRHA

Borderline resectable adenocarcinoma of pancreatic head

Resectable Pancreas Cancer Patterns of Treatment Failure Early Spread to Regional Nodes Subclinical Liver Metastasis in Majority In Resected Pts Loco-regional Failure > 85% without Adjuvant Treatment Liver Metastasis in > 75% Patients with Improved Local Control Poor Prognostic Factors + LN, + margins (R1 - R2 resections)

Localized Pancreatic Cancer Multi-Modality Treatment Surgical Treatment - Necessary but not sufficient for cure Goal is R0 resection Morbidity and difficult recovery following surgery Radiation Therapy - Enhances local control in resected pts As neoadjuvant tx, increases R0 resection rate Underutilized (?) Systemic Chemotherapy - Increases survival Combinations enhance benefits Majority of patients still suffer distant recurrence

Resectable Pancreatic CA – Adjuvant Treatment Study year n Intervention Median Survival (mos) ESPAC 11 2004 289 Obs vs. 5FU 15.5 vs. 20.1 Conko 0012 2007 354 Obs vs. Gem 20.2 vs. 22.1 ESPAC 43 2017 732 Gem vs. Gem / Cape 25.0 vs. 28.5 Prodige4 2018 493 Gem vs. m-Folfirinox 35.0 vs. 54.4 Apact 2019 866 Gem vs. Gem+nab-Pacli TBD 1NEJM 2004:350;1200 2JAMA 2007:297;267 3Lancet 2017:389;1011 4NEJM 2018:379;2395

Resectable Pancreatic CA Receipt and Timing of Multimodality Therapy1 NCDB 2004-2011 39,441 pts stage I and II 22.8% received no treatment 18.5% chemotherapy only 23.0% surgery only 35.8% multimodality treatment Age is a barrier to multimodality treatment OR as compared to < 55 yo 56-64 - 0.83, 65-75 – 0.60, > 76 - 0.17 Multimodality tx increased over time (31.3  37.9%) 1J Gastrointestinal Surg 2016;20:93

Resectable Pancreatic Cancer Surgery  Adjuvant Therapy m-FOLFIRINOX Gemcitabine/Capecitabine +/- RT / Capecitabine Single agent chemotherapy Neoadjuvant Therapy  Surgery Chemotherapy (same) as in adjuvant +/- RT Surgery if no progression, metastatic disease

Rationale for preop therapy Provides early treatment of micrometastatic disease Treating an intact patient Delayed recovery may prevent the delivery of postoperative adjuvant therapy Patients with rapidly progressive disease will not be subjected to surgery A logical strategy for the high incidence of positive margins

Potential Barriers to Neoadjuvant Therapy Need for biopsy EUS – FNA Biliary decompression and a continuing risk of cholangitis Patient / Family Concern for localized disease progression

Neoadjuvant Gemcitabine-based Therapy in Resectable Pancreas Cancer - MDAH Experience 1 Gem 400 mg/m2 wkly x 7 + 30 Gy RT wk 1-2 or 2 Gem 750 mg/m2 + Cis 30 mg/m2 qow x 4  Gem 400 mg/m2 wkly x 4 + 30 Gy RT wk 1-2 followed by surgery in those that remain resectable Note: only 1 of 176 pts had isolated local progression 1 J Clin Oncol 26:3496, 2008 2 J Clin Oncol 26:3487, 2008

Localized / Resectable Pancreatic Cancer Adjuvant 100 Surgery Neoadjuvant 100 Chemo +/- RT 20 20 80 Resected 80 Explored 20 20 60 Resected 60 Chemo +/- RT

Preop vs Postop No. Patients Benefit Morbidity Med S of of (Resected) Chemo XRT Surg Neoadj 100 60 > 20 mo Adj. 60 80 < 20 mo

Neoadjuvant Gemcitabine-based Therapy in Resectable Pancreas Cancer - MDAH Experience Comp/ Med Surv Med Surv n Resected Resected not Oper Gem/RT1 86 74% 34.0 mos 7.1 mos Gem-Cis 90 66% 31.0 mos 10.1 mos Gem/RT2 Most failures systemic More difficult to complete longer preop course 1 J Clin Oncol 26:3496, 2008 2 J Clin Oncol 26:3487, 2008

Resectable/Resected Pancreatic CA Nationwide Trends and Results with Neoadjuvant TX1 NCDB 1998-2011 18,243 resections Post-op adjuvant tx (58% che, 39% RT) 7.5% received neoadj tx (>99% che, 82% RT) Use increased over time (4.3%  17%) Neoadjuvant treatment associated with R0 resection 85.5% vs 77.8% Negative lymph nodes 59.3% vs 42.9% Lower 30 day mortality 2.0% vs. 4.6% Lower 30 day readmission rate 7.4% vs 9.5% Median survival 24.3 mos vs. 18.7 mos 1J Surg Oncol. 2017;116:127

Phase II Full Dose Gemcitabine with RT Week 1 Week 2 Week 4 Week 5 Week 6 Week 7 Week 8 M T W T F S S M T W T F S S M T W T F S S M T W T F S S M T W T F S S M T W T F S S M T W T F S S XRT XRT XRT G G G G G G G G Gemcitabine: 1000 mg/m2 30 min IV infusion XRT 36 Gy in 15 fractions

Phase II Full Dose Gemcitabine with RT n=41 8 (19.5%) ≥ grade 3 non-heme toxicity1 20 pts entered as resectable2 20 explored, 17 resected Clear margins in 16/17 Uninvolved LN in 11/17 One Path CR , 3 microscopic foci only Average LOS 13.5 days No 30-day mortality Median f/u 12 mos - 10/17 alive without recurrence 1J Clin Oncol 2008, 26(6):942 2Ann Surg Oncol 2006, 13(2):150

Baseline Characteristics Immediate Surgery (n=127) PREOPANC-1 Preoperative chemo/RT vs surgery for resectable/borderline resectable pancreatic cancer - Phase III trial Surgery  6 mos Gemcitabine Preop Gem/RT  Surgery  Adj Gem x 4 mos CMT – RT 36 Gy in 15 fractions + Gem 1 g/m2 R Baseline Characteristics Immediate Surgery (n=127) Preoperative Chemo / RT (n=119) Median age (range) 67 (37-81) 65 (33-80) WHO PS 0-1 94% 92% Location Head 88% Head 87% Borderline Resectable 46% 53% J Clin Oncol 36, 2018 (suppl; abstr LBA4002)

Immediate Surgery (n=127) PREOPANC-1 Preoperative chemo/RT vs surgery for resectable/borderline resectable pancreatic cancer - Phase III trial Accrual April 2013–July 2017 Results Immediate Surgery (n=127) Preoperative Chemo / RT (n=119) P Value Resection Rate 72% 60% p=0.065 R0 Resection Rate 31% 63% p<0.001 Serious Adverse Events 39% 46% p=0.28 Median OS 13.7 mos 17.1 mos p=0.074 Median DFS 7.9 mos 9.9 mos p=0.023 Resected Med OS 16.8 mos (n=91) 42.2 mos (n=72) J Clin Oncol 36, 2018 (suppl; abstr LBA4002)

UMCC 6-25 Phase II Trial Neoadjuvant Gemcitabine, Oxaliplatin and RT Treatment Schema SURGERY ? Week 1 Week 2 Week 3 Week 5 Week 6 Week 7 M T W T F S S M T W T F S S M T W T F S S M T W T F S S M T W T F S S M T W T F S S XRT XRT XRT G G G G G G O O O O XRT 30 Gy in 15 fractions G Gemcitabine: 1 g/m2, 30 minutes Oxaliplatin: 85 mg/m2 O

UMCC 6-25 Phase II Trial Neoadjuvant Gemcitabine, Oxaliplatin and RT n=68 pts (4 institutions) 12 resectable, 49 borderline, 7 unresectable 61 (90%) completed neoadjuvant treatment 5 PR, 50 SD (including 19 with MR), 12 PD 5/9 with Primary PD had RO resection 43 (63%) resected; 36/43 RO (84%) (32 whipple, 11 distal, 40% with vascular R&R) Cancer 2013;119:2692

Median OS 18.2 months

Med OS Not Resected 10.9 mos Med OS Resected – 27.1 mos Med OS R0 Resection – 34.6 mos

UMCC 6-25 - Conclusions Radiologic response not necessary for RO resection CA19-9 response associated with RO resection Evidence for downstaging (+LN 49% vs. ~70% post-op) 55% of treated patients received adjuvant therapy Cancer 2013;119:2692

Total Neoadjuvant Therapy (TNT) in Borderline Resectable Pancreatic CA UMCC 11.007 n=25 3 mos m-FOLFIRINOX  5 weeks IMRT/Gem  1 mos Gem  Surgery 21 pts completed 3 mos chemo, 19 all protocol tx Per serial CTs - 44% PR, 44% SD One early death, 4 liver metastasis, 2 pts inoperable 18 explored, 13 resected (all R0), venous resect 9 pts By ITT – med PFS 13.1 mos, med OS 24.4 mos Resected pts - PFS 21.6 mos, OS 37.0 mos Unresected pts – PFS 8.9 mos, OS 12.6 mos submitted Int J Rad Onc Biol phys

TNT in Borderline Resectable Pancreatic CA DFCI - Phase II Trial in Borderline Resectable Dz 4 months of m-FOLFIRINOX then Individualized RT (SBRT or long course IMRT) + Cape n=48 79% received 8 cycles of m-FOLFIRINOX 35% IMRT, 56% SBRT per serial CTs 44% PR, 30% SD R0 Resection in 65% By ITT med PFS 14.7 mos, med OS 37.7 mos Resected pts - PFS 48.6 mos, OS NR Unresected pts – PFS 8.9 mos, OS 12.6 mos Jama Oncol. 2018;4(7);963

A021501 – Neoadjuvant FOLFIRINOX +/- SBRT in borderline resectable pancreas cancer Pancreatic head adenocarcinoma Borderline resectable per intergroup criteria No prior treatment ECOG 0-1 No neuropathy No ca19-9 limit FOLFIRINOX x 8 If no metastasis, surgical exploration and resection Resected patients receive post-op FOLFOX x 4 Primary: 18 mos OS Secondary: PFS, QOL R0 resection rate, Safety N=67 R N=67 FOLFIRINOX x 7 then SBRT As of 3/21/19, accrual at 121 of planned 134 SBRT arm closed 8/13/18 when interim data analysis < 11/30 with R0 resection met the protocol specified futility boundary

Neoadjuvant Tx - Resectable Pancreas Cancer S1505–FOLFIRINOX vs. Gemcitabine/nab-Paclitaxel Primary Endpoint - 2 Year Overall Survival with a “pick the winner” design Accrual completed April 2018 with 147 registrations 39 registered patients ineligible due to > resectable disease on baseline CT scan Grade 3-4 toxicity ~ 2/3 of patients = with either regimen ________________________________________________ GI Intergroup/NCTN planning randomized trial in Surgery adjuvant FOLFIRINOX vs. Neoadjuvant FOLFIRINOX  Surgery

Neoadjuvant Therapy of Pancreatic Cancer Practical Considerations Chemotherapy m-FOLFIRINOX, gemcitabine/capecitabine standard adjuvant therapies gemcitabine/nab-paclitaxel (?), single agent therapy Radiation Surgeon and institutional preferences Continuing arterial contact SBRT, 3 weeks of 3D conformal, 5 (or more) weeks of IMRT Concurrent chemotherapy – capecitabine (or 5FU), gemcitabine Duration of neoadjuvant treatment 3 to 6 months - shorter for resectable disease, longer for borderline Surgical treatment response not required for operation prepare for vascular resection / reconstruction Post-operative adjuvant treatment target 6 mos of systemic therapy Postoperative RT in R1 resections, LN + resections