Adjuvant Therapy for Biliary Cancer Abby Siegel MD, MS Associate Professor of Medicine Columbia University Co-Chair, Hepatobiliary Committee, SWOG NCI Task Force for Hepatobiliary Cancers

Adjuvant Therapy for Biliary Cancers Models and Meta analyses Trials Which chemo (s) to use? Potential targets to consider for the future Treatment guidelines

Anatomic and Molecular Heterogeneity Gallbladder EHCC IHC KRAS 3-38 10-15 45-54 BRAF 0-33 0-22 EGFR 9-12 5-18 10-20 ERBB2/HER2 16 5 PI3K 4 9 Adapted from De Groen et al. NEJM; 341(18):1368-78, 1999 Hezel et al, JCO, 2010 28:3531-3540

Gallbladder Nomogram 1137 patients from SEER-Medicare between 1995-2005 ChemoRT performed better than chemo alone for almost all groups, particularly T2, node (+) Caveats: margin status and performance status not reported in SEER, numbers too small to control for radical resection Most got 5FU, and chemo likely underreported Wang et al. JCO; 29:4627-4632, 2011

Gallbladder cancer: Online prediction calculator estimating benefit of adjuvant chemotherapy or chemoradiotherapy http://skynet.ohsu.edu/nomograms. Wang et al. JCO;29:4627-4632,2011

Review and Meta-analysis Pooled analysis of 20 studies; 6712 pts Overall survival improved with adjuvant therapy compared with surgery alone (p=0.06) Node and margin-positive patients benefit most (OR, 0.49; P =0.004, and OR, 0.36; P= 0.002) CT or CRT gave statistically greater benefits than RT alone (P = 0.02) Suggestion of benefit for radiation only for margin positive disease Horgan et al. JCO; 30:1934-1940, 2012

Efficacy Outcomes for Overall Population Horgan et al. JCO;30:1934-1940, 2012

Efficacy Outcomes for Node-Positive Disease Horgan et al. JCO;30:1934-1940, 2012

Efficacy Outcomes for Margin-Positive Disease Horgan et al. JCO;30:1934-1940, 2012

Meta analysis and Model Summary Depends whom you ask! Chemo looked better in the Knox meta analysis ChemoRT looked better in SEER-Medicare Few received radical resection in SEER-Medicare (maybe radiation was more important there?) Different types of chemo More “modern” in meta analysis Better recording of chemo in meta analysis SEER-Medicare claims don’t include those in HMOs or who go to another setting, like VA

Clinical Trials Also limited so far No large randomized controlled trials reported Asian randomized trial SWOG 0809: Intergroup Phase II

One Randomized Trial From Japan, pts with pancreas, biliary, gallbladder, and ampullary cancers assessed Chemo: 5FU, mitomycin “atypically given” Only difference seen for GB cancer No difference by ITT Benefit only seen for GB cases who underwent noncurative resections (were they really “adjuvant?”) Takada et al. Cancer, 95(8):1685-95, 2002

Phase III Adjuvant Chemotherapy: Gallbladder Cancer Takada et al. Cancer, 95(8):1685-95, 2002

SWOG 0809 Eligibility T2-T4 N1 Positive margins Gallbladder cancer or EHCC At least one of the following: T2-T4 N1 Positive margins Gemcitabine 1000 mg/m2 IV over 30 min D1 and D8 + Capecitabine 750 mg/m2 PO BID x 14 days X 4 cycles Concurrent EBRT with Capecitabine 665 mg/m2 BID x 7 days for 6 weeks (45 Gy to regional lymphatics, 54-59.4 Gy to the tumor bed)

SWOG 0809: Statistical plan With 80 evaluable pts, results would be promising if the 2-year survival was >45% R0/R1 estimates were ≥65%/45%, respectively

SWOG 0809: Patient Characteristics   R0 (n=54) R1 (n=25) Age (years) Median 65.0 59.2 Sex Males 24 44% 14 56% Females 30 11 Hispanic Yes 4 7% 1 4% No 49 91% 17 68% Unknown 2% 7 28% Race White 45 83% 21 84% Black 5 9% 2 8% Asian 0% Primary disease site Bile Duct 35 65% 19 76% Gallbladder 35% 6 24% Performance status 32 59% 22 41% 18 72% Baseline lab values CA 19-9 (U/ml) N 53 23 15.0 24.0 SWOG 0809: Patient Characteristics Ben-Josef et al, in press, JCO

SWOG 0809 Results 2 year OS=65%, median OS=35 months 79 eligible; 54 R0, 25 R1 68% EHBD, 32% GB 86% completed treatment Grade 3-4 toxicities included neutropenia (44%), hand-foot (11%), diarrhea (8%) One death due to duodenal bleed Ben-Josef et al, in press, JCO

Overall Survival: SWOG 0809 2-year estimate of OS=65% OS not significantly different by margin status: 2-year OS 67% vs 60%

Sites of Recurrence Recurrence EHCC Distal (n=38) EHCC Hilar (n=13)   Recurrence EHCC Distal (n=38) EHCC Hilar (n=13) GBCA (n=25) Local only 3 (8) 1 (8) Local plus distant 5 (13) 2 (15) 2 (8) Distant only 11 (29) 11 (44) Total 19 (50) 4 (31) 13 (52)

Notable Findings Feasibility established for national intergroup trial with central reviews of surgery, pathology, and radiation oncology plan High rates of R0 resection (68%) OS and local control similar in R0 and R1 groups (perhaps due to XRT)? Difficult to compare biliary to GB due to differences in the populations

Adjuvant Therapy in Biliary Cancers: Current Landscape S0809: completed Data important to guide future study UK phase 3 study: capecitabine versus observation in GB, IHCC, EHCC (n=360) Completed, awaiting results French phase 3 study: gemcitabine and oxaliplatin versus observation in GB, IHCC, EHCC (n=190) German phase III gem/cis vs observation underway

Gem/platinum x 4 months (6 cycles) followed by Planned North American Trial: A randomized phase II/III of gemcitabine and cisplatin followed by capecitabine/radiation versus gemcitabine and cisplatin alone Gem/platinum x 4 months (6 cycles) followed by 5-FU (or capecitabine)/RT Patients with EHCC or GB CA Gem/platinum

Which Chemotherapy? Gem vs gem/cis Combination: Gemcitabine: “It’s not that much more toxic” “Looks better in the advanced setting” Gemcitabine: More is not always better in adjuvant setting… Remember the adjuvant story with irinotecan in CRC? Possibility of toxicity with cis is real: neutropenia, thrombosis risk Moore et al, JCO 29:25,3466-3473, 2011

Potential Targets for the Future? HER-2 IDH FGFR2

HER-2 Neu Javle… Siegel et al, submitted Overexpressed or amplified in 10-15% of gallbladder cancers Series of 8 GB pts with overexpression or amplification Used HER-2 directed therapy in advanced disease; 1CR, 4PR Should we try in adjuvant setting, like in breast? Would use with chemotherapy backbone Javle… Siegel et al, submitted

IDH Pathway Yen et al, Oncologist 2012 17:5-8

IDH Mutations Seen in Cholangiocarcinomas Borger et al, Oncologist, 2010 17:72-79

FGFR2 Fusions Define a Unique Molecular Subtype of Cholangiocarcinoma Seen in intrahepatic cholangiocarcinomas Most common mutation—up to 45% Targetable! Studies ongoing with BGJ398 showing responses in cholangiocarcinoma Sia et al. Nat Commun. 6:6087,2015, Wu Y et al. Cancer Discovery; 3:636-647,2013, Arai et al, Hepatology; 59:1427, 2014

Incidental Gallbladder Cancer 750,000 cholecystectomies annually in the U.S. Annual incidence of cancer of 0.3 to 1% Stage Residual disease Lymph nodes Recurrence Rate 5 Year Survival T1b 10% 10-20% 20% 40% T2 20-30% 30% 15 % T3 50% >50% 5 %* * Or Node Positive Hueman et al. Annals Surg Onc; 16: 2101-15, 2009 (Slide courtesy of Dr. Milind Javle)

NCCN Surgical Re-evaluation: Gallbladder Cancer T1b and greater tumors should undergo radical resection Underused; compliance increased from 12% to 16% from 1991-95 to 2003-5 Mayo et al. J Gast Surg 14:1578-1591, 2010

NCCN Guidelines Gallbladder: consider 5FU-based chemoRT (except T1a or T1b, N0), 5FU or gemcitabine chemotherapy, or observe Extrahepatic cholangiocarcinoma R0, (-) nodes or CIS at margin: 5FU ChemoRT or 5FU or Gem, observe, or trial R1 or R2 or (+) nodes: 5FU chemoRT, then 5FU or gem-based chemo 5FU or gem-based chemo for node (+) Intrahepatic cholangiocarcinoma R0: observe, trial, or 5FU or gem-based chemo R1 or (+) nodes: 5FU-based chemoRT or 5FU or gem-based chemo R2: Gem/Cis (category 1) Or: clinical trial, 5FU or gem-based chemo, locoregional therapy, or best supportive care Consider re-resection for any margin (+) disease

Summary For gallbladders: For extrahepatics: T1b or greater: radical resection T2 or node (+): give 6 months gemcitabine R1: try to re-resect, or else give chemoRT then gem For extrahepatics: Clean margins: give 6 months gemcitabine R1: consider re-resection, or give chemoRT followed by chemo For intrahepatics, very little data: I usually give 6 months gem For R1, try 2 months gem, then try to re-resect, otherwise chemoRT, then complete 6 months gem For R2, give gem/cis

Thank you! aas54@cumc.columbia.edu