Treatment of Biliary Cancers

Abby B. Siegel, MD, MS Columbia University

Co-Chair, SWOG Hepatobiliary CommitteeNCI Task Force, Hepatobiliary Cancers

Biliary Anatomy

Adapted from De Groen et al, NEJM 1999 Oct 28;341(18):1368-78

Treatment arm Gem Gem + Cis

Number of patients n=206 n=204

Deaths n(%)141

(68.5) 122 (59.8)

Median survival (mo) 8.3 11.7Log rank p value 0.002Hazard ratio (95% CI) 0.70 (0.54, 0.89)

Gemcitabine With or Without Cisplatin in Advanced or Metastatic Biliary Cancer

(UK ABC-02 trial)

Gemcitabine/Cisplatin in Perspective

• A standard for advanced disease• Study results influenced by:

• GB vs IHCC vs EHCC• Included ampullary cancers• Patient selection:

– AST/ALT/Alk phos<3XULN– T Bili < 1.5 ULN– Accrual in select centers with experience– 27% locally advanced disease

• Caution about using Gem/cis as the only backbone in first line therapy

• What about other effective therapies: Gem/cape?

Single Agent Targeted Therapy

Target Agents in testing Study type # of patients Results

VEGF/Ras-Raf-MAPK

Sorafenib (SWOG 0514)

Phase II single agentNCT01093222

N=31 Median PFS 3 moMedian OS 9 mo

Sorafenib Phase II single agentNCT00238212

N=46 Median PFS 2.3 moMedian OS 4.4 mo

EGFR/Her-2 neu Trastuzumab Phase II single agent Closed d/t slow accrual1CR

Erlotinib Phase II single agentNCT00033462

N=42 Median TTP 2.6 moMedian OS 7.5 mo

Lapatinib Phase II single agent N=17 Median PFS 1.8 moMedian OS 5.2 mo

mTOR Sirolimus Phase II single arms for HCC and ICC

N=9 3/9 SDMedian survival 7 mo

MEK MEK-162 Phase I N=26 1CR

AZD6244 Phase II single agent N=28 1 CRMedian TTP 5.4 mo

AKT MK-2206 Phase II single agent(Second line)

On-going

Bengala C et al, British Journal of Cancer 2010,102: 68 – 72; Rizell et al, Int J Clin Oncol 2007 13:66-70 Philip, P. A. et al. J Clin Oncol 2006, 24:3069-3074, Ramantaan et al, Cancer Chemother Pharmacol 2009 64:777–783

Combination Targeted Agents

Targets Agents Study type Number of patients

Results

VEGF/EGFR Bevacizumaband Erlotinib

Phase II(Ph II consortium)

34 pts (interim report)

RR 17%Median TTP 8 months

Bevacizumab and Erlotinib

Phase II (Wisconsin)NCT00356889

53 RR 12%Median TTP 4.4OS 9.9 months

Bevacizumab and Erlotinib

Phase II (Denmark)NCT00350753

On-going

VEGF/EGFRRas/Raf

Sorafenib and Erlotinib

Phase II(SWOG0941)NCT01093222

32 RR 6% (unconf)PFS 2 monthsOS 6 months

Cytotoxic Chemotherapy with Targeted AgentsCombination Targeted

agent(s)Study type Number Results

Gemcitabine, oxaliplatin

Cetuximab Rand Phase II 150 RR 29%Median PFS 6 moMedian OS 12.4 mo

Gemcitabine, oxaliplatin

Erlotinib Phase III 268 RR 30%Median PFS 5.8 moMedian OS 9.5 mo

Gemcitabine, oxaliplatin

Bevacizumab Phase II 35 RR 40%PFS 8.8 moOS 11.6 mo

Gemcitabine, oxaliplatin, capecitabine

Panitumumab Phase IINCT00779454

On-going

Gemcitabine, oxaliplatin

Sorafenib Phase IINCT00955721

On-going

Gemcitabine, cisplatin

Sorafenib Phase II (MSK)NCT00919061

On-going

Gemcitabine, capecitabine

Bevacizumab Phase IINCT01007552

On-going

Gemcitabine Vandetanib (VEGFR/EGFR)

Randomized Phase IINCT00753675

On-going

Adjuvant Therapy for Biliary Cancers

• No clear prospective randomized data

• Best evidence so far is a meta-analysis

• 6712 patients, non significant improvement in OS for any adjuvant therapy (HR 0.74, p=0.06)

Adjuvant Therapy for Biliary Cancer:

Horgan A M et al. JCO 2012;30:1934-1940

Adjuvant Therapy for Biliary Cancers

• No large randomized trials yet, and no clear guidelines

• Metaanalysis suggests possible benefit of chemotherapy for all, particularly for node (+) and margin positive disease

• Radiation is often added in margin (+) disease

I usually give 6 months gem or gem/cis for margin (-), consider XRT + chemo for margin (+) disease; consider re-resection also

Horgan et al. JCO 2012;30:1934-1940

Adjuvant Therapy: SWOG 0809• Eligibility

– 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 withCapecitabine 665 mg/m2 BID

x 7 days

For 6 weeks

4500 cGy (5 days a week, 180 cGy daily) with 900 cGy boost

Adjuvant Therapy in Biliary Cancers: Current Landscape

• BILCAP (UK): Phase 3: capecitabine versus observation in GB, IHCC, EHCC (n=360)

• French phase 3 study: gemcitabine and oxaliplatin versus observation in GB, IHCC, EHCC (n=190)

• ACTICCA-01: Phase 3: adjuvant gemcitabine and cisplatin versus BSC or capecitabine (depends on BILCAP)

Potential New Targets in Cholangiocarcinoma

• MEK

• IDH1/2

• FGFR

MEK Inhibition in Cancer TherapyRAS-RAF-MEK pathway

implicated in many tumors

• B-Raf mutations:

0-22% Bile duct tumors

• K-Ras mutations 3-54% Bile duct tumors

H-Ras K-Ras N-Ras

A-Raf B-Raf C-Raf

MEK1&2

ERK1&2

Receptor Tyrosine Kinase

Mutated and activatedin multiple cancers

Activation of Transcription/Proliferation

MEK Inhibitors in Biliary CancerTreatment Target No. of

Patients RR (%) PFS

(months)OS (months)

Toxicity Profile ( grade 3 and 4)

AZD6244 (first and second line)

MEK1/2

28 12 1 CR

5.4 9.8 Fatigue (8%), diarrhea ( 16%), rash, cellulitis

No ocular toxicities reported

MEK162 (ARRY-438162)

(first and second line)

MEK 1/2

26 eval 8

1 CR

2.6 N/A Anasarca, hypokalemia, hyponatremia, upper/lower gastrointestinal hemorrhage and mucositis (1 pt each)

Retinopathy was the most frequently reported event (6 pts)

Bekaii-Saab et al. JCO 2011 29:2357-63, Finn et al, GI ASCO 2012

Mek Inhibition Second Line: Trametinib(SWOG 1310)

Patients with refractory advanced biliary cancer

who have failed one prior line of treatment

Randomize

5-FU or capecitabinea

(N = 40)

Single Agent Trametinib

(2mg QD) (N=40)

IDH PathwayYen et al, Oncologist 2012 17:5-8

Yen et al, Oncologist 2012 17:5-8

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

Borger et al, Oncologist, 2010 17:72-79

IDH Inhibitors• Isocitrate dehydrogenase mutations lead to

production of 2-hydroxyglutamate

• 2HG as potential non-invasive biomarker of response– Plasma– MRS

• Inhibitors being actively developed

FGFR2 Fusions Define a Unique Molecular Subtype of Cholangiocarcinoma

Wu Y et al. Cancer Discovery 2013;3:636-647, Arai et al, Hepatology 2013, EPUB ahead of print

Optimizing the Evaluation of Targeted Agents in Cholangiocarcinoma

• Choosing the “relevant” target(s) or combination of targets

• Having appropriate preclinical models• Stratifying by site if target differs based on

location• Enriching clinical trial population for target