Biliary tract cancer epidemiology

GB incidence :1.8/100000 GLOBOCANGB Ca Delhi 9.2/100000 Cholangiocarcinoma incidencePrognosis of GC is poor, with <10% survival at 5 years

IRCH Protocol in GB malignancy

ICMR Consensus document for management of gallbladder cancer 2014

Treatment of Biliary tract malignancy

Lancet Oncol. 2014 Jul;15(8):819-28J Clin Oncol. 2010 Oct 20;28(30):4581-6.

Genomic landscape of Biliary tract cancer Gene and Reference Gallbladder

Carcinoma (%)Cholangiocarcinoma (%) Detection Method

EHCC IHCC

CTNNB1/β-catenin

    Yanagisawa et al

5-9 SEQ

KRAS

Hanada et al 19-38 10-15 45-54 PCR-SSCP

BRAF

Saetta et al 33 0 22 SEQ

EGFR

Leone et al 9-12 6-18 10-20 SEQ

PIK3CA

Riener et al 4 0 9 SEQ

ERBB2/HER2

Nakazawa et al 16 5 0 IHC and FISHJCO July 20, 2010 vol. 28 no. 21 3531-3540

Ca GB carcinogenesis

• GB Ca Cholangiocarcinoma

b Catenin KRAS P53/EGFR/P16INK4

Cholangiocarcinoma pathogenesis

BilN1 BILN 2 BILN 3 CIN CARCINOMA

P53 /SMAD KRAS/EGFR/BRAF

Targeted therapy in Biliary tract malignancy

EGFR-MAb and Chemotherapy

• blocks EGFR nuclear import

EGFR Mab

• DNA Repair enzyme

Inhibits

• Oxaliplatin induced DNA damage

Augments

EGFR Mab+Chemotherapy

Synergism

Mahtani R.The Oncologist January 2008 vol. 13 no. 1 39-50

EGFR Inhibitor in BTC

Study Methodology

Open labelsingle-arm phase II studyMulticentric 7 center in USA

Study design

Inclusion criteria

Metastatic or unresectable KRAS WT biliary tract adenocarcinoma(bile ducts, hepatic duct, cystic duct, common bile duct, ampulla of Vater or gallbladder adenocarcinoma)

>18 yearNo history of chemotherapy or anti-EGFR therapy ECOG performance status of 0 or 1 Adequate hepatic, renal and hematologic function

Exclusion criteria

Patients with concurrent malignancies Patients with known brain metastasis Pre-existing grade 2 or higher peripheral neuropathy

Study methodology• CT scans and CA19-9 levels q8wk • Toxicity :CTCAE version 4.0. • Treatment was discontinued

disease progression ECOG PS 3 participant withdrawal.

• Panitumumab symptomatic skin nail-related toxicity any clinically related grade 3 toxicity.

• Gemcitabine and oxaliplatin ANC <1000 mcl platelet count <75 000mcl other grade 3 non-haematologic

toxicities.

D1•panitumumab at 6mg/kg D1•Gemcitabine 1000mg/m2•oxaliplatin at 85mg/m2

D15 •Gemcitabine 1000mg/m2•oxaliplatin at 85mg/m2

Baseline characteristics

Statistical analysis• Intention-to-treat (ITT) principles• The primary endpoint :radiographic response rate by RECIST • secondary endpoints :PFS, OS and toxicity. • sample size of 30 • power of 80% with a type 1 error set at 0.10.• PFS:The time from study enrolment to date of cancer progression or

death, whichever occurred first• OS : the time of enrolment in the study until the date of death from

any cause. The survival analysis calculated by Kaplan–Meier. • SAS software (v9.3; SAS Institute, Cary,NC, USA)

Best reduction of tumor size

Response to Gem-Ox+ Panitumumab

PFS OS

Treatment related adverse events

No statistical correlation between the presence of rash/hypomagnesemia and response

Discussion

• This open-label phase II trial was designed to evaluate the efficacy of panitumumab to GemOx among selected patients with a KRAS WT allele.• Response rate of 50%, in evaluable patients and 45% in patients who

received at least one dose of study drug.• The median PFS was 10.6 months and median OS 20.3 months.• The combination of gemcitabine, oxaliplatin and panitumumab was

well tolerated with manageable grade 3 and 4 toxicities

Critical appraisal

Sample size Adequate :30 patients was required to achieve with power of 80% to detect an absolute difference in response rate of20% (50% vs 30%) using a one-sided binomial test with a type 1error set at 0.102. Statistics well defined

Combinations regimen chosen: A large effect demonstrated Preclinical synergy

Pre specified improvement in response rate compared to historical data :Done

Journal of Clinical Oncology, Vol 27, No 19 (July 1), 2009: pp 3073-3076

Critical appraisal

Sample size adequate

Statistics well defined yes

Novel single agent tested yes

Pre specified improvement in response rate compared to historical data

yes

Ongoing phase 3 trial on basis of this trial yes

End point tailored to drug’s mechanism of action

ORR

Appropriate criteria for assessment yes

In the sea of pessimism about Ca GBstill there is hope……

Thank You