1) This open-label phase II trial evaluated the efficacy of panitumumab in combination with gemcitabine and oxaliplatin (GemOx) in patients with KRAS wild-type biliary tract cancer. 2) The response rate was 50% with this combination, and median progression-free survival and overall survival were 10.6 months and 20.3 months respectively. 3) The combination showed manageable toxicity and was well-tolerated by patients.

2. Biliary tract cancer epidemiology
GB incidence :1.8/100000 GLOBOCAN
GB Ca Delhi 9.2/100000
Cholangiocarcinoma incidence
Prognosis of GC is poor, with <10% survival at 5 years

3. IRCH Protocol in GB malignancy
ICMR Consensus document for management of gallbladder cancer 2014

4. Treatment of Biliary tract malignancy
Lancet Oncol. 2014 Jul;15(8):819-28J Clin Oncol. 2010 Oct 20;28(30):4581-6.

5. 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 FISH
JCO July 20, 2010 vol. 28 no. 21 3531-3540

6. Ca GB carcinogenesis
• GB Ca Cholangiocarcinoma
b Catenin  KRAS  P53/EGFR/P16INK4

7. Cholangiocarcinoma pathogenesis
BilN1 BILN 2 BILN 3 CIN CARCINOMA
P53 /SMAD  KRAS/EGFR/BRAF

8. Targeted therapy in Biliary tract malignancy

9. EGFR-MAb and Chemotherapy
•blocks
EGFR
nuclear
import
EGFR Mab
•DNA
Repair
enzymeInhibits
•Oxaliplatin
induced
DNA
damage
Augments
EGFR
Mab+Chemotherapy
Synergism
Mahtani R.The Oncologist January 2008 vol. 13 no. 1 39-50

11. EGFR Inhibitor in BTC

13. Study Methodology
Open label
single-arm phase II study
Multicentric 7 center in USA

14. Study design

15. 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 year
No history of chemotherapy or anti-EGFR therapy
ECOG performance status of 0 or 1
Adequate hepatic, renal and hematologic function

16. Exclusion criteria
Patients with concurrent malignancies
Patients with known brain metastasis
Pre-existing grade 2 or higher peripheral neuropathy

17. 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

18. Baseline characteristics

19. 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)

20. Best reduction of tumor size

21. Response to Gem-Ox+ Panitumumab

22. PFS OS

23. Treatment related adverse events
No statistical correlation between the presence of rash/hypomagnesemia and response

25. 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

26. Critical appraisal
 Sample size Adequate :30 patients was required to achieve with
power of 80% to detect an absolute difference in response rate of
20% (50% vs 30%) using a one-sided binomial test with a type 1
error set at 0.102.
 Statistics well defined

27. 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

28. 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