Background: Biliary tract cancer encompasses a group of genetically heterogeneous tumors. Panitumumab is a human EGFR inhibitor and has shown anti-tumor activity in RAS WT colorectal cancer. Methods: Pts with advanced KRAS wild type biliary tract or gallbladder adenocarcinoma were 2:1 randomized to receive Cis (25mg/m2) followed by Gem (1000mg/m2) on days 1 and 8 of a 21-day cycle, plus Panitumumab (6mg/kg) in arm A until disease progression. Primary endpoint was the progression-free survival rate at 6 months. For genetic profiling, massive parallel multigene sequencing was done by using a custom designed cholangiocarcioma multigene panel on an IonTorrent Proton. Mutations (21 genes) as well as amplifications and deletions (19 genes) were identified by panel tailored bioinformatic algorithms. Results: 93 pts were enrolled (63 per arm A and 30 arm B). Pts characteristics (panitumumab vs. control): median age 61.5 vs. 58.5 years; 59% vs. 50% male; intrahepatic, extrahepatic, gall bladder (%): 63, 16, 17 vs. 71, 11, 11; ECOG PS 0, 1, 2 (%): 64, 33, 2 vs. 45, 55; prior resection (%): 46 both arms. The most common grade 3-4 non-haematological adverse event (AE) was skin toxicity (39% vs 0%). Distribution of other grade 3-4 haematological and non-haematological AEs were not significantly different between both arms. 6-months PFS rate was not significantly different (55% vs 73%), mPFS was 6.7 vs. 8.2 mo, HR (95% CI, Gem/Cis ref.): 0.73 (0.43 – 1.24), p = 0.24; mOS was 12.8 vs. 21.4 mo, HR (95% CI, Gem/Cis ref.): 0.74 (0.39 – 1.4), p = 0.35; response rate (in evaluable pts): panitumumab (28/63 [45%] vs. control 11/28 [39%]. The most frequent genetic variations were detectable in p53 (34%), IDH1/2 (19%) and SMAD4 (11%) with up to 9 events per patient. The prognostic and predictive role of the variants is currently under investigation and will be presented. Conclusions: Panitumumab in combination with chemotherapy does not improve response rate, PFS and OS in patients with advanced bilary tract cancer. Further investigations of chemotherapy in combination with anti-EGFR antibodies are not warranted. Clinical trial information: NCT01320254