Neoadjuvant chemotherapy with gemcitabine plus cisplatin followed by radical liver resection versus immediate radical liver resection alone followed adjuvant therapy in biliary tract cancer: Final results from the phase III AIO/CALGP/ACO-GAIN-Trial.

4008 Background: Radical surgical resection represents the only potentially curative treatment option for Biliary Tract Cancer (BTC) and (incidental) Gallbladder Carcinoma ((I)GBC). Nevertheless, 5-year OS is only 20–40% after curatively intended resection and data regarding pure adjuvant chemotherapy in BTCs are currently conflicting. Encouraging results of neoadjuvant/perioperative concepts in other malignancies provide a rationale to use this treatment in the early phase management of GBC and intrahepatic as well extrahepatic cholangiocarcinoma (ICC/ECC). Methods: GAIN is a multicenter, randomized, controlled, open-label phase III trial, including patients (pts) with localized or locally advanced resectable non metastatic biliary tract cancer (intra-/extrahepatic cholangiocarcinoma ICC/ECC; GBC in front of radical liver resection). Pts were randomized to either neoadjuvant (perioperative) systemic chemotherapy (Gemcitabine + Cisplatin 3 cycles pre- and post-surgery) followed by radical surgery (Arm A) or to direct surgery followed by adjuvant treatment (Arm B) according to investigators choice. Primary endpoint was OS; secondary endpoints were PFS/EFS, R0-resection rate, toxicity, perioperative morbidity, mortality and QoL. Recruitment was stopped after enrollment of 68 pts due to a slow enrollment rate. Results: Between Dec 2019 and Feb 2024, 68 pts were randomized and the ITT comprised 32 pts in Arm A and 30 pts in Arm B. Baseline characteristics were similar between arms (overall, male 55%; median age 66.0; cT3/T4 29.0%; cN+ 30.6%; 37.1% ICC, 30.6% ECC and 32.3% GBC). 90.6% of pts in Arm A completed all 3 pre-operative cycles. 43.8% in Arm A completed adjuvant treatment and 23.3% in Arm B received adjuvant treatment. Median follow-up was 11.8 months. Neoadjuvant treatment improved OS (mOS, Arm A 27.8 vs. 14.6 months Arm B; HR 0.46 [0.22 - 0.96]; p = 0.04) and R0 resection rate (62.5% vs 33.3%). This effect was also seen in event-free survival. Postoperative morbidity rates were similar in both arms (33.3% (A) vs. 32% (B)) and the 30- and 90-days mortality rates were lower for Arm A (30-days: 4.2% vs. 24%; 90-days: 4.2% vs. 28%). No new safety/toxicity signals were observed. In Arm A, 12 pts (38.7%) had at least one treatment related adverse event (TRAE) with grade 3 and 1 pt (3.2%) with grade 4. No fatal TRAEs were observed. Conclusions: Neoadjuvant / perioperative gem/cis clearly improved OS and R0 resection rate in pts with biliary tract cancer compared to direct surgery and was able to nearly double mOS while not increasing the morbidity rate and even decreasing mortality rates. Clinical trial information: NCT03673072 .