Chemotherapy and liver transplantation versus chemotherapy alone in patients with definitively unresectable colorectal liver metastases: A prospective multicentric randomized trial (TRANSMET).

3500 Background: Despite the increasing efficacy of chemotherapy (CT) and advances in surgical techniques for initially unresectable colorectal liver metastases (uCLM), secondary resection rate remains low. For definitively uCLM, CT remains the standard of care but liver transplantation (LT) has shown promising results. This first randomized trial aimed to assess the efficacy of CT combined to LT for uCLM. Methods: Patients with definitively uCLM from resected BRAF non mutated colorectal cancer, having responded to CT (≥ 3 months and ≤ 3 lines) in the absence of extrahepatic disease, were validated by an independent experts’ committee and randomly assigned (1:1) to receive CT and LT (CT+LT arm) or CT alone (CT arm). The primary endpoint was 5-year overall survival (OS). Secondary endpoints were progression free survival (PFS) and patterns of recurrence. In order to detect a 40% difference in OS from 10% (CT) to 50% (CT+LT) (2-sided α level 5% - 90% power), 29 events were initially needed, secondly re-estimated to 50 according to the rate of patients not receiving LT in the CT+LT arm during the study. Results: Between February 2016 and July 2021, 94 patients (median age 54 years, IQR 47-59) were randomly assigned to CT+LT arm (n = 47) or CT arm (n = 47). Median number and maximal diameter of uCLM at diagnosis were 20 (13-25) and 51.5 (37-78) mm, respectively. At randomization, objective response was obtained after a median number of 20 (14-27) CT cycles during 1 (44%), 2 (40%) or 3 (16%) lines. Median delay between primary tumour resection and randomisation was 14.6 (10.6-22.3) months. In CT+LT arm, 38 (81%) underwent LT after a median of 51 (30-65) days from randomization. Nine patients did not receive LT because of tumour progression during the waiting time or intraoperative finding of extrahepatic disease. Three (8%) of the 38 transplanted patients were retransplanted, one of whom (3%) died postoperatively. Post-transplant CT was administered in 26 (68%) patients. In CT arm, 9 (19%) patients unexpectedly underwent partial hepatectomy (7) or LT (2). In intent-to-treat analysis, 5-year OS was 57% in CT+LT arm and 13% in CT alone arm (log-rank test: p = 0.0003 - HR 0.37; 95%CI 0.21-0.65). In per protocol analysis, 5-year OS rate was 73% and 9%, respectively (HR 0.16; 95%CI 0.07-0.33). Median PFS was 17.4 months versus 6.4 months (HR 0.34; 95%CI 0.20-0.58), respectively. Among transplanted patients, 28 (74%) had lung (39%), liver (3%), other (21%) or multisite (11%) recurrence, optionally treated by surgery (36%) or local ablation (11%). Fifteen (40%) patients were ultimately disease-free. Conclusions: LT combined with CT significantly improved survival in selected patients with uCLM compared to CT alone. These results argue for validating LT as a new standard option that may change the treatment strategy for liver-only uCLM patients. Clinical trial information: NCT02597348 .