TRANSMET Regimen Proves Safe, Feasible for Definitively Unresectable CRC Liver Metastasis

The addition of liver transplantation to standard chemotherapy not only improved progression-free survival (PFS) and overall survival (OS) vs chemotherapy alone in patients with definitively unresectable colorectal cancer (CRC) liver metastasis but demonstrated no concerning safety signals or long-term deterioration in quality of life (QOL), according to an updated analysis of the TRANSMET trial (NCT02597348) that was presented at the 2024 ESMO Gastrointestinal Cancers Congress.¹

Regarding post–liver transplantation morbidity 3 months or less from transplant in the investigational arm (n = 36), grade 3 or higher complications, retransplantation, and death occurred at rates of 34% (n = 13), 8% (n = 3), and 3% (n = 1), respectively. Any grade and grade 3b or greater adverse effects (AEs) were divided by hepatic, digestive, pulmonary, renal (any grade, 22%; grade ≥3b, 3%), and superficial site infection events (any grade, 8%; grade ≥3b, 6%).

Hepatic events were the most common and were categorized as biliary (any grade, 14%; grade >3b, 11%), arterial (17%; 3%), early graft dysfunction (11%; 8%), collection (8%; 3%), PNF (6%; 6%), hemorrhage (6%; 6%), hepatic or caval (3%; 3%), ascites (6%; 0%), portal (3%; 0%), or rejection (8%; 0%). Digestive issues were tied to the ileus (any grade, 8%; grade ≥3b, 3%) and denutrition (3%; 0%). Pulmonary events were pleural effusion (any grade, 17%; grade ≥3b, 3%) or other (11%; 8%), and superficial site infection included CMV (8%; 0%), other (19%; 3%), or diabetes (17%; 0%).

“Liver transplantation in the per-protocol population achieves similar results in term of morbidity/mortality and survival compared to liver transplantation for established indications,” Dr Maximiliano Gelli, presenting study author and head of the Surgical and Interventional Department at Gustave Roussy in Paris, France, said in a presentation of the data. “Post liver transplantation chemotherapy is feasible with acceptable toxicity [although] the impact on survival [is unknown].”

Liver resection with or without local ablation is the standard intervention for patients with resectable CRC liver metastasis and the only to afford the chance for long-term survival. Patients with initially unresectable CRC liver metastasis may be able to undergo secondary resection after conversion chemotherapy and derive survival benefit, whereas those with definitively unresectable CRC liver metastasis are limited to systemic chemotherapy, which is associated with poor long-term survival.

TRANSMET is an international, multicenter, open-label, randomized trial that enrolled patients with definitively unresectable CRC metastasis. Eligibility criteria required that patients were no older than 65 years of age and have an ECOG performance status of 0 or 1; resection of the primary tumor; no extrahepatic disease; objective response to no more than 3 lines of chemotherapy for at least 3 months; carcinoembryonic antigen levels below 80 ng/mL or have a 50% reduction from baseline; and platelet count above 80,000 and white blood cell count above 2500.

The primary end point was OS. Secondary end points included 3-year OS, PFS, recurrence rate, and health-related QOL.

A total of 157 patients were evaluated for eligibility by the independent monitoring committee, 63 of whom were not eligible because they were resectable, had tumor progression, received more than 3 lines of chemotherapy, or other reasons. Ninety-four patients were randomly assigned to liver transplantation (n = 47) or chemotherapy alone (n = 47). Thirty-six and 38 patients in the transplantation and chemotherapy arms, respectively, were ultimately included in the per protocol analysis because 11 and 9 patients in each arm deviated from study inclusion criteria.

Baseline characteristics in the investigational and control arms, respectively, indicated that the minority of patients had a right-sided primary tumor (15%; 15%); most had a Fong’s clinical risk score above 2 (89%; 89%); and patients had a median of 20 nodules at diagnosis (IQR, 14-25; IQR, 12-25). The median maximum tumor diameters were 55 mm (IQR, 43-76) and 50 (IQR, 27-83) in the investigational and control arms, respectively, and most patients had synchronous disease (100%; 96%).

Findings from the study previously presented at the 2024 ASCO Annual Meeting revealed an 84% reduction in the risk of death with the added intervention in the per protocol population (HR, 0.16; 95% CI, 0.07-0.33; P <.0001), exceeding the hypothesis of 5-year OS rates of 50% and 10% with transplantation and chemotherapy alone, respectively. At a median follow-up of 59 months, the 5-year OS rate in the intention-to-treat population was 57% in the transplantation arm vs 13% in the chemotherapy alone arm (HR, 0.37; 95% CI, 0.21-0.65; P =.0003).²

Additional findings indicated that the 3- and 5-year PFS rates in the per protocol population were 33% and 20%, respectively, in the transplantation arm vs 4% and 0% in the chemotherapy alone arm (HR, 0.34; 95% CI, 0.20-0.57; P <.0001). The 5-year PFS rate after surgical rescue defined as the time from randomization to failure of curative-intent treatment of recurrence with surgery or ablation was 36% (95% CI, 21.9%-59.4%).²

Additional results from the present analysis indicated that 72% of patients in the investigational arm (n = 26/36) received adjuvant chemotherapy. The delay in starting adjuvant chemotherapy was 68 days (IQR, 44-109), and the number of cycles of chemotherapy after transplant for more than 6 or at least 3 months was 15 (58%). Grade 3 or higher chemotherapy-related toxicities after transplant (36%) included hematologic disorders (17%), gastrointestinal disorders (14%), nervous system disorders (5%), and other disorders (14%).¹

A total of 259 and 179 serous AEs occurred in the as-treated population. In the investigational arm, 90% and 80% of patients experienced at least 1 AE and serious AE (SAE), respectively, vs 54% and 83% of those in the chemotherapy alone arm. When evaluated by time period, 28% vs 4% of patients in the investigational and chemotherapy alone arms, respectively, had at least 1 SAE in the first 3 months of the study; these rates were 30% vs 9% during months 3 and 6 and 60% vs 80% after 6 months on study.

Additionally, of 74 patients at inclusion, 55 had data available for QOL analysis. The median global health score at inclusion was 75 (range, 58-83) in the investigational arm vs 71 (range 58-83) in the chemotherapy alone group.

“[There was] no major long-term deterioration in terms of quality of life in the liver transplantation plus chemotherapy group,” Gelli concluded.

Disclosures: Gelli reported honoraria for medical education programs with Baxter, AstraZeneca, Jazz, and MSD; consulting (non-remunerated) for advisory role with Twincal; research fundings from INCa and ARCAD; and membership with IHPBA, AFC, and ACHBT.

References

1. Chemotherapy and liver transplantation versus chemotherapy alone in patients with definitively unresectable colorectal liver metastases: Updated results from the randomized TRANSMET trial. Presented at: 2024 ESMO Gastrointestinal Cancers Congress; June 26-29, 2024; Munich, Germany. Abstract 1O.
2. Adam R, Piedvache C, Chiche L, et al. Chemotherapy and liver transplantation versus chemotherapy alone in patients with definitively unresectable colorectal liver metastases: a prospective multicentric randomized trial (TRANSMET). J Clin Oncol. 2024;42(suppl 16):3500. doi:10.1200/JCO.2024.42.16_suppl.3500