TransMet Trial - Liver transplantation plus chemotherapy vs chemotherapy alone in permanently unresectable colorectal liver metastases.pptx

A journal club discussion on Recently published Transmet trial which describes good outcomes of transplant in unresectable colorectal liver metastasis with liver transplantation after long term systemic therapy.
Key words- colorectal liver metastasis (CRLM), Liver transplantation

1. TransMet Trial Liver transplantation plus chemotherapy vs chemotherapy alone In permanently unresectable colorectal liver metastases PI – Prof Rene Adam, France. Multicenter, open label, prospective, RCT Conducted in multiple centers in France, Italy, Belgium between Feb 2016 to July 2021. Published in Lancet 2024. Funded by French NCI Dr Afroj Ismail Bagwan Senior fellow, GI-HPB Oncology, Tata Memorial Hospital, Mumbai.

2. Introduction Complete surgical resection plus systemic chemotherapy – Standard of care for CRLM 5 year survival = 40% ( Osterlund P. et. al. 2021) However, < 30% - resectable ; suitable for upfront surgery. Tumor downstaging f/b secondary resection – 5 year survival close to 33%. (Adam R. et. al. 2004) Only 13-50% cases – secondary curative intent surgery possible even after doublet or triplet regimens with targeted therapy. (Bond MJG et. al. 2023)

3. Systemic therapy is standard of care for unresectable CRLM . Initial results with LT in such cases had poor outcome (5yr survival 18%). 1980-90s. Recent times, increased efficacy of chemotherapy and increased expertise of transplantation teams… Need for revisiting LT in carefully selected patients who responded to chemotherapy.

4. Evidence before TransMet

5. SECA I study

6. SECA II study

7. Material & methods Eligibility criteria – <65 years ECOG 0 or 1 Confirmed unresectability of CRLM by expert surgeons High standard resection of primary No extrahepatic disease Partial response or stability with < 3 line of CT with > 3 months as per RECIST criteria No BRAF mutation CEA < 80 ng/ml or 50% decrease from baseline No general contraindication to liver transplantation.

8. Study design 1:1 randomization between two study arms. Block randomization using pseudo random number generator. Radiological evaluation by 2 expert liver surgeons, 2 expert oncologists and 1 expert radiologist at diagnosis, after chemotherapy for defining unresectability . Previous hepatic resection not a contraindication provided there was technical unresectability . Initially, 29 deaths were needed in combined groups which later revised to 50 for drop-outs in LT+C group to preserve intended power of trial.

9. Once eligible for LT – waiting list. LT within two months from last chemotherapy cycle. If progression while on waiting list, chemotherapy was restarted. Temporarily C/I until disease control is achieved. Transplant techniques and immunosuppression – conventional and standard.

10. In chemotherapy group – Systemic chemotherapy continued as per the discretion of treating team Follow up – standard In LT + C group additionally , PET CT at 6 months, 12 months and annually upto 5 years.

11. Outcomes Primary end point : 5 year overall survival Secondary end points : 3 year overall survival, 3 and 5 year progression free survival, 3 and 5 year recurrence rate, and Health related quality of life.

12. Trial profile 157 assessed for eligibility. 63 excluded. 94 enrolled & randomised. 47 to each arm intention-to-treat analysis. 36 in LT + C arm & 38 in CT arm as per protocol criteria

13. Results Baseline characteristics at diagnosis – Comparable between two groups. 100 % synchronous mets at diagnosis in LT + C group All but 2 (4%) synchronous mets at diagnosis in CT alone arm Average number of mets - 20 Diameter of largest lesion comparable

14. Baseline characters at randomization .. Average number of CRLM 14 & 15 respectively. Diameter of largest metastasis - 27 mm Fong’s score – Low in 43% & high in 57 % patients in LT + C arm While in chemo alone group, 28 % & 72 % resp.

15. Gd 3 or more toxicity in 13 % vs 17 % of patients resp. Total number of chemotherapy cycle 21 vs 17 in either arms. Previous curative intent hepatectomies in 14 patients across both the arms. 9 patients did not undergo LT as planned for various reasons like progression on waiting list (n=5), intra op finding of extrahepatic disease (N=3), prostate cancer of pre-LT check up (n=1). Median time for LT from randomization was 50.5 days with 79 % patients having surgery within 2 months.

16. Perioperative characteristics Severe morbidity 34 % Re-transplantation 8% Mortality 3% Median hospital stay – 6 days ICU 16 days hospital. Post transplant chemotherapy administered in 26 (68%) patients ; with 15 patients receiving more than 6 cycles.

17. Chemotherapy alone arm – Median 16 cycles of all line CT 6 patients 1 line ; 3 patients 2 lines and 37 patients received 3 lines of CT 3 patients in CT arm u/w local ablation ; 11 had radioembolization. 7 patients u/w partial hepatectomies and 2 patients received LT.

18. Survival outcomes Median f/u – 59.3 months (42.4 – 60.2 ) – 56 deaths were reported. 5 year OS – 56.6 % in LT +C group vs 12.6% in Chemo alone group 3 year OS – 65.5% vs 38.9% .

19. Median PFS 17.4 months in LT + C group vs 6.4 months in CT alone group. 3 year PFS – 32.9% vs 19.9% 5 year PFS 19.9% vs 0% resp.

20. In LT + C group, 26 had isolated recurrence. 19 of these 26 received chemotherapy 12 of these 26 patients received curative intent surgery or ablation. No patient received BSC at first recurrence. Median secondary PFS in LT + C arm, 35.4 months ; 5 year secondary PFS rate 36.1%. At last follow up, 15 of 36 patients were alive without disease in LT + C arm vs 1 in chemo alone arm.

21. MC Gr 3 or worse complications in LT + C group were biliary (4) > pulmonary (3) > graft dysfunction (3) > PNF (2) = hemorrhage (2) = SSI (2). QoL – comparable with a trend towards physical functioning decline over time in chemotherapy alone group.

22. Discussion TransMet trial showed significantly better 5-year survival for liver transplantation plus chemotherapy group in permanently unresectable CRLM. Otherwise, this patients would have received palliative chemotherapy. First RCT which shows clear benefit in OS with addition of transplantation in unresectable CRLM.

23. Attributed to three key factors.. Strict patient selection by rigorous eligibility criteria . Partial response or stable disease prior to LT – prerequisite. BRAF mutation was an exclusion. Implementation of independent expert committee . 40 % patients excluded which were considered potentially eligible by local tumor boards. Compassionate indications. Prioritizing transplants . 79% within 2 months. Only 1 patient waiting for more than 3 months.

24. 73 % 5 year survival in this cohort of patients is in line with established indications of LT. However, sub-optimal progression free survival because of significant recurrence (74%). Patient selection can be further improved by molecular biology and detection of microscopic residual disease using ctDNA . Exclusive lung recurrence seen in >50% ; treated by Surgery or local ablation. Secondary 5 year PFS of 36%. 42% of transplanted patients were disease free at last follow up – Cure !!

25. Limitations Heterogeneity in chemotherapy regimens – since it was left to the discretion of treating oncologists Post transplant chemotherapy wasn’t possible in all patients Super stringent patient selection may not be practical in real world practice

26. Summary Liver transplantation + chemotherapy significantly improves OS and PFS in selected patients with unresectable colorectal liver metastases compared to C alone This results were obtained through a rigorous patient selection and prioritization of organ allocation Transplanted patients have similar survival (73% at 5 years) which is comparable to those transplanted for established indications LT + C offers a potential of cure to cancer patients with otherwise poor long term outcome

27. Thank you !!