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TRANSMET: liver transplantation combined with chemotherapy significantly enhances survival for patients with unresectable colorectal liver metastases
The TRANSMET trial (NCT02597348) investigated the efficacy of adding liver transplantation (LT) to chemotherapy (CT) for patients with definitively unresectable colorectal liver metastases (uCLM). This international, multicenter, open-label, randomized trial aimed to improve the poor long-term survival rates associated with uCLM, despite advancements in chemotherapy.1
From February 2016 to July 2021, 157 patients from 20 centers across three countries were assessed. 94 patients were randomly assigned to either the CT+LT arm or the CT-alone arm. The trial required participants to have undergone resection of their primary tumor, possess no extrahepatic disease, and demonstrate a response to up to three lines of chemotherapy over a minimum of three months.
The primary endpoint was five-year overall survival (OS), with a goal to detect a 40% improvement in OS from 10% (CT alone) to 50% (CT+LT).
The trial achieved its primary endpoint, with an intention-to-treat (ITT) analysis revealing a five-year OS of 57% in the CT+LT arm versus 13% in the CT-alone arm (p=0.0003, HR 0.37, 95% CI 0.21-0.65). In the per-protocol analysis, the five-year OS was even more pronounced at 73% for the CT+LT group compared to 9% for the CT-alone group (p<0.0001, HR 0.16, 95% CI 0.07-0.33).
Secondary endpoints included progression-free survival (PFS) and quality of life (QoL). The median PFS was 17.4 months in the CT+LT arm versus 6.4 months in the CT-alone arm (HR 0.34, 95% CI 0.20-0.58). Of the transplanted patients, 74% experienced recurrence, with 36% undergoing surgical treatment and 11% local ablation. Ultimately, 40% of these patients achieved disease-free status.
Regarding QoL, the CT+LT group showed a trend towards degradation in physical functioning and main symptoms compared to the CT-alone group. Additionally, adverse effects in the CT+LT arm included grade 3 or higher complications at 34%, retransplantation at 8%, and a 3% mortality rate within three months post-transplant. Hepatic events were most common, with biliary complications occurring in 14% of cases.
Conclusively, the TRANSMET trial demonstrated that liver transplantation, when combined with chemotherapy, significantly enhances survival rates for patients with uCLM, establishing it as a potential new standard of care. This combination therapy offers a promising alternative for patients who previously had limited treatment options, significantly improving long-term outcomes compared to chemotherapy alone.
[177Lu]Lu-DOTA-TATE demonstrates promise in newly diagnosed patients with advanced grade 2 and grade 3, well-differentiated gastroenteropancreatic neuroendocrine tumors
The Phase III NETTER-2 trial (NCT03972488) has yielded significant results, showcasing the efficacy of [177Lu]Lu-DOTA-TATE (177Lu-DOTATATE) as a first-line treatment for patients with advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs), particularly those of high grade 2 (G2) and grade 3 (G3). This study, the first to evaluate first-line radioligand therapy in any solid tumor, demonstrated significant improvements in progression-free survival (PFS) and objective response rates (ORR), potentially establishing a new standard of care for this patient population.2
The trial enrolled 226 patients with newly diagnosed, somatostatin receptor-positive high G2 or G3 advanced GEP-NETs, stratified by tumor grade and origin (pancreas vs. other). Patients were randomized 2:1 to receive either 177Lu-DOTATATE plus octreotide (n=151) or high-dose octreotide alone (n=75). The primary endpoint was PFS, while secondary endpoints included ORR, duration of response (DOR), and time to response (TTR).
The results demonstrated a remarkable improvement in median PFS for those receiving 177Lu-DOTATATE, extending to 22.8 months compared to just 8.5 months in the control arm. This reflects a 72.4% reduction in the risk of disease progression. Furthermore, the ORR was significantly higher in the 177Lu-DOTATATE group at 43.0%, compared to 9.3% in the control group.
Subgroup analyses revealed consistent benefits of 177Lu-DOTATATE across different NET grades and origins. For instance, patients with G2 NETs had a median PFS of 29.0 months, while those with G3 NETs saw a median PFS of 22.2 months.
Pancreatic NETs (pNETs) had a median PFS of 19.4 months, whereas small intestine NETs (SI NETs) achieved a median PFS of 29.0 months. ORR was notably high in patients with G3 NETs at 48.1% and in those with pNETs at 51.2%. Median TTR was approximately 5.8 months across all subgroups. Median DOR was 24.9 months for G2 NETs, 19.3 months for G3 NETs, and 18.4 months for pNETs. Due to the low number of responders in the control group, detailed DOR and TTR analyses were not feasible for that arm.
These findings underline the clinical benefits of 177Lu-DOTATATE in prolonging PFS and improving ORR for patients with advanced GEP-NETs. The NETTER-2 trial’s results support the consideration of 177Lu-DOTATATE as a new standard of care in this setting, paving the way for further investigations of radioligand therapy in other oncological settings.
TOPAZ-1 trial: durvalumab with chemotherapy improves survival at 3 years in advanced biliary tract cancer
The Phase III TOPAZ-1 trial (NCT03972488) presented updated results demonstrating significant improvements in overall survival (OS) with the combination of durvalumab and standard chemotherapy (gemcitabine and cisplatin) compared to chemotherapy alone in patients with advanced biliary tract cancer (BTC). This study included 685 participants who were randomly assigned to receive either durvalumab (n=341) or a placebo (n=344), in addition to chemotherapy, followed by monotherapy with either durvalumab or placebo.3
After a median follow-up of 41.3 months, the median OS for patients receiving the durvalumab combination was 12.9 months, compared to 11.3 months for those receiving chemotherapy alone. The hazard ratio (HR) for this comparison was 0.74, indicating a 26% reduction in the risk of death with the durvalumab regimen. Notably, the 3-year OS rate was significantly higher in the durvalumab group at 14.6% versus 6.9% in the placebo group.
After a median follow-up of 41.3 months, the median OS for patients receiving the durvalumab combination was 12.9 months, compared to 11.3 months for those receiving chemotherapy alone. The hazard ratio (HR) for this comparison was 0.74, indicating a 26% reduction in the risk of death with the durvalumab regimen. Notably, the 3-year OS rate was significantly higher in the durvalumab group at 14.6% versus 6.9% in the placebo group.
In patients who achieved disease control, the 3-year OS rate was 17.0% for the durvalumab combination compared to 7.6% for the chemotherapy-alone group. The extended long-term survival (eLTS) analysis showed that 12.8% of the total study population were long-term survivors, with a higher proportion in the durvalumab arm (17.0%) than in the placebo arm (8.7%).
Safety profiles between the two groups were comparable, with serious adverse events (SAEs) occurring in 32.8% of patients in the durvalumab group and 36.7% in the placebo group among the long-term survivors. These rates were lower than those observed in the overall study population, where SAEs were reported in 48.8% and 44.4% of patients in the durvalumab and placebo groups, respectively.
The findings from the TOPAZ-1 trial reinforce the clinical benefits of the addition of durvalumab to standard chemotherapy for patients with advanced BTC, highlighting its role in improving long-term survival without introducing new safety concerns. This regimen represents a significant advancement in the treatment landscape for this patient population, providing a new standard of care option.
EMERALD-1 shows PFS advantage with addition of durvalumab to TACE in unresectable, embolization-eligible hepatocellular carcinoma
The CAPRI 2-GOIM trial (NCT05312398) represents a pivotal advancement in the treatment landscape for metastatic colorectal cancer (mCRC), focusing on the evaluation of comprehensive genomic profiling (CGP) through plasma-based next generation sequencing (NGS) as a tool to guide therapeutic decisions in RAS/BRAF V600E wild type (WT) patients. This Phase II trial aimed to assess the efficacy and safety of cetuximab-based therapy across three treatment lines, predicated on molecular profiling derived from both tissue and plasma circulating tumor DNA (ctDNA).4
In this trial, a total of 240 patients were screened, with 202 ultimately enrolled. Each patient underwent baseline genomic profiling using FoundationOneCDx for tumor tissue and FoundationOneLiquidCDx, targeting 324 genes, for plasma ctDNA. Notably, all 202 enrolled patients had baseline plasma ctDNA results available, underscoring the feasibility of plasma-based NGS in this setting. The majority of patients (88%) were identified as having RAS/BRAF WT mCRC, pivotal for predicting response to anti-epidermal growth factor receptor (EGFR) therapies.
Genomic analysis revealed specific molecular alterations potentially influencing therapeutic outcomes. Among the identified alterations, RAS mutations (13 KRAS/NRAS mutations, 3 KRAS amplifications) and BRAF mutations (1 BRAF V600E mutation, 7 non-V600E mutations or rearrangements) were notable. Additionally, mutations in other key genes such as APC, TP53, PI3KCA, and SMAD4 were prevalent, reflecting the complex genomic landscape of mCRC.
Of significant clinical importance was the reclassification of 24 out of 199 enrolled patients (12%) based on plasma-based NGS findings.
These molecular alterations could potentially contribute to resistance against anti-EGFR therapies, thereby emphasizing the critical role of comprehensive genomic profiling in treatment stratification and selection.
Furthermore, concordance between tissue and plasma ctDNA was observed in the majority of cases with RAS mutations, further validating the utility of plasma-based NGS as a non-invasive alternative for genomic profiling.
In conclusion, the CAPRI 2-GOIM trial establishes baseline plasma-based NGS as a feasible and effective method for molecular assessment in mCRC, particularly in identifying actionable alterations that may inform treatment decisions. These findings contribute significantly to the expanding body of evidence supporting the integration of liquid biopsy-derived genomic data in clinical practice, offering promise for enhanced outcomes in patients with mCRC eligible for anti-EGFR therapies based on RAS/BRAF status.
References
- Adam R, C. Piedvache, L. Chiche, et al. 1O Chemotherapy and liver transplantation versus chemotherapy alone in patients with definitively unresectable colorectal liver metastases: Updated results from the randomized TRANSMET trial. Annals of oncology. 2024 Jun 1;35:S1–1.
- Singh S, Halperin D, S. Myrehaug, Herrmann K, Pavel ME, Kunz PL, et al. 211MO First-line efficacy of [177Lu]Lu-DOTA-TATE in patients with advanced grade 2 and grade 3, well-differentiated gastroenteropancreatic neuroendocrine tumors by tumor grade and primary origin: Subgroup analysis of the phase III NETTER-2 study. Annals of oncology. 2024 Jun 1;35:S92–3.
- Oh D-Y, He AR, Qin S, Chen L-T, T. Okusaka, Vogel A, et al. 279MO Three-year survival, safety and extended long-term survivor (eLTS) analysis from the phase III TOPAZ-1 study of durvalumab (D) plus chemotherapy in biliary tract cancer (BTC). Annals of oncology. 2024 Jun 1;35:S117–7.
- Martini G, Martinelli E, Troiani T, Napolitano S, Nicastro A, Maiello E, et al. 6MO Evaluation of plasma assessed comprehensive genomic profiling before first-line treatment with FOLFIRI plus cetuximab in RAS/BRAFV600E wild type metastatic colorectal cancer patients in the CAPRI 2-GOIM trial. Annals of oncology. 2024 Jun 1;35:S4–5.
Written by Ellie Jackson
