Outcomes by prior transarterial chemoembolization (TACE) in the phase III CELESTIAL trial of cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC)

Yau, Thomas; Cheng, A-L.; Meyer, Tim; Ryoo, Baek‐Yeol; Park, J.-W.; Klümpen, Heinz Josef; Lim, Ho Yeong; Kim, Stéfano; Knox, Jennifer J.; Patel, Manali I.; El-Khoueiry, Anthony B.; Kelley, Robin Kate; Abou‐Alfa, Ghassan K.

doi:10.1093/annonc/mdy282.087

Cited by 13 publications

(14 citation statements)

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“…Cabozantinib also demonstrated statistically significant superiority to placebo in PFS and ORR (Table 2). Cabozantinib may be considered an ‘all‐comer’ second‐line treatment for patients with advanced HCC because benefit vs placebo was shown in patients who showed radiological progression or were intolerant to prior sorafenib treatment consistently across multiple subgroup analyses, including those of aetiological factors, demographic characteristics and treatment history 49,51‐55 . This is in contrast to regorafenib (benefit demonstrated in patients who showed radiological progression only [see above]) and ramucirumab (benefit demonstrated in patients with elevated AFP only [see below]).…”

Section: Summary Of Data For Approved Second‐line Systemic Agentsmentioning

confidence: 99%

Navigating the new landscape of second‐line treatment in advanced hepatocellular carcinoma

Rimassa

Wörns

2020

Liver International

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Sorafenib and lenvatinib are approved for first-line treatment of patients with advanced hepatocellular carcinoma (HCC), and the efficacy of atezolizumab plus bevacizumab has been demonstrated versus sorafenib. Over time, first-line treatment frequently fails, and regorafenib, cabozantinib, ramucirumab (for patients with alpha fetoprotein ≥400 ng/mL), nivolumab, pembrolizumab and ipilimumab plus nivolumab are approved for use after sorafenib (but not lenvatinib) treatment in advanced HCC. Given the considerable complexity in the therapeutic landscape, the objective of this review was to summarize the clinical evidence for second-line agents and provide practical guidance for selecting the best sequential treatment approach. The timing and sequencing of treatment switches are key to optimizing patient outcomes in advanced HCC, and decisions should be informed by reasons for discontinuation of previous therapy and disease progression. It is important not to switch too soon, because sequential treatment benefit may then be lost, nor should switching be delayed too long. Effectiveness, safety and tolerability, patient quality of life, route of administration, dosing regimen, drug class, molecular target and individual patients' characteristics, including comorbidities, inform the selection of second-line systemic treatment, independently of the aetiology of HCC, tumour stage and the response to previous treatment. Biomarkers predictive of treatment effectiveness are of great value, but currently biomarker-driven patient selection is possible only in the case of ramucirumab. The approval of new combination therapies for advanced HCC in the first-line setting will further increase the complexity of decision-making. However, the important factors will remain the individual patient's characteristics and preferences.

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Section: Summary Of Data For Approved Second‐line Systemic Agentsmentioning

confidence: 99%

Navigating the new landscape of second‐line treatment in advanced hepatocellular carcinoma

Rimassa

Wörns

2020

Liver International

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“…47 A phase III CELESTIAL trial on 707 participants concluded that the cabozantinib could significantly extend OS and PFS compared with placebo, especially in patients with high AFP, but regardless of Albumin-Bilirubin (ALBI) grade or prior transarterial chemoembolization (TACE) therapy. [48][49][50][51] However, according to several retrospective cost-effectiveness analyses extracted from the CELESTIAL trial, the cabozantinib treatment yield high incremental costs and financially inviable for patients in the United States, United Kingdom, and China. [52][53][54] The findings remind an important element, which is to weigh a trade-off between costs and clinical benefits, and the willingness of conventional cost-effectiveness thresholds while developing a new treatment.…”

Section: Anti-hgf/c-met Therapy In Clinical Trailsmentioning

confidence: 99%

“…A phase II randomized study of 41 advanced HCC patients showed that by comparing with placebo control (1.4 months), the longer median PFS was observed in the cabozantinib group (2.5 months) 47 . A phase III CELESTIAL trial on 707 participants concluded that the cabozantinib could significantly extend OS and PFS compared with placebo, especially in patients with high AFP, but regardless of Albumin–Bilirubin (ALBI) grade or prior transarterial chemoembolization (TACE) therapy 48‐51 . However, according to several retrospective cost‐effectiveness analyses extracted from the CELESTIAL trial, the cabozantinib treatment yield high incremental costs and financially inviable for patients in the United States, United Kingdom, and China 52‐54 .…”

Section: Therapeutic Strategies Of Hgf/c‐met Inhibition In Hccmentioning

confidence: 99%

Targeting hepatocyte growth factor/c‐mesenchymal–epithelial transition factor axis in hepatocellular carcinoma: Rationale and therapeutic strategies

Chen

Lai

2020

Medicinal Research Reviews

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Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide. The outcome of current standard treatments, as well as targeted therapies in advanced stages, are still unsatisfactory. Attention has been drawn to novel strategies for better treatment efficacy. Hepatocyte growth factor/c‐mesenchymal–epithelial transition factor (HGF/c‐Met) axis has been known as an essential element in the regulation of liver diseases and as an oncogenic factor in HCC. In this review, we collected the evidence of HGF/c‐Met as a tumor progression and prognostic marker, discussed the anti‐c‐Met therapy in vitro, summarized the outcome of c‐Met inhibitors in clinical trials, and identified potential impetus for future anti‐c‐Met treatments. We also analyzed the inconsistency of HGF/c‐Met from various publications and offered reasonable explanations based on the current understanding in this area. In conclusion, HGF/c‐Met plays a crucial role in the progression and growth of HCC, and the strategies to inhibit this pathway may facilitate the development of new and effective treatments for HCC patients.

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“…In the subgroup of patients who had received only sorafenib as previous systemic treatment, median OS was 11.3 mo in the cabozantinib group and 7.2 mo in the placebo group (HR = 0.70, 95%CI: 0.55-0.88), and median PFS was 5.5 mo in the cabozantinib group and 1.9 mo in the placebo group (HR = 0.40, 95%CI: 0.32-0.50). Cabozantinib improved clinical outcomes irrespective of prior sorafenib duration[36], age (cutoff 65 years)[37], baseline AFP values[38], prior transarterial chemoembolization (TACE)[39], tumor burden[40], and in patients with HBV etiology[41]. Furthermore, 47% of patients on cabozantinib compared to 11% of patients on placebo had any reduction in target lesions, and among patients with elevated baseline AFP levels, 23% of patients on cabozantinib compared to 5% of patients on placebo achieved ≥ 50% reduction in AFP levels[35].…”

Section: Introductionmentioning

confidence: 99%

“…Of note, albeit patients ≥ 65 years more frequently discontinued treatment due to AEs, rate of dose reductions and median average daily dose were similar irrespective of age[37]. Grade 3-4 AEs were similar for HBV-positive patients and for patients with prior TACE compared to the overall study population and to patients without prior TACE, respectively [39-41]. Also, a post hoc QOL analysis estimated the incremental quality-adjusted life-years (QALYs) accrued with cabozantinib.…”

Section: Introductionmentioning

confidence: 99%

Targeted agents for second-line treatment of advanced hepatocellular carcinoma

Personeni

Pressiani

Bozzarelli

et al. 2019

WJGO

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Over the past ten years, sorafenib, a multikinase inhibitor, has been the standard of care for patients with unresectable hepatocellular carcinoma (HCC) and well-preserved liver function. Recently, lenvatinib, a different multikinase inhibitor, was shown to be non-inferior to sorafenib, in terms of survival, while all other agents previously tested failed to prove non-inferiority (or superiority) when compared to sorafenib. Similarly, in the second-line setting, most investigational drugs failed to provide better survival outcomes than placebo. However, in the last 2 years three positive phase III trials have been published in this setting. The RESORCE trial, a phase III study evaluating regorafenib in HCC patients who experienced disease progression after first-line treatment with sorafenib, showed better outcomes with regorafenib compared to placebo. More recently, the phase III CELESTIAL trial demonstrated the superiority of cabozantinib, a multikinase inhibitor targeting vascular endothelial growth factor receptor, MET, and AXL, vs placebo in the second- and third-line setting in patients progressing on or intolerant to sorafenib. The survival benefits of a sustained anti-angiogenic inhibition were demonstrated also with ramucirumab in the phase III REACH-2 trial in patients previously treated with sorafenib and who had high baseline alpha-fetoprotein levels. Overall, the adverse events reported in these trials were in line with the known safety profiles of the tested agents. After nearly a decade of a certain degree of stagnation, we are now witnessing a period of novel therapeutic advances with multikinase inhibitors and monoclonal antibodies that will likely change the treatment scenario of HCC.

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Outcomes by prior transarterial chemoembolization (TACE) in the phase III CELESTIAL trial of cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC)

Cited by 13 publications

References 0 publications

Navigating the new landscape of second‐line treatment in advanced hepatocellular carcinoma

Navigating the new landscape of second‐line treatment in advanced hepatocellular carcinoma

Targeting hepatocyte growth factor/c‐mesenchymal–epithelial transition factor axis in hepatocellular carcinoma: Rationale and therapeutic strategies

Targeted agents for second-line treatment of advanced hepatocellular carcinoma

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