Outcomes Based on Plasma Biomarkers for the Phase 3 CELESTIAL Trial of Cabozantinib versus Placebo in Advanced Hepatocellular Carcinoma

Rimassa, Lorenza; Kelley, Robin Kate; Meyer, Tim; Ryoo, Baek‐Yeol; Merle, Philippe; Park, Joong-Won; Blanc, Jean‐Frédéric; Lim, Ho Yeong; Tran, Albert; Chan, Yi‐Wah; McAdam, Paul R.; Wang, Evelyn; Cheng, Ann‐Lii; El-Khoueiry, Anthony B.; Abou‐Alfa, Ghassan K.

doi:10.1159/000519867

Cited by 23 publications

(25 citation statements)

References 38 publications

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“…In addition, as there is no established biomarker for the selection of therapeutic agents in HCC except AFP for ramucirumab, further efforts are required to define additional specific biomarkers for the prediction of each agent’s efficacy or toxicity. 33 …”

Section: Discussionmentioning

confidence: 99%

Real-world efficacy and safety of cabozantinib in Korean patients with advanced hepatocellular carcinoma: a multicenter retrospective analysis

et al. 2022

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Background: Cabozantinib, a multiple kinase inhibitor, was recently approved for patients with previously treated unresectable hepatocellular carcinoma (uHCC). We investigated the real-world safety and efficacy profiles of cabozantinib. Methods: This multicenter retrospective study included 110 patients with uHCC who received cabozantinib after progression on other systemic treatments between October 2019 and May 2021. Results: The median age was 58 (range, 20–77) years, and 98 (89.1%) were male. Prior to cabozantinib, all patients were treated with other systemic therapies: sorafenib ( n = 104, 94.5%) and regorafenib ( n = 91, 82.7%) were the most commonly used agents. Immune checkpoint inhibitors were previously used in 93 patients (84.5%). Cabozantinib was used beyond the third-line of therapy in most patients ( n = 90, 81.8%). With a median follow-up duration of 11.9 months [95% confidence interval (CI), 10.8–17.2], the median progression-free survival (PFS) was 3.7 months (95% CI, 3.1–4.9), and the median overall survival (OS) was 7.5 months (95% CI, 5.5–9.5). The disease control rate and overall response rate (ORR) were 66.3% and 3.6%, respectively. In the Child–Pugh A cohort ( n = 88), the ORR was 4.5%, and the median PFS and OS were 4.3 months (95% CI, 3.6–5.8) and 9.0 months (95% CI, 7.5–11.7), respectively. Conclusion: Cabozantinib showed consistent efficacy outcomes with a prior phase III trial, although in this study, it was used as later-line therapy for patients who were refractory to multiple systemic treatments, including immune checkpoint inhibitors.

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Section: Discussionmentioning

confidence: 99%

Real-world efficacy and safety of cabozantinib in Korean patients with advanced hepatocellular carcinoma: a multicenter retrospective analysis

et al. 2022

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“…[65][66][67][68][69][70][71][94][95][96][97] Further circulating biomarkers, including MKIs targets, their ligands, and other plasma proteins, mainly with a role in inflammation/HCC pathogenesis were found to be prognostic and sometimes predictive in retrospective analyses of the SHARP, REFLECT, RESORCE, and CELESTIAL trials. 95,[100][101][102] However, they were not evaluated as biomarkers of response, and the non-homogenous significance across different studies and treatment arms, the lack of established cut-offs and uniform protocols for their measurement, and the rather intricate process required for their analysis limit further validation and make their use not yet feasible in clinical practice.…”

Section: Discussionmentioning

confidence: 99%

Assessment and Monitoring of Response to Systemic Treatment in Advanced Hepatocellular Carcinoma: Current Insights

Cammarota¹,

Zanuso²,

Pressiani³

et al. 2022

JHC

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Advanced hepatocellular carcinoma (HCC) management has become more complex as novel therapies have been proven effective. After sorafenib, the approval of other multikinase inhibitors (MKIs) and immune checkpoints inhibitors (ICIs) has considerably increased the number of systemic therapies available. Therefore, careful assessment and monitoring of response to systemic treatment are essential to identify surrogate endpoints of overall survival (OS) in clinical trials and reliable tools to gauge treatment benefit in clinical practice. Progression-free survival (PFS) and objective response rate (ORR) are early informative parameters of efficacy that are not influenced by further lines of therapy. However, none of them has shown sufficient surrogacy to be recommended in place of OS in phase 3 trials. With such a wealth of therapeutic options, the prime intent of tumor assessments is no longer limited to identifying progressive disease to spare ineffective treatments to non-responders. Indeed, the early detection of responders could also help tailor treatment sequencing. Tumor assessment relies on the Response Evaluation Criteria for Solid Tumors (RECIST), which are easy to interpret – being based on dimensional principles – but could misread the activity of targeted agents. The HCC-specific modified RECIST (mRECIST), considering both the MKI-induced biological modifications and some of the cirrhosis-induced liver changes, better capture tumor response. Yet, mRECIST could not be considered a standard in advanced HCC. Further prognosticators including progression patterns, baseline and on-treatment liver function deterioration, and baseline alpha-fetoprotein (AFP) levels and AFP response have been extensively evaluated for MKIs. However, limited information is available for patients receiving ICIs and regarding their predictive role. Finally, there is increasing interest in incorporating novel imaging techniques which go beyond sizes and novel serum biomarkers in the advanced HCC framework. Hopefully, multiparametric models grouping dimensional and functional radiological parameters with biochemical markers will most precisely reflect treatment response.

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“…In addition, the CELESTIAL trial showed that a better prognosis during treatment with Cabozantinib was correlated with low levels of MET, GAS6, HGF, ANG2, VEGF-A, Interleukin (IL)-8, and high levels of insulin-like growth factor 1 in serum. However, these data have yet to be confirmed in clinical practice [ 75 ].…”

Section: Targeted Therapiesmentioning

confidence: 99%

Targeted Therapy for Hepatocellular Carcinoma: Old and New Opportunities

Laface¹,

Fedele²,

Maselli³

et al. 2022

Cancers

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Hepatocellular carcinoma (HCC) is the most frequent primitive cancer of the liver, accounting for 90% of all recorded cases. HCC is the third most common cause of cancer-related death, with a 5-year survival rate of just 3%. In the advanced stages, systemic treatments allow doctors to obtain clinical benefits, although the prognosis remains very poor. In the past few decades, new molecular targeted therapies against receptor tyrosine kinases have been developed and clinically evaluated. Sorafenib was the first oral tyrosine kinase inhibitor (TKI) approved for the treatment of advanced HCC in 2007. Subsequently, other TKIs, including Cabozantinib, Regorafenib, Lenvatinib, and vascular endothelial growth factor receptor (VEGFR) inhibitors such as Ramucirumab and VEGF inhibitors such as Bevacizumab have been approved as first- or second-line treatments. More recently, the combination of immune checkpoint inhibitors and VEGF inhibitors (Atezolizumab plus Bevacizumab) have been analyzed and approved for the treatment of advanced HCC. On the basis of the poor prognoses and the meager benefits deriving from the available systemic therapies, research into new treatments is extremely necessary. In this review, we focus on the available systemic therapies for advanced HCC, with a look toward the future.

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Outcomes Based on Plasma Biomarkers for the Phase 3 CELESTIAL Trial of Cabozantinib versus Placebo in Advanced Hepatocellular Carcinoma

Cited by 23 publications

References 38 publications

Real-world efficacy and safety of cabozantinib in Korean patients with advanced hepatocellular carcinoma: a multicenter retrospective analysis

Real-world efficacy and safety of cabozantinib in Korean patients with advanced hepatocellular carcinoma: a multicenter retrospective analysis

Assessment and Monitoring of Response to Systemic Treatment in Advanced Hepatocellular Carcinoma: Current Insights

Targeted Therapy for Hepatocellular Carcinoma: Old and New Opportunities

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