Second-line cabozantinib after sorafenib treatment for advanced hepatocellular carcinoma: a subgroup analysis of the phase 3 CELESTIAL trial

Kelley, Robin Kate; Ryoo, Baek‐Yeol; Merle, Philippe; Park, Joong-Won; Bolondi, Luigi; Chan, Stephen L.; Lim, Ho Yeong; Baron, Ari David; Parnis, Francis; Knox, Jennifer J.; Cattan, Stéphane; Yau, Thomas; Lougheed, Julie C.; Milwee, Steven; El-Khoueiry, Anthony B.; Cheng, Ann‐Lii; Meyer, Tim; Abou‐Alfa, Ghassan K.

doi:10.1136/esmoopen-2020-000714

Cited by 70 publications

(81 citation statements)

References 18 publications

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“…Post-hoc exploratory analysis of the RESORCE study illustrated that sequential treatment with sorafenib and regorafenib resulted in a median OS of 26 months from start of sorafenib compared to 19 months in those that received sorafenib followed by placebo ( 45 ). Similar results were observed in a post-hoc analysis of the CELESTIAL trial that illustrated patients who had received prior sorafenib, cabozantinib significantly improved OS, 24.5 months compared to 18.8 months in those receiving placebo ( 46 ). In addition, post-hoc analysis of the REFLECT data that illustrates an OS benefit of second-line therapy, OS 20.8 vs. 17.0 months (HR 0.87; 95% CI 0.67–1.14) ( 47 ).…”

Section: The Role Of Tyrosine Kinase Inhibitors Post-icisupporting

confidence: 73%

Beyond First-Line Immune Checkpoint Inhibitor Therapy in Patients With Hepatocellular Carcinoma

Sharma

Aval

2021

Front. Immunol.

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Until recently, the treatment landscape for hepatocellular cancer (HCC) was dominated by tyrosine kinase inhibitors (TKIs) which offered an overall survival (OS) benefit when used both in the first-and second-line setting compared to best supportive care. However, the treatment landscape has changed with the introduction of immune checkpoint inhibitors (ICIs) for the treatment of HCC with significant improvement in OS and progression free survival reported with combination atezolizumab and bevacizumab compared to sorafenib in the first-line setting. Nonetheless, the response to ICIs is 20–30% and invariably patients will progress. What remains unclear is which therapeutics should be used following ICI exposure. Extrapolating from the evidence base in renal cell carcinoma, subsequent therapy with TKIs offers both a response and survival benefit and are recommended by European guidelines. However, there are a number of novel therapies emerging that target mechanisms of ICI resistance that hold promise both in combination with ICI or as subsequent therapy. This paper will discuss the evidence for ICIs in HCC, the position of second-line therapies following ICIs and research strategies moving forward.

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Section: The Role Of Tyrosine Kinase Inhibitors Post-icisupporting

confidence: 73%

Beyond First-Line Immune Checkpoint Inhibitor Therapy in Patients With Hepatocellular Carcinoma

Sharma

Aval

2021

Front. Immunol.

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“…In detail, patients who had received at least one TACE treatment reached a median OS of 11.4 months with cabozantinib (versus 8.6 months with placebo) whereas patients without a prior TACE reached a median OS of 9.5 months with cabozantinib (versus 7.2 months with placebo) (Table 3). Moreover, as highlighted in a recently published post hoc analysis, 22 cabozantinib used after sorafenib as a second-line option provided a survival benefit regardless of the duration of prior sorafenib treatment (<3 months, 3 to 6 months or ≥6 months). Of note, for patients who received sorafenib for ≥6 months, median OS reached 29.9 months with cabozantinib versus 25.8 months with placebo, considering survival from the start of sorafenib.…”

Section: Efficacy By Prior Treatmentsmentioning

confidence: 92%

“…Moreover, as highlighted in a recently published post hoc analysis, 22 cabozantinib used after sorafenib as a second-line option provided a survival benefit regardless of the duration of prior sorafenib treatment (<3 months, 3 to 6 months or ≥6 months). Of note, for patients who received sorafenib for ≥6 months, median OS reached 29.9 months with cabozantinib versus 25.8 months with placebo, considering survival from the start of sorafenib.…”

Section: Efficacy Of Cabozantinibmentioning

confidence: 92%

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The Role of Cabozantinib as a Therapeutic Option for Hepatocellular Carcinoma: Current Landscape and Future Challenges

D’Alessio¹,

Prete²,

Cammarota³

et al. 2021

JHC

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The systemic treatment of advanced hepatocellular carcinoma (HCC) has significantly changed over the last years, with the introduction of two new standard-of-care firstline treatments (lenvatinib and the combination of atezolizumab and bevacizumab) and the success of several new agents in second line. In particular, after the approval of regorafenib, ramucirumab and cabozantinib, the landscape of second-line treatment has become notably complex, providing a serious challenge in clinical practice. In this review, we focus on cabozantinib, a multikinase inhibitor which was proven effective in improving overall and progression-free survival of patients previously treated with sorafenib in the randomized Phase III CELESTIAL trial. CELESTIAL is the only phase III study to have included patients in the third-line setting and cabozantinib efficacy was confirmed in several post hoc analyses, irrespective of alpha-fetoprotein levels, albumin-bilirubin score, age, and duration of previous sorafenib treatment. The safety profile of cabozantinib in the CELESTIAL trial was comparable with other multikinase inhibitors used for HCC and the most frequent grade ≥3 adverse events were diarrhea, palmar-plantar erythrodysesthesia, fatigue, hypertension, and aspartate aminotransferase increase. Tolerability did not differ between younger and older patients and quality of life was significantly improved compared to placebo during the treatment. In this review, we also make a particular mention to the use of cabozantinib in populations which are normally excluded from clinical trials, such as older patients and Child-Pugh B patients. Finally, we present the new treatment strategies in which cabozantinib is being tested, most notably the combination of cabozantinib and atezolizumab in the first-line setting in the phase III COSMIC-312 trial and the use of cabozantinib after progression on immune-checkpoint inhibitors.

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“…Lenvatinib was compared to Sorafenib as a first-line treatment in a phase III clinical trial evidencing its non-inferiority in OS [ 13 ]. Cabozantinib was tested as a second-line treatment in the CELESTIAL trial, resulting in longer OS (10.2 months vs. 8.0 months for placebo; hazard ratio for death, 0.76; p = 0.005), progression-free survival (PFS, 5.2 months vs. 1.9 months; p < 0.001), and RR (4% vs. less than 1%; p = 0.009) [ 14 ]. The RESORCE phase III clinical trial compared Regorafenib to placebo in patients with progression disease during the Sorafenib treatment, showing an improvement of median OS (10.6 months vs. 7.8 months; p < 0.0001) [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Hepatic Arterial Infusion of Chemotherapy for Advanced Hepatobiliary Cancers: State of the Art

Laface

Laforgia

Molinari

et al. 2021

Cancers

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Liver functional failure is one of the leading causes of cancer-related death. Primary liver tumors grow up mainly in the liver, and thus happens for liver metastases deriving from other organs having a lower burden of disease at the primary site. Systemic chemotherapy usually offers a modest benefit in terms of disease control rate, progression-free survival, and overall survival at the cost of a significant percentage of adverse events. Liver malignancies are mostly perfused by the hepatic artery while the normal liver parenchyma by the portal vein network. On these bases, the therapeutic strategy consisting of hepatic arterial infusion (HAI) of chemotherapy takes place. In literature, HAI chemotherapy was applied for the treatment of advanced hepatobiliary cancers with encouraging results. Different chemotherapeutic agents were used such as Oxaliplatin, Cisplatin, Gemcitabine, Floxuridine, 5-Fluorouracil, Epirubicin, individually or in combination. However, the efficacy of this treatment strategy remains controversial. Therefore, this review aims to summarize the current knowledge on this approach from different points of view, such as techniques, drugs pharmacology and pharmacokinetics, and clinical outcomes for advanced hepatobiliary cancers.

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Second-line cabozantinib after sorafenib treatment for advanced hepatocellular carcinoma: a subgroup analysis of the phase 3 CELESTIAL trial

Cited by 70 publications

References 18 publications

Beyond First-Line Immune Checkpoint Inhibitor Therapy in Patients With Hepatocellular Carcinoma

Beyond First-Line Immune Checkpoint Inhibitor Therapy in Patients With Hepatocellular Carcinoma

The Role of Cabozantinib as a Therapeutic Option for Hepatocellular Carcinoma: Current Landscape and Future Challenges

Hepatic Arterial Infusion of Chemotherapy for Advanced Hepatobiliary Cancers: State of the Art

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