Introduction

Cabozantinib was approved for hepatocellular carcinoma (HCC) treatment based on the results of CELESTIAL trial. The study showed a significant overall survival benefit in second or thirdline therapy following sorafenib failure. Despite the growing use of immunooncology agents in first line, cabozantinib remains an important sequential option after sorafenib in realworld practice

Aim

This phase-4 prospective multicenter CLERANCE trial evaluated safety & efficacy of cabozantinib after prior sorafenib failure in real-life setting

Patient Profile

• Adults with HCC confirmed via pathology or non-invasive AASLD criteria 
• At least one measurable lesion per RECIST v1.1

Methods

• Single-arm, open, prospective, multicentric phase-4 trial
• 110 patients with unresectable HCC
• 99 eligible patients initiatedcabozantinib (intention‑to‑treat population). 
• Cabozantinib initiated at 60 mg/day (dose‑adjustments permitted) 
• Treatment continued until: 
  1. radiologic progression
  2. clinical deterioration
  3. unacceptable toxicity
  4. death
  5. withdrawal of consent
• Tumor assessments every 3 months, follow‑up up to 12 months

Primary Endpoint

• Incidence of grade 3/4 treatment‑related adverse events (TRAEs) (CTCAE v5)

Secondary Endpoints

• Overall survival (OS)
• Progression‑free survival (PFS)
• Time to progression (TTP)
• Objective response rate (ORR)
• Disease control rate (DCR)
• Cabozantinib dose management patterns

Results

Primary Endpoint : Safety

• All 99 patients experienced at least one TEAE (426 total TEAEs).
• Grade 3–4 TEAEs: 96 events in 64 patients (65%).
• Grade 3–4 TRAEs: 42 events in 31 patients (31.3%).
• Most common grade 3–4 TRAEs: 
  • Hand‑foot skin reaction 
  • Diarrhea 
  • Asthenia 
  • Anorexia 
  • Hypertension
• No treatment‑related deaths.
• Primary cause of death was  liver failure with or without tumor progression.

Table 1 : Grade 3–4 Treatment-Related Adverse Events (TRAEs)

TRAE	Patients (%)
Hand–foot skin reaction	12.1
Diarrhea	10.1
Asthenia	7
Anorexia	4
Arterial hypertension	3
Nausea/vomiting	1
Gastric fistula	1
Hypomagnesemia	1
Hypothyroidism	1
Mandibular osteonecrosis	1
Wave burst arrhythmia	1
Total	42.4

 

Cabozantinib Administration Management

• Starting dose was
  • 60 mg/day in 87.9%
  • 40 mg/day in 8.1%
  • 20 mg/day in 4%
• Dose modifications were required in65.7% of patients.
• Median treatment duration: 5.2 months; median administered dose was 40 mg/day.

Table 2: Cabozantinib administration and dose management

Parameter	Value
Starting daily dose 60/40/20 mg	87.9% / 8.1% / 4.0%
Median treatment duration, months	5.2
Patients with dose modification	65
Median administered dose, mg/day	40
Mean administered dose, mg/day	38.2
Reasons for reduction/interruption	Diarrhea 21.3% Asthenia 18.1%  HFSR 14.2% General status 33.3% Hepatic encephalopathy 5.5%
Permanent discontinuation reasons	Progression 53.5% TEAEs 15.2%  Death 7.1%

Efficacy and survival outcomes 

• The median OS from the start of cabozantinib was 11.5 mos. 
• The median OS from the start of the first systemic therapy was 23.2 mos, which varied significantly depending on the number of treatment lines received before & after cabozantinib. 
• Patients who had better preserved liver function (mALBI grade 1 + 2a) experienced significantly longer OS at 16.4 mos vs 7.2 mos. for those with more impaired mALBI grade 2b + 3. 
• A baseline AFP level <400 ng/mL was associated with significantly longer OS of 14.8 mos. vs 7.8 mos. in patients with AFP ≥400 ng/mL. 
• The survival outcomes did not differ between patients who received cabozantinib in the second line vs the third line setting, indicating similar benefit irrespective of treatment line. 
• Patients who were able to receive subsequent systemic therapies after cabozantinib discontinuation achieved prolonged survival, demonstrating the importance of sequential treatment strategies

Figure 1: Survival outcomes 

              

Prognostic markers

• Better survival linked to
  • Modified ALBI grade 1/2a (vs 2b/3)
  • AFP <400 ng/mL
  • Discontinuation of prior sorafenib due to progression (trend)
• Cabozantinib line (2L vs 3L) did not significantly affect OS

Conclusion

In the CLERANCE study, the safety and therapeutic efficacy of cabozantinib were consistent with outcomes reported in the CELESTIAL trial.The analysis highlights dose optimization strategies, surrogate markers associated with improved prognosis, and patients receiving additional subsequent therapies achieved extended overall survival.

Reference 

Liver Cancer. 2025 Nov 17.doi: 10.1159/000549076.