What is the management of Carbazamtinib in adult cancer patients?

Management of Cabozantinib in Adult Cancer Patients

Cabozantinib is a multi-targeted tyrosine kinase inhibitor approved for specific advanced cancers with distinct indications, dosing, and monitoring requirements that vary by tumor type and treatment line.

Approved Indications and Patient Selection

Thyroid Cancer

Differentiated Thyroid Cancer (DTC)

• Cabozantinib is recommended for adults with RAI-refractory advanced/metastatic DTC that has progressed following prior MKI therapy 1
• Requires documented disease progression during or after prior systemic therapy 1
• Genetic testing targeting actionable mutations (preferably NGS analysis) should be considered to individualize therapy 1
• ESMO-MCBS score: 2, indicating moderate clinical benefit 1

Medullary Thyroid Cancer (MTC)

• Cabozantinib is indicated for progressive, unresectable locally advanced or metastatic MTC 1
• Genetic testing for RET mutations should be strongly considered using allelic-specific real-time PCR or NGS analysis 1
• In treatment-naive MTC patients with RET mutations, selective RET inhibitors (selpercatinib or pralsetinib) may be preferred over cabozantinib, though optimal sequencing remains undetermined 1

Renal Cell Carcinoma (RCC)

Second-Line Treatment

• Cabozantinib is recommended for advanced RCC following prior VEGF-targeted therapy 1
• Demonstrated OS improvement (HR 0.66,95% CI 0.53-0.83) versus everolimus 1
• ESMO-MCBS score: 3 1

First-Line Combination Therapy

• Cabozantinib plus nivolumab is recommended for first-line treatment of advanced RCC 1
• Particularly effective in IMDC intermediate- and poor-risk disease 1
• PFS HR: 0.51 (0.41-0.64) versus sunitinib 1
• ESMO-MCBS score: 4 1
• For patients who cannot receive PD-1 inhibitor-based therapy, cabozantinib monotherapy is an alternative in intermediate- and poor-risk disease 1

Hepatocellular Carcinoma (HCC)

Second-Line Treatment

• Cabozantinib is indicated for HCC patients with preserved liver function (Child-Pugh A) who have progressed after at least one prior systemic therapy 1
• Demonstrated OS improvement (HR 0.76,95% CI 0.63-0.92) versus placebo 1
• PFS improvement (HR 0.44,95% CI 0.36-0.52) versus placebo 1
• Nearly all patients (99%) in efficacy trials had Child-Pugh A liver function 2

Dosing and Administration

Standard Dosing

• MTC and DTC: 140 mg orally once daily 3, 4
• RCC (monotherapy): 60 mg orally once daily 1
• RCC (with nivolumab): 40 mg orally once daily 1
• HCC: 60 mg orally once daily 1

Dose Modifications

• Dose reductions are required in the majority of patients (79% in MTC trials) due to adverse events 3
• More than half of patients require dose reduction, but discontinuation rates remain relatively low (16-21% versus 3-5% with placebo/comparator) 2

Adverse Event Monitoring and Management

Critical Adverse Events Requiring Systematic Assessment

Hypertension

• Grade 3-4 hypertension occurs in 16% of cabozantinib patients versus 2% on placebo 2
• Monitor blood pressure at each visit 2

Hand-Foot Skin Reaction (HFSR)

• Grade 3-4 HFSR occurs in 17% of cabozantinib patients versus 0% in controls 2
• Systematically examine palms and soles for erythema, tenderness, blistering, or desquamation at each visit 2

Gastrointestinal Toxicity

• Grade 3-4 diarrhea occurs in 10% versus 2% with placebo 2
• Assess frequency, severity, and impact on hydration status 2
• Common adverse events include diarrhea, nausea, decreased appetite, and fatigue 5, 3

Hepatotoxicity

• Grade 3-4 elevated AST occurs in 12% versus 7% with placebo 2
• Monitor liver function tests regularly, particularly in HCC patients with baseline liver dysfunction 2
• For HCC patients, monitor for signs of hepatic decompensation 2

Fatigue

• Grade 3-4 fatigue occurs in 10% versus 4% with placebo 2
• Quantify impact on daily activities and quality of life 2

Serious Adverse Events

• Serious adverse events occur in approximately 50% of cabozantinib patients versus 21% with placebo 2
• Bleeding risk is particularly relevant in HCC patients 2

Laboratory Monitoring

• Baseline and periodic liver function tests 2
• Regular blood pressure monitoring 2
• Monitor for signs of hepatic decompensation in HCC patients 2

Treatment Duration and Follow-Up

Efficacy Outcomes by Indication

MTC

• Median PFS: 11.2 months versus 4.0 months with placebo (HR 0.28,95% CI 0.19-0.40) 3
• Objective response rate: 28% versus 0% with placebo 3
• Responses observed regardless of RET mutation status 3

DTC

• Partial response rate: 53% in phase I study 5
• PFS gain: 6.7 months versus placebo 1

RCC (Second-Line)

• Median OS: 21.4 months versus 17.1 months with everolimus 1
• Particularly effective in patients with bone metastases (median OS 20.1 vs 12.1 months; HR 0.54) 6

HCC

• Median OS improvement with HR 0.76 1
• Disease control rate significantly higher than placebo 1

Imaging Follow-Up

• For RCC patients during systemic therapy, 2- to 4-month follow-up with CT scan is advised 1
• RECIST is the most frequently used method to assess drug efficacy 1

Special Considerations

Bone Metastases

• Cabozantinib demonstrates particular efficacy in patients with bone metastases 6
• In RCC with bone metastases: improved PFS (HR 0.34) and OS (HR 0.54) with cabozantinib-nivolumab versus sunitinib 6
• In VEGF-refractory setting with bone metastases: median OS 20.1 vs 12.1 months versus everolimus 6
• Consider concurrent bone-targeted agents (zoledronic acid or denosumab) to prevent skeletal-related events 6

Treatment Sequencing

• The optimal sequence of MKIs and selective kinase inhibitors cannot be determined based on currently available evidence 1
• For MTC with RET mutations, selective RET inhibitors (selpercatinib, pralsetinib) may be considered before or after cabozantinib 1
• For DTC, cabozantinib is positioned after progression on first-line MKIs (sorafenib, lenvatinib) 1

Contraindications and Precautions

• HCC patients must have Child-Pugh A liver function 2
• Avoid in patients with active bleeding or recent gastrointestinal perforation 2
• Exercise caution in patients at risk for thromboembolic events 2