What are the side effect risks of axitinib (Inlyta) vs tivozanib (Fotivda) in a patient with advanced renal cell carcinoma and a history of adverse effects to tyrosine kinase inhibitors?

Tivozanib vs Axitinib Side Effect Comparison in Advanced RCC

For patients with advanced renal cell carcinoma and a history of adverse effects to tyrosine kinase inhibitors, tivozanib offers a significantly more favorable toxicity profile than axitinib, with substantially lower rates of diarrhea, hand-foot syndrome, and dose modifications, making it the preferred choice when tolerability is the primary concern.

Key Safety Differences

Tivozanib's Superior Tolerability Profile

Tivozanib demonstrates markedly better tolerability compared to other TKIs, with specific advantages that are critical for patients who have experienced prior TKI toxicities:

• Hypertension is the most common grade 3-4 adverse event with tivozanib (20-24%), which is dose-related and manageable 1, 2
• Hand-foot syndrome occurs in only 14% of patients with tivozanib versus 54% with sorafenib, representing a dramatic reduction in this debilitating toxicity 3
• Diarrhea is significantly less common with tivozanib (23%) compared to other TKIs, and is not dose-related 3, 4
• Dysphonia (hoarseness) occurs in 21% but is typically mild and not dose-limiting 3, 4
• Fatigue is common but not dose-related, making it more manageable 4

Axitinib's Toxicity Profile

Axitinib carries a different spectrum of adverse effects that may be more challenging for patients with prior TKI intolerance:

• Hypertension is the most common grade 3+ adverse event (17%), similar to tivozanib 5
• Diarrhea occurs as a grade 3+ event in 11% of patients 5
• Fatigue is a grade 3+ event in 10% of patients 5
• Hand-foot syndrome occurs but at lower rates than with sorafenib 5

Treatment Modification Rates: A Critical Distinction

The most clinically significant difference is that tivozanib requires substantially fewer dose modifications than other TKIs, which directly impacts quality of life and treatment continuity:

• Patients receiving tivozanib had lower rates of dose reduction, interruption, or permanent discontinuation compared to sorafenib 2
• This translates to better treatment adherence and potentially improved outcomes in real-world practice 2

Clinical Context and Treatment Selection

When to Choose Tivozanib

Tivozanib is FDA-approved specifically for patients with relapsed or refractory advanced RCC who have received 2 or more prior systemic therapies 6:

• It is a Category 2A recommendation by NCCN as a subsequent therapy option for clear cell RCC 6
• The TIVO-3 trial demonstrated superior progression-free survival (5.6 months vs 3.9 months) compared to sorafenib in heavily pretreated patients 1, 2
• Overall survival was similar between groups (HR 0.97), indicating no detrimental effect despite the favorable toxicity profile 2

When to Choose Axitinib

Axitinib is primarily used in different clinical contexts:

• First-line combination therapy with pembrolizumab or avelumab, where it has Level I, A evidence 7
• Second-line monotherapy after progression on cytokine therapy, where it demonstrated superior PFS compared to sorafenib 6, 5
• As a Category 3 subsequent therapy option when combined with avelumab 6

Practical Treatment Algorithm for Your Patient

Given the specific context of a patient with prior TKI adverse effects:

1. If the patient has received 2+ prior systemic therapies: Tivozanib is the optimal choice due to its superior tolerability profile and FDA approval in this exact setting 1, 2

2. If the patient is being considered for second-line therapy after one prior treatment: Consider the specific toxicities experienced previously:

   • If hand-foot syndrome or diarrhea were limiting: Strongly favor tivozanib 3, 1
   • If hypertension was the primary issue: Both agents carry similar hypertension risk, so other factors should guide selection 5, 1

3. If combination therapy is being considered: Axitinib combinations (with pembrolizumab or avelumab) may be appropriate, but only if the patient can tolerate immunotherapy and the prior TKI toxicities were manageable 7

Critical Caveats

Target Selectivity Advantage

Tivozanib's highly selective VEGFR-1, -2, and -3 inhibition with minimal off-target effects explains its superior tolerability compared to multi-targeted TKIs 4:

• Its long half-life allows more consistent VEGFR blockade with once-daily dosing 4
• Less affinity for other receptor tyrosine kinases reduces off-target toxicities 4

Monitoring Requirements

Both agents require specific monitoring, but the focus differs:

• Tivozanib: Primary focus on blood pressure monitoring due to dose-related hypertension 4, 2
• Axitinib: Broader monitoring for multiple toxicities including GI symptoms, skin reactions, and cardiovascular effects 5

Quality of Life Considerations

Patient-reported outcomes were maintained during treatment with axitinib but decreased at end-of-treatment 5, while tivozanib's lower toxicity burden suggests better sustained quality of life, though direct comparative data are limited 3, 1, 2.