Multikinase inhibitors

I. Introduction

Multikinase inhibitors (MKIs) are a subclass of targeted cancer therapies that block multiple protein kinases involved in tumor growth, angiogenesis, and metastatic spread. These small-molecule agents act primarily by inhibiting tyrosine kinases and serine/threonine kinases that regulate key signaling pathways in cancer, including VEGF, PDGF, FGF, RET, RAF, and others. Their ability to simultaneously block several pathways makes them particularly effective in tumors with complex signaling redundancies and in tumors driven by multiple kinases.

MKIs have transformed the treatment landscape in renal cell carcinoma, hepatocellular carcinoma, thyroid cancers, colorectal cancer, non-small cell lung cancer, GISTs, and other solid tumors. Unlike highly selective tyrosine kinase inhibitors (TKIs), MKIs exert broader-spectrum inhibition across various oncogenic and angiogenic pathways.

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II. Mechanism of Action

Multikinase inhibitors bind to the ATP-binding site of several kinases, thereby inhibiting their phosphorylation and downstream signal transduction. This leads to:

• Inhibition of tumor cell proliferation (through blocking oncogenic signaling)

• Inhibition of angiogenesis (via VEGFR and PDGFR inhibition)

• Induction of apoptosis

• Suppression of metastasis

Key kinases targeted by MKIs include:

• VEGFR (Vascular Endothelial Growth Factor Receptor)

• PDGFR (Platelet-Derived Growth Factor Receptor)

• FGFR (Fibroblast Growth Factor Receptor)

• RET (Rearranged during Transfection)

• KIT (Stem cell factor receptor)

• BRAF / RAF-1 (Serine/threonine kinases)

Some MKIs are more antiangiogenic in action, while others target oncogenic driver mutations or fusion kinases directly.

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III. Commonly Used Multikinase Inhibitors

1. Sorafenib

   • Targets: RAF, VEGFR-1/2/3, PDGFR-β, c-KIT, RET

   • Indications: Advanced hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), differentiated thyroid cancer

2. Sunitinib

   • Targets: VEGFRs, PDGFRs, KIT, FLT3, RET

   • Indications: RCC, GIST, pancreatic neuroendocrine tumors (pNETs)

3. Lenvatinib

   • Targets: VEGFR1-3, FGFR1-4, PDGFR-α, KIT, RET

   • Indications: HCC (with pembrolizumab or alone), thyroid cancer, RCC, endometrial cancer

4. Regorafenib

   • Targets: VEGFR1-3, PDGFR, FGFR, KIT, RET, BRAF

   • Indications: Colorectal cancer, GIST, HCC

5. Cabozantinib

   • Targets: MET, VEGFR2, AXL, RET, KIT

   • Indications: RCC, HCC, medullary thyroid cancer (MTC)

6. Pazopanib

   • Targets: VEGFR, PDGFR, KIT

   • Indications: RCC, soft tissue sarcoma

7. Vandetanib

   • Targets: RET, VEGFR, EGFR

   • Indications: Medullary thyroid cancer

8. Axitinib

   • Targets: VEGFR1-3

   • Indications: RCC (monotherapy or combination)

9. Midostaurin

   • Targets: FLT3, KIT, PDGFR, VEGFR

   • Indications: FLT3-mutant AML, systemic mastocytosis

10. Ripretinib

    • Targets: KIT and PDGFRA (including secondary mutations)

    • Indications: Advanced GIST

11. Avapritinib

    • Targets: KIT and PDGFRA (especially PDGFRA exon 18 mutations)

    • Indications: GIST

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IV. Therapeutic Indications by Cancer Type

Cancer Type	Commonly Used MKIs
Renal cell carcinoma (RCC)	Sunitinib, Cabozantinib, Lenvatinib + Everolimus, Axitinib
Hepatocellular carcinoma (HCC)	Sorafenib, Regorafenib, Lenvatinib, Cabozantinib
Differentiated thyroid cancer (DTC)	Lenvatinib, Sorafenib
Medullary thyroid cancer (MTC)	Cabozantinib, Vandetanib
Colorectal cancer (mCRC)	Regorafenib
GIST (gastrointestinal stromal tumor)	Sunitinib, Regorafenib, Ripretinib, Avapritinib
Pancreatic neuroendocrine tumors	Sunitinib
Soft tissue sarcoma	Pazopanib
AML (FLT3+)	Midostaurin

V. Dosing and Administration (Selected Agents)

• Sorafenib: 400 mg orally twice daily

• Sunitinib: 50 mg daily (4 weeks on, 2 weeks off)

• Lenvatinib: 8–24 mg once daily (dose based on cancer type)

• Regorafenib: 160 mg daily for 3 weeks on, 1 week off

• Cabozantinib: 60 mg daily (dose varies by indication)

• Pazopanib: 800 mg daily

• Vandetanib: 300 mg daily

Note: Many MKIs are administered continuously, others on cyclic regimens.

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VI. Pharmacokinetics

• Oral bioavailability: Generally good, but affected by food (especially high-fat meals)

• Metabolism: Predominantly hepatic (CYP3A4 involvement)

• Half-life: Variable (e.g., vandetanib ~19 days; sorafenib ~25–48 hours)

• Excretion: Fecal and renal

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VII. Adverse Effects

Common across MKIs due to overlapping targets (especially VEGFR and PDGFR inhibition):

Adverse Effect	Explanation
Hypertension	VEGF inhibition → decreased nitric oxide
Hand-foot skin reaction	Common with sorafenib, regorafenib
Diarrhea	GI epithelial toxicity
Fatigue	Central or systemic toxicity
Proteinuria	VEGF pathway suppression → glomerular injury
Hepatotoxicity	Elevated liver enzymes
Hypothyroidism	Sunitinib, Lenvatinib
QT prolongation	Vandetanib, others
Mucositis, stomatitis	Especially with regorafenib
Cardiac dysfunction	Risk with some agents (e.g., sunitinib)
Bleeding/Thrombosis	Anti-angiogenic effects
Wound healing impairment	VEGF inhibition delays healing

VIII. Monitoring Parameters

• Blood pressure: Monitor frequently during first 6–8 weeks

• Liver function tests: AST, ALT, bilirubin

• Renal function: Serum creatinine, proteinuria (urinalysis)

• Thyroid function tests: Especially with lenvatinib, sunitinib

• ECG monitoring: QT interval in patients on vandetanib

• CBC: Especially in midostaurin or those affecting bone marrow

• Cardiac function: Ejection fraction in selected agents

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IX. Contraindications and Cautions

• Pregnancy: All MKIs are teratogenic and contraindicated

• Uncontrolled hypertension: Can exacerbate cardiovascular events

• Recent surgery: Delay initiation due to impaired wound healing

• QT prolongation history: Use with caution (vandetanib)

• Hepatic impairment: Dose modification or avoidance needed

• Drug-drug interactions: Strong CYP3A4 inhibitors/inducers alter plasma levels

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X. Drug Interactions

Interacting Drug Class	Effect
CYP3A4 inhibitors	↑ MKI levels (toxicity risk) – e.g., ketoconazole
CYP3A4 inducers	↓ MKI levels (reduced efficacy) – e.g., rifampin
QT-prolonging agents	Additive QT prolongation – caution with vandetanib
Antihypertensives	May require dose adjustment to control BP
Warfarin	Increased bleeding risk (VEGF inhibitors)
Grapefruit juice	Inhibits CYP3A4 → increased drug exposure

XI. Resistance Mechanisms

• Kinase domain mutations (e.g., KIT exon mutations in GIST)

• Upregulation of alternative pathways (e.g., FGFR, MET)

• Angiogenic escape: Activation of non-VEGF angiogenic pathways

• Intratumoral heterogeneity

• Development of resistance often leads to sequencing of MKIs or switching to more selective agents.

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XII. Clinical Practice Considerations

• Baseline assessment: BP, ECG, labs (renal, hepatic, thyroid)

• Educate patients on adherence, side effects, and timing with food

• Dose interruptions and modifications: Common and necessary

• Multidisciplinary approach: Oncology, cardiology, nephrology

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XIII. Newer and Emerging MKIs

• Tepotinib (MET inhibitor)

• Selpercatinib (RET inhibitor)

• Pralsetinib (RET inhibitor)

• Entrectinib (NTRK, ROS1, ALK)

• Larotrectinib (NTRK)

While some are highly selective, combination-targeted MKIs are being developed for tumor types with multiple kinase drivers.

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XIV. Summary of FDA-Approved Multikinase Inhibitors (2025)

Drug	Main Targets	Key Indications
Sorafenib	VEGFR, RAF, PDGFR, KIT, RET	HCC, RCC, DTC
Sunitinib	VEGFR, PDGFR, KIT, FLT3	RCC, GIST, pNET
Lenvatinib	VEGFR, FGFR, RET	HCC, DTC, RCC, endometrial cancer
Regorafenib	VEGFR, BRAF, KIT, RET	CRC, GIST, HCC
Cabozantinib	MET, VEGFR2, RET	RCC, MTC, HCC
Pazopanib	VEGFR, PDGFR	RCC, soft tissue sarcoma
Vandetanib	RET, VEGFR, EGFR	MTC
Midostaurin	FLT3, KIT	AML (FLT3+), mastocytosis
Ripretinib	KIT, PDGFRA	GIST (4th-line)
Avapritinib	PDGFRA exon 18	GIST with PDGFRA D842V mutation