Multikinase Inhibitors

Mechanism & Class Overview

• Class mechanism: Broad-spectrum TKIs targeting VEGFR, PDGFR, c-KIT, RET, and other kinases; inhibit angiogenesis plus direct anti-tumor effects.
• Resistance: Kinase domain mutations, ↑ expression of the target kinase, activation of bypass pathways.
• Class adverse effects: The shared "AEs due to VEGF inhibition" recur across agents: hypertension (control BP early), arterial thrombosis (MI, stroke/TIA), proteinuria, hemorrhage (avoid with recent significant hemorrhage, hemoptysis, or GI bleed; severity- and agent-specific, no universal cutoff), impaired wound healing (hold around surgery), and RPLS/PRES. On top of these, hand-foot skin reaction (HFSR), diarrhea, and fatigue are common and often dose-limiting.

Renal Cell Carcinoma & Multi-Organ TKIs

Sunitinib (Sutent)

• Mechanism: Inhibits VEGFR (1, 2, 3), PDGFR, c-KIT, FLT3, RET, CSF1R.
• Indications: Renal cell cancer (first-line and refractory), GIST (after imatinib), pancreatic neuroendocrine tumors.
• Pharmacokinetics: Hepatic metabolism (CYP3A4). RCC/GIST: 50 mg daily, 4 weeks on / 2 weeks off. pNET: 37.5 mg daily continuous (no scheduled break).
• Toxicities: ↑ QT (monitor EKG), ↑ LFTs, HTN, hand-foot syndrome, diarrhea, fatigue, thyroid dysfunction (monitor TSH), adrenal dysfunction (check cortisol), cardiotoxicity (↓ EF; baseline/follow-up TTE; caution within 12 months of CAD/MI/unstable angina/CABG; avoid in symptomatic CHF), yellow discoloration of skin/sclera.

Sorafenib (Nexavar)

• Mechanism: Inhibits VEGFR (1, 2, 3), PDGFR, RAF kinase, c-KIT, FLT3, RET.
• Indications: Hepatocellular carcinoma, renal cell cancer, differentiated thyroid cancer (radioactive iodine-refractory).
• Pharmacokinetics: Hepatic metabolism (UGT1A9, CYP3A4); food ↓ absorption so take without food; ↑ INR on warfarin; avoid grapefruit.
• Toxicities: Hand-foot syndrome (dose-limiting), diarrhea, rash, HTN, fatigue, ↑ LFTs, ↓ phosphate, cardiac ischemia (monitor), prolonged QT.

Pazopanib (Votrient)

• Mechanism: Inhibits VEGFR (1, 2, 3), PDGFR-α/β, FGFR-3, c-KIT, Itk, cFms. Inhibits UGT1A1 (↑ SN-38, irinotecan toxicity).
• Indications: Renal cell cancer (advanced; see COMPARZ; adjuvant PROTECT negative), soft tissue sarcoma (2nd line).
• Pharmacokinetics: Hepatic metabolism (CYP3A4); half-life ~30h; dose reduce in moderate hepatic dysfunction.
• Toxicities: ↑↑ LFTs (mainly ALT; monitor frequently; hold if ALT >8× ULN), ↑ QT (periodic EKG; watch electrolytes), hypothyroidism (monitor TSH), mild myelosuppression, HTN, arterial thrombosis, proteinuria, hemorrhagic events.

Cabozantinib (Cometriq, Cabometyx)

• Mechanism: Inhibits VEGFR (1, 2, 3), MET, AXL, RET, c-KIT.
• Indications: Renal cell cancer (first-line and TKI-refractory; see CheckMate-9ER, METEOR, CABOSUN), medullary thyroid cancer, hepatocellular carcinoma (see CELESTIAL). Avoid food for 2h around dosing; dose-adjust in moderate hepatic dysfunction.
• Toxicities: Hand-foot syndrome (major, often dose-limiting), N/V/D, stomatitis, HTN, ↑ LFTs, fatigue, proteinuria, ↓ weight/appetite, alopecia/hair color change, arterial thrombosis, impaired wound healing, jaw osteonecrosis/bone erosions (obtain dental clearance/oral exam), RPLS.

Lenvatinib (Lenvima)

• Mechanism: Inhibits VEGFR (1, 2, 3), FGFR (1, 2, 3, 4), RET, c-KIT, PDGFR.
• Indications: Differentiated thyroid cancer (radioactive iodine-refractory), renal cell cancer (1L with pembrolizumab, see CLEAR; after prior anti-angiogenic therapy with everolimus, Study 205), hepatocellular carcinoma, endometrial cancer.
• Pharmacokinetics: Hepatic metabolism; oral bioavailability ~85% (absolute not determined; mass-balance estimate); half-life ~28h.
• Toxicities: ↑↑↑ HTN (often severe; check BP weekly initially; may need aggressive management), diarrhea, fatigue, hand-foot syndrome, appetite suppression, proteinuria, ↑ LFTs, thyroid dysfunction, ↑ QTc, cardiac toxicity/CHF (monitor EKG and TTE), ↓ calcium, RPLS.

Regorafenib (Stivarga)

• Mechanism: Inhibits VEGFR (1, 2, 3), FGFR, RET, c-KIT, PDGFR, RAF1, BRAF (V600E) and others.
• Indications: CRC (refractory: after fluoropyrimidine, oxaliplatin, irinotecan, anti-VEGF, and anti-EGFR if RAS wild-type), hepatocellular carcinoma, GIST (refractory to imatinib and sunitinib). Inhibits UGT1A1 (↑ irinotecan toxicity). ReDOS trial supports weekly dose escalation to improve tolerability and outcomes.
• Toxicities: Black box warning hepatotoxicity (monitor LFTs; fatal cases reported), hand-foot syndrome (severe, often dose-limiting), alopecia, diarrhea, fatigue, HTN (control early), rash, RPLS.

Axitinib (Inlyta)

• Mechanism: Selective VEGFR TKI (VEGFR 1, 2, 3); minor PDGFR/c-KIT activity; higher selectivity than sunitinib/pazopanib.
• Indications: Renal cell cancer (advanced; 1st line with pembrolizumab (KEYNOTE-426) or avelumab (JAVELIN Renal 101), or 2nd line (AXIS)). Dose titration may improve ORR. Doses ~12 h apart, with or without food.
• Toxicities: HTN (significant; monitor BP; dose adjust for uncontrolled HTN), diarrhea, fatigue, dysphonia, hand-foot syndrome, proteinuria, thyroid dysfunction, cardiac failure, hepatotoxicity, RPLS.

GIST-Specific Kinase Inhibitors

Ripretinib (Qinlock)

• Mechanism: Switch-control inhibitor of KIT and PDGFRα (also PDGFRβ, VEGFR2, BRAF, TIE2). CYP3A4 metabolism; active metabolite DP-5439.
• Indications: 4th-line GIST (see INVICTUS). Remember the GIST sequence: imatinib → sunitinib → regorafenib → ripretinib.
• Toxicities: Cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma (baseline and periodic derm exam), ↓ phosphate, ↑ lipase, cardiotoxicity/CHF (baseline TTE/MUGA), hand-foot syndrome, alopecia, HTN, myalgias/arthralgias, impaired wound healing (hold around surgery).

Avapritinib (Ayvakit)

• Mechanism: Targets PDGFRα D842V mutants and KIT exon 11, 11/17, and 17 mutants. CYP3A4 metabolism; half-life ~50h.
• Indications: GIST with a PDGFRα exon 18 (D842V) mutation (see NAVIGATOR); advanced systemic mastocytosis (2021) and indolent systemic mastocytosis (2023, PIONEER).
• Toxicities: Intracranial bleeding (subdural, cerebral; monitor for confusion, dizziness, vision changes, headache), edema/fluid retention, fatigue, pyrexia, N/V/D/constipation, increased lacrimation, rash, alopecia.

Thyroid-Specific & RET-Targeting

Vandetanib (Caprelsa)

• Mechanism: Inhibits RET, VEGFR, EGFR, TIE-2, EPH, SRC. CYP3A4 metabolism; hepatic and renal elimination (starting dose 200 mg in moderate renal impairment, not recommended in severe renal impairment; not recommended in moderate or severe hepatic impairment); half-life ~19 days; not affected by food.
• Indications: Medullary thyroid cancer (symptomatic or progressive).
• Toxicities: ↑↑↑ QT prolongation (dose-limiting; can cause sudden death; black box warning (REMS no longer required); do not use in congenital long-QT; correct Mg/K/Ca; avoid other QT-prolonging agents), diarrhea, acneiform rash/dermatitis (EGFR inhibition), HTN, fatigue, photosensitivity, ↑ LFTs, N/V/D, cough/SOB (pneumonitis/ILD), RPLS.

2026 update: new multikinase indications

Cabozantinib: pan-NET (CABINET)

• CABINET (Chan NEJM 2025): cabozantinib vs placebo in pretreated advanced neuroendocrine tumors (pancreatic and extra-pancreatic). Extra-pNET mPFS 8.4 vs 3.9 mo (HR 0.38); pNET mPFS 13.8 vs 4.4 mo (HR 0.23). Halted early for efficacy. FDA Mar 26, 2025 approval, first multikinase TKI across the full NET spectrum.

Fruquintinib (Fruzaqla)

• Mechanism: highly selective VEGFR-1/2/3 TKI (few off-target kinases).
• FRESCO-2 (Dasari Lancet 2023): refractory metastatic CRC after all standard therapies incl prior trifluridine/tipiracil and/or regorafenib (US indication: prior fluoropyrimidine, oxaliplatin, irinotecan, anti-VEGF, and anti-EGFR if RAS wild-type); mOS 7.4 vs 4.8 mo (HR 0.66). FDA Nov 8, 2023 approval.
• Toxicities: HTN, hand-foot syndrome, proteinuria; class VEGFR-TKI AEs; less GI than regorafenib.

Selpercatinib / pralsetinib: RET-selective

• Selpercatinib (Retevmo): RET-selective TKI (not multikinase). LIBRETTO-431 (Zhou NEJM 2023): 1L RET-fusion+ NSCLC vs pem+carbo ± pembro; mPFS 24.8 vs 11.2 mo. FDA NSCLC approval 2020 (accelerated), regular 2022; LIBRETTO-431 added randomized 1L evidence 2023. Tumor-agnostic RET-fusion approval (FDA Sep 2022).
• Selpercatinib in RET-mutant MTC: LIBRETTO-531 (Hadoux NEJM 2023) vs cabozantinib or vandetanib; superior PFS in RET-mutant MTC; supersedes multikinase TKIs as 1L for RET-mutant MTC.

Ivonescimab: PD-1 × VEGF bispecific

• HARMONi-2 (Zhou WCLC 2024): ivonescimab vs pembrolizumab monotherapy 1L PD-L1+ advanced NSCLC; mPFS 11.14 vs 5.82 mo (HR 0.51), the first therapy to beat pembro head-to-head in 1L NSCLC. Chinese approvals 2024 (EGFR-mutant) and 2025 (1L PD-L1+); FDA BLA (EGFR-mutant post-TKI) under review, PDUFA Nov 14, 2026.

Class updates

• Cabozantinib + nivolumab (CheckMate-9ER, Choueiri NEJM 2021, final analysis 2025): 1L advanced RCC (all IMDC risk groups); mOS 46.5 vs 35.5 mo (HR 0.79; median follow-up 67.6 mo). Lenvatinib + pembro (CLEAR) similar. Axitinib + pembro (KEYNOTE-426) mature.
• Lenvatinib + pembro in endometrial cancer: 2L pMMR (Study 309/KEYNOTE-775, Makker NEJM 2022, mature 2024); mOS benefit; SOC 2L pMMR endometrial.