Last updated: July 1, 2026
Class hub: Oral once-daily multikinase tyrosine kinase inhibitors (TKIs) that block multiple receptor kinases simultaneously — targeting VEGFR-1/2/3 (classical anti-angiogenic axis) plus PDGFR-alpha (class-common) plus varying combinations of FGFR-1/2/3/4 (distinctive to lenvatinib), MET/AXL (distinctive to cabozantinib), KIT (distinctive to sunitinib for GIST), RET (varied). This class has been the workhorse of anti-angiogenic oncology since sorafenib's 2005 FDA approval — the first VEGFR-TKI approved for a solid tumor. 8+ FDA-approved multikinase TKIs deployed across HCC, RCC, DTC, MTC, GIST, STS, NET, pNET, endometrial + pembrolizumab, cervical + pembrolizumab, and metastatic colorectal cancer 2L+.
Class distinction: Multikinase TKIs remain first-line for cancers where anti-angiogenic activity is the dominant mechanism (HCC, RCC, DTC) and where no single driver mutation dominates. In molecularly-selected subsets — RET-fusion-positive DTC/NSCLC (selpercatinib, pralsetinib), NTRK-fusion tumors (larotrectinib, entrectinib), FGFR2-fusion intrahepatic cholangiocarcinoma (pemigatinib, futibatinib), BRAF V600E anaplastic thyroid (dabrafenib + trametinib) — selective single-target TKIs are now preferred.
A multikinase inhibitor is an oral once-daily small molecule that blocks multiple tyrosine kinase receptors simultaneously. The class shares a common receptor foundation and diverges at the margins:
Mechanism of action: By blocking VEGFR on tumor endothelial cells, multikinase TKIs prevent tumor angiogenesis (new blood vessel formation) — starving tumors of the vasculature they need to grow and metastasize. Additional receptor coverage (FGFR, MET, RET, KIT) provides secondary tumor-cell-intrinsic activity beyond anti-angiogenesis.
FDA-approved multikinase TKIs (chronological by first approval):
| Drug | Sponsor | First FDA approval | All FDA-approved cancers | CTF drug page |
|---|---|---|---|---|
| Sorafenib (Nexavar) | Bayer / Onyx | Dec 2005 | Advanced RCC (2005, first VEGFR-TKI FDA-approved), unresectable HCC (2007 SHARP Phase 3), RAI-refractory DTC (2013 DECISION Phase 3) | Not built |
| Sunitinib (Sutent) | Pfizer | Jan 2006 | GIST 2L+ (2006 first FDA target-approved GIST post-imatinib), advanced RCC (2006), pancreatic NET (pNET, 2011) | Not built |
| Pazopanib (Votrient) | Novartis / GSK | Oct 2009 | Advanced RCC (2009), advanced non-adipocytic soft tissue sarcoma (STS, 2012 PALETTE Phase 3) | Not built |
| Vandetanib (Caprelsa) | Sanofi | Apr 2011 | Medullary thyroid cancer (MTC, 2011); largely superseded by cabozantinib EXAM and selective RET inhibitors | Not built |
| Axitinib (Inlyta) | Pfizer | Jan 2012 | Advanced RCC 2L+ (2012 AXIS Phase 3), 1L advanced RCC + pembrolizumab (2019 KEYNOTE-426 Phase 3) or avelumab (2019 JAVELIN Renal 101 Phase 3) | Not built |
| Regorafenib (Stivarga) | Bayer | Sep 2012 | mCRC 2L+ (2012 CORRECT Phase 3), GIST 2L+ (2013 GRID Phase 3), unresectable HCC 2L+ post-sorafenib (2017 RESORCE Phase 3) | Not built |
| Cabozantinib (Cabometyx / Cometriq) | Exelixis / Ipsen | Nov 2012 | MTC (2012 EXAM Phase 3), advanced RCC 2L+ (2016 METEOR Phase 3), HCC 2L+ post-sorafenib (2019 CELESTIAL Phase 3), 1L advanced RCC + nivolumab (2021 CheckMate-9ER Phase 3), DTC post-lenvatinib or sorafenib (2021 COSMIC-311 Phase 3), advanced NET post-somatostatin (August 2025 CABINET Phase 3) | Not built — natural next candidate |
| Lenvatinib (Lenvima) | Eisai / Merck (2018 partnership) | May 2015 | DTC (2015 SELECT Phase 3), RCC + everolimus (2016 Study 205 Phase 2), 1L unresectable HCC (2018 REFLECT Phase 3 non-inferiority vs sorafenib), 1L RCC + pembrolizumab (2021 CLEAR Phase 3), advanced endometrial + pembrolizumab (2019 accelerated / 2021 regular per KEYNOTE-775) | ✅ Live drug page |
| Zanzalintinib (XL092) | Exelixis | In development | Multi-tumor Phase 3 program (RCC, mCRC, HCC, PDAC, HNSCC); Cabozantinib successor with optimized PK | Not built (investigational) |
| Anlotinib (Focus V) | Chia Tai Tianqing (China) | May 2018 (China NMPA) | NSCLC 3L+ (2018 China ALTER-0303 Phase 3), STS (2019 China), medullary thyroid (2019 China), SCLC 3L+ (2019 China), esophageal squamous cell carcinoma (2022 China). Not FDA-approved. | Not built (China-only) |
| Drug | VEGFR-1/2/3 | FGFR-1/2/3/4 | PDGFR-α | MET | AXL | KIT | RET | FLT3 / RAF |
|---|---|---|---|---|---|---|---|---|
| Sorafenib | 2/3 | — | β | — | — | ✅ | — | FLT3, RAF, B-RAF |
| Sunitinib | ✅✅✅ | — | ✅ | — | — | ✅ (GIST) | ✅ | FLT3 |
| Pazopanib | ✅✅✅ | 1/3 | β | — | — | ✅ | — | — |
| Axitinib | ✅✅✅ | — | β | — | — | ✅ | — | — |
| Regorafenib | ✅✅✅ | 1 | β | — | — | ✅ | ✅ | RAF, B-RAF, TIE-2 |
| Cabozantinib | ✅✅✅ | — | — | ✅ (HCC 2L) | ✅ (HCC 2L) | ✅ | ✅ (MTC) | ROS1 |
| Lenvatinib | ✅✅✅ | ✅✅✅✅ (all 4) | ✅ | — | — | ✅ | ✅ | — |
| Zanzalintinib | ✅✅✅ | — | — | ✅ | ✅ | ✅ | ✅ | ROS1 (cabo-like) |
Note: β = PDGFR-beta (rather than or in addition to α). All class members inhibit VEGFR to varying degrees; the class-differentiating panels are FGFR (lenvatinib unique), MET+AXL (cabozantinib unique), KIT (sunitinib GIST driver).
★ Why the FGFR + MET/AXL Distinctions Matter Clinically
Lenvatinib's FGFR1-4 coverage explains why REFLECT (Phase 3 1L HCC vs sorafenib) achieved mRECIST ORR 40.6% vs 12.4% despite OS non-inferiority (HR 0.92). HCC tumors upregulate FGF19 and FGFR4 as a resistance escape from pure VEGFR inhibition — lenvatinib's dual VEGFR + FGFR blockade closes the escape pathway.
Cabozantinib's MET + AXL coverage explains why CELESTIAL (Phase 3 2L HCC post-sorafenib) demonstrated OS benefit (HR 0.76) — sorafenib-resistant HCC upregulates MET as a documented resistance mechanism; cabozantinib's MET blockade re-sensitizes.
Sunitinib's KIT coverage explains why sunitinib works in imatinib-resistant GIST — most GIST tumors have KIT-driven biology, and imatinib-resistant clones commonly retain KIT sensitivity to alternative TKIs.
Pipeline dominated by lenvatinib + Chinese PD-1 (sintilimab, tislelizumab, pucotenlimab, toripalimab, camrelizumab) + locoregional (TACE, HAIC, SBRT, I-125) combinations. Headline Phase 3 trials:
1L RCC has 4 standard IO-TKI Phase 3-validated options: lenvatinib + pembrolizumab (CLEAR), cabozantinib + nivolumab (CheckMate-9ER), axitinib + pembrolizumab (KEYNOTE-426), axitinib + avelumab (JAVELIN Renal 101). Plus ipilimumab + nivolumab (CheckMate-214) for intermediate/poor-risk IMDC as IO-only alternative. Recruiting trials extend these combinations into earlier lines and post-adjuvant settings:
DTC RAI-refractory 1L: lenvatinib (SELECT Phase 3, PFS HR 0.21) or sorafenib (DECISION Phase 3). 2L post-lenvatinib or sorafenib: cabozantinib (COSMIC-311 Phase 3). For RET-fusion-positive DTC, selective RET inhibitors selpercatinib or pralsetinib are preferred over multikinase agents.
Cabozantinib (EXAM Phase 3, 2012 FDA) and vandetanib historically. Selective RET inhibitors preferred for RET-mutant subsets.
GIST TKI sequencing: imatinib 1L (2001 FDA) → sunitinib 2L (2006 FDA) → regorafenib 3L (GRID Phase 3, 2013 FDA) → ripretinib 4L (INVICTUS Phase 3, 2020 FDA). For PDGFRA D842V-mutant GIST, avapritinib preferred (NAVIGATOR Phase 1 basket, 2020 FDA).
Pazopanib (PALETTE Phase 3, 2012 FDA) for advanced non-adipocytic soft tissue sarcoma post-chemotherapy. Anlotinib (China NMPA 2019) approved in China.
Sunitinib pancreatic NET (pNET, 2011 FDA per Study 100). Cabozantinib advanced NET post-somatostatin analog therapy (August 2025 FDA per CABINET Phase 3). Lenvatinib + pembrolizumab in well-differentiated G3 NET is in Phase 2 (NCT05746208). See the NET-related wizard-input tasks (Task 410 Ki-67 numeric grade, Task 411 primary site sub-typing, Task 412 functional carcinoid syndrome).
Lenvatinib + pembrolizumab (KEYNOTE-775 / Study 309 Phase 3, September 2019 accelerated / July 2021 regular per OS confirmation). 2L standard after platinum-based chemotherapy progression.
Pembrolizumab + lenvatinib in multiple Phase 2 trials (advanced cervical, high-risk locally advanced, recurrent/persistent).
Regorafenib (CORRECT Phase 3, 2012 FDA) for mCRC 2L+ post-standard chemotherapy.
Anlotinib (Focus V, Chia Tai Tianqing) is China-approved for advanced NSCLC 3L+ (ALTER-0303 Phase 3), STS, medullary thyroid, SCLC 3L+, and esophageal squamous cell carcinoma. Not FDA-approved. Represents the Chinese multikinase competitor to lenvatinib and cabozantinib in multi-cancer development.
Selective single-target TKIs have superseded multikinase inhibitors in molecularly-defined subsets where cleaner on-target activity outperforms broad-spectrum multikinase blockade:
Cardinal principle: multikinase TKIs remain first-line for cancers where anti-angiogenic activity is the dominant mechanism and no single molecular driver dominates (1L HCC atezo+bev-alternative, 1L RCC IO-TKI combinations, RAI-refractory DTC without RET fusion). Full genomic profiling (RET, NTRK, BRAF V600E, FGFR2 fusions, PDGFRA) is recommended at diagnosis to identify subsets where selective TKIs are preferred.
What is a multikinase inhibitor?
A multikinase inhibitor is an oral once-daily small molecule that blocks multiple tyrosine kinase receptors simultaneously, typically including VEGFR-1/2/3 (vascular endothelial growth factor receptor, the classical anti-angiogenic axis), PDGFR-alpha, and varying combinations of FGFR, RET, KIT, MET, and AXL. The class targets tumor angiogenesis as its primary mechanism, with additional pathway blockade depending on receptor coverage. FDA-approved multikinase inhibitors include lenvatinib (Lenvima), cabozantinib (Cabometyx), sunitinib (Sutent), sorafenib (Nexavar), regorafenib (Stivarga), pazopanib (Votrient), axitinib (Inlyta), and vandetanib (Caprelsa, MTC only). Investigational: zanzalintinib (XL092, Exelixis). China-approved (not FDA): anlotinib (Focus V).
Which multikinase inhibitor is used for which cancer?
By indication: 1L unresectable HCC — atezolizumab + bevacizumab (IMbrave150) preferred; lenvatinib alternative per REFLECT non-inferiority. 2L HCC — cabozantinib (CELESTIAL), regorafenib (RESORCE), ramucirumab if AFP ≥400 ng/mL. RCC 1L IO-TKI — lenvatinib + pembrolizumab (CLEAR), cabozantinib + nivolumab (CheckMate-9ER), axitinib + pembrolizumab (KEYNOTE-426), axitinib + avelumab (JAVELIN Renal 101). RCC 2L+ post-IO — cabozantinib monotherapy or lenvatinib + everolimus. DTC RAI-refractory — lenvatinib (SELECT) or sorafenib (DECISION) 1L; cabozantinib COSMIC-311 2L; selective RET inhibitors selpercatinib or pralsetinib preferred if RET-fusion positive. MTC — cabozantinib (EXAM) or vandetanib; selective RET inhibitors preferred for RET-mutant. GIST — sunitinib 2L post-imatinib, regorafenib 3L (GRID). STS — pazopanib (PALETTE). pNET — sunitinib. NET post-SSA — cabozantinib (CABINET Aug 2025 FDA). Advanced endometrial — lenvatinib + pembrolizumab (KEYNOTE-775). Advanced cervical — pembrolizumab + lenvatinib. mCRC 2L+ — regorafenib (CORRECT).
How do multikinase inhibitors differ from each other?
All share VEGFR-1/2/3 + PDGFR-alpha coverage — the classical anti-angiogenic core. Receptor differentiation matters at the margins. Lenvatinib uniquely covers all four FGFR receptors (FGFR1-4) at clinically achievable concentrations — enabling distinctive HCC activity (REFLECT mRECIST ORR 40.6% vs sorafenib 12.4%) because HCC upregulates FGF19/FGFR4 as VEGFR-resistance escape. Cabozantinib uniquely covers MET and AXL — enabling 2L HCC activity post-sorafenib (CELESTIAL) because MET upregulation is documented sorafenib-resistance, and MTC activity. Sunitinib covers KIT — enabling GIST activity (imatinib-resistant GIST retains KIT sensitivity). Sorafenib was the first VEGFR-TKI FDA-approved for solid tumors (2005 RCC, 2007 HCC per SHARP) but has narrower target profile. Regorafenib is structurally similar to sorafenib but broader (adds VEGFR-1, TIE-2, FGFR1, RET, B-RAF). Pazopanib and axitinib are relatively selective for VEGFR-1/2/3.
What are the class-level side effects of multikinase inhibitors?
Defining class toxicity: hypertension (Grade 3 or higher approximately 25-45% class-wide; highest for lenvatinib at ~40%). Pre-existing HTN must be controlled to less than 150/90 mmHg before initiation; weekly BP monitoring for the first 8 weeks; antihypertensive regimens routinely require escalation. Other common class-shared adverse events: diarrhea, fatigue, decreased appetite, weight loss, palmar-plantar erythrodysesthesia (hand-foot syndrome), proteinuria, hypothyroidism (paradoxically common despite class members treating thyroid cancer). Class-level warnings: cardiac dysfunction (LVEF decrease), arterial and venous thromboembolic events, hepatotoxicity, renal failure, GI perforation, fistula formation, hemorrhagic events, QT prolongation, hypocalcemia, RPLS, impaired wound healing (treatment holds around surgery).
When are selective single-target TKIs preferred over multikinase inhibitors?
Selective single-target TKIs are preferred when a single driver alteration dominates. RET-fusion-positive DTC + NSCLC: selpercatinib and pralsetinib preferred over lenvatinib and cabozantinib. RET-mutant MTC: selective RET inhibitors preferred over cabozantinib or vandetanib. BRAF V600E anaplastic thyroid: dabrafenib + trametinib preferred. NTRK-fusion solid tumors: larotrectinib and entrectinib preferred. FGFR2-fusion intrahepatic cholangiocarcinoma: pemigatinib, infigratinib, futibatinib preferred. PDGFRA D842V-mutant GIST: avapritinib preferred. Cardinal principle: multikinase TKIs remain first-line for cancers where anti-angiogenic activity is dominant and no single molecular driver dominates (1L HCC atezo+bev-alternative, 1L RCC IO-TKI combinations, RAI-refractory DTC without RET fusion). Full genomic profiling (RET, NTRK, BRAF, FGFR2, PDGFRA) is recommended at diagnosis to identify selective-TKI-preferred subsets.
Find Multikinase Inhibitor Trials Matched to Your Situation
Use ClinTrialFinder's AI-powered matching to find lenvatinib, cabozantinib, sunitinib, sorafenib, regorafenib, and other multikinase TKI trials based on your specific cancer type (HCC, RCC, DTC, MTC, GIST, STS, NET, endometrial, cervical), molecular profile, prior therapy, and country.
Find Matching Trials via Lenvima