Lenvima (Lenvatinib) Clinical Trials (June 2026): ~100 Recruiting Interventional Studies Across 1L HCC, RCC, DTC, Endometrial, Cervical, Breast, Sarcoma, NET, and Cross-Cancer Combinations

Last updated: June 30, 2026

Drug profile:

Lenvima (lenvatinib mesylate, E7080) is an oral once-daily multikinase inhibitor developed by Eisai, with a global pembrolizumab-combination partnership signed with Merck in March 2018. Lenvima blocks VEGFR1, VEGFR2, VEGFR3 (classical anti-angiogenic), FGFR1, FGFR2, FGFR3, FGFR4 (the angiogenesis-escape pathway that limits pure VEGFR inhibitors), plus PDGFR-alpha, KIT, and RET. This broad receptor profile is the basis for Lenvima's cross-cancer activity across 4 different cancer types.

Mechanism of action:

Lenvatinib's distinctive feature is full coverage of all four FGFR receptors (FGFR1-4) at clinically achievable concentrations — addressing the FGF/FGFR-mediated angiogenesis escape that drives resistance to VEGFR-only inhibitors. The drug also targets RET and KIT, providing activity in RET-driven thyroid cancers and KIT-driven contexts. Lenvatinib + pembrolizumab combinations leverage VEGFR-mediated normalization of the tumor microenvironment to enhance checkpoint immunotherapy efficacy — the rationale behind the CLEAR (RCC) and KEYNOTE-775 (endometrial) regulatory wins.

Regulatory status:

Lenvima holds 5 distinct FDA approvals across 4 cancer types: differentiated thyroid cancer (May 2015), renal cell carcinoma + everolimus (May 2016), 1L unresectable hepatocellular carcinoma (Aug 2018), renal cell carcinoma + pembrolizumab 1L (Aug 2021), and advanced endometrial cancer + pembrolizumab (Sep 2019 accelerated / Jul 2021 regular all-comers). Dosing is weight-based for HCC (12 mg daily ≥60 kg; 8 mg daily <60 kg) and fixed for DTC (24 mg daily, with defined reduction schedule).

Why Lenvima Matters — In Plain Language

Multi-cancer reach. Few oncology drugs hold FDA approvals across four different cancer types. Lenvima does — thyroid cancer, hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), and advanced endometrial cancer. The breadth reflects the wide receptor profile (VEGFR + FGFR + RET + KIT) and Eisai's investment in developing both monotherapy (HCC, DTC) and combination therapies (RCC + everolimus, RCC + pembrolizumab, endometrial + pembrolizumab) over more than a decade.

HCC and the 1L decision. The largest patient population is 1L unresectable hepatocellular carcinoma. The REFLECT Phase 3 trial (NCT01761266, 954 patients) demonstrated lenvatinib was non-inferior to sorafenib on overall survival (median OS 13.6 vs 12.3 months, OS HR 0.92, 95% CI 0.79-1.06) with substantially higher objective response rate (40.6% vs 12.4% by mRECIST). FDA-approved August 2018. However, the subsequent IMbrave150 Phase 3 (atezolizumab + bevacizumab vs sorafenib, demonstrated superior OS — median OS 19.2 vs 13.4 months) reshaped the 1L HCC field: atezolizumab + bevacizumab is now the preferred 1L option for eligible patients, with lenvatinib reserved as the 1L alternative for patients ineligible for atezo + bev (active autoimmune disease, untreated esophageal varices, severe portal hypertension, recent hemorrhage, bevacizumab contraindications). Lenvatinib also remains widely used in 2L HCC after atezo + bev progression.

The pembrolizumab + lenvatinib combination. The 2018 Eisai-Merck global partnership led to two pivotal regulatory wins: CLEAR (Phase 3 pembrolizumab + lenvatinib vs sunitinib in 1L advanced RCC, median OS 53.7 vs 54.3 months — non-inferior with markedly higher ORR 71% vs 36%) and KEYNOTE-775 / Study 309 (Phase 3 pembrolizumab + lenvatinib vs investigator's choice chemotherapy in advanced endometrial cancer post-systemic therapy, OS HR 0.62 in pMMR and OS HR 0.68 in all-comers). The combination is now a standard option in both indications. Cervical, breast, ovarian, sarcoma, and rare-tumor extensions of the pembro + lenvima regimen dominate the cross-cancer recruiting pipeline.

FDA-Approved Indications

Lenvima has 5 active FDA approvals across 4 cancer types.

1. Differentiated Thyroid Cancer (DTC) — RAI-Refractory (SELECT, May 2015)

Pivotal trial: SELECT Phase 3 (NCT01321554), n=392, lenvatinib monotherapy vs placebo · FDA: May 13, 2015 · Setting: Adults with locally recurrent or metastatic, progressive, radioactive iodine (RAI)-refractory differentiated thyroid cancer (papillary, follicular, Hurthle cell variants) · Primary endpoint: median PFS 18.3 vs 3.6 months (PFS HR 0.21), ORR 64.8% vs 1.5%. Lenvima monotherapy. Dosing: 24 mg orally once daily; reductions per AE.

2. Renal Cell Carcinoma + Everolimus (Study 205, May 2016)

Pivotal trial: Study 205 Phase 2 (NCT01136733), n=153, 3-arm (lenvatinib + everolimus vs lenvatinib alone vs everolimus alone) · FDA: May 13, 2016 (combination) · Setting: Advanced RCC after prior VEGF-targeted therapy (2L+) · Primary endpoint: median PFS 14.6 vs 5.5 vs 7.4 months (combination superior). Pre-IO era approval; role narrowed after CLEAR + IO-TKI combinations established. Still relevant for IO-refractory or IO-ineligible RCC patients.

3. 1L Unresectable Hepatocellular Carcinoma (REFLECT, Aug 2018)

Pivotal trial: REFLECT Phase 3 (NCT01761266), n=954, lenvatinib vs sorafenib (non-inferiority design) · FDA: August 16, 2018 · Setting: 1L unresectable hepatocellular carcinoma, Child-Pugh A, ECOG 0-1 · Primary endpoint: median OS 13.6 vs 12.3 months (OS HR 0.92, 95% CI 0.79-1.06, non-inferior); ORR 40.6% vs 12.4% by mRECIST · Honest framing required: REFLECT was non-inferiority not superiority; IMbrave150 (atezo + bev) demonstrated superior OS vs sorafenib (median OS 19.2 vs 13.4 months); atezo + bev is the preferred 1L HCC standard for eligible patients. Lenvima is the 1L alternative for atezo + bev-ineligible patients (active autoimmune disease, untreated varices, hemorrhage history, bevacizumab contraindications).

4. 1L Advanced RCC + Pembrolizumab (CLEAR, Aug 2021)

Pivotal trial: CLEAR Phase 3 (NCT02811861), n=1,069, 3-arm (lenvatinib + pembrolizumab vs lenvatinib + everolimus vs sunitinib) · FDA: August 10, 2021 · Setting: 1L advanced or metastatic renal cell carcinoma · Primary endpoint: median PFS 23.9 vs 14.7 vs 9.2 months (pembro + lenva vs everolimus + lenva vs sunitinib), OS HR 0.66 (pembro arm), ORR 71% vs 53% vs 36% · Pembro + lenva is among the standard 1L IO-TKI RCC options alongside axitinib + pembro (KEYNOTE-426), cabozantinib + nivolumab (CheckMate-9ER), and ipi + nivo (CheckMate-214 for intermediate/poor risk).

5. Advanced Endometrial Cancer + Pembrolizumab (KEYNOTE-775, Sep 2019 / Jul 2021 regular)

Pivotal trial: KEYNOTE-775 / Study 309 Phase 3 (NCT03517449), n=827, lenvatinib + pembrolizumab vs investigator's choice chemotherapy · FDA: September 17, 2019 (accelerated, pMMR), July 21, 2021 (regular approval all-comers based on OS readout) · Setting: Advanced endometrial cancer that is not MSI-H or dMMR, after at least one prior platinum-based regimen for any setting (initially); regular approval extended to all comers · Primary endpoint: median OS 18.3 vs 11.4 months (OS HR 0.62 in pMMR), HR 0.68 all-comers; median PFS 7.2 vs 3.8 months · First FDA accelerated → regular conversion of a pembrolizumab combination based on OS confirmation. Pembro + lenva is a guideline-endorsed 2L endometrial option.

★ The Honest 1L HCC Framing — Lenvatinib vs Atezolizumab + Bevacizumab

A common point of patient confusion in HCC is whether lenvatinib is the "best" 1L option. The honest answer based on Phase 3 head-to-head and indirect comparison: atezolizumab + bevacizumab (IMbrave150) is the preferred 1L HCC standard for eligible patients — it demonstrated superior OS vs sorafenib (median OS 19.2 vs 13.4 months), while lenvatinib was non-inferior (REFLECT median OS 13.6 vs 12.3 months). Direct head-to-head lenvatinib vs atezo + bev has not been performed in a Phase 3, but the IMbrave150 OS magnitude makes atezo + bev the consensus preferred regimen.

Lenvatinib remains the 1L HCC alternative for patients ineligible for atezolizumab + bevacizumab: active or recent autoimmune disease (relative contraindication for pembrolizumab and atezolizumab), untreated esophageal varices with high bleeding risk, recent or significant hemorrhage history, severe portal hypertension, prior solid organ transplant, anti-VEGF contraindications, or patient preference for an oral once-daily regimen over IV infusion every 3 weeks plus the bevacizumab risk profile.

In 2L HCC after atezo + bev progression, lenvatinib is widely used (no Phase 3 establishes its 2L role specifically, but real-world practice supports it). Cabozantinib (CELESTIAL Phase 3 vs placebo 2L HCC post-sorafenib) and regorafenib (RESORCE Phase 3 vs placebo 2L HCC post-sorafenib) are the formal Phase 3-validated 2L options but were developed in the pre-IO 2L setting; sequencing after atezo + bev is an active area of investigation. Pembrolizumab monotherapy and ramucirumab (AFP ≥400 ng/mL) are additional 2L options.

Recruiting Lenvima Trials

Curated subset of recruiting interventional lenvatinib trials in the ClinTrialFinder corpus as of June 30, 2026 (approximately 100 recruiting interventional trials total). Trials are grouped by clinical setting and ordered by phase and clinical significance.

Phase 3 — HCC (Lenvatinib + Chinese PD-1 + Locoregional Combinations)

NCT05608200 — Phase 3: Lenvatinib + sintilimab + TACE vs lenvatinib + TACE for advanced HCC. Tests whether adding a Chinese PD-1 (sintilimab) to the lenvatinib + TACE backbone improves outcomes in advanced HCC.
NCT05985798 — Phase 3 (Head-to-Head): Sintilimab + bevacizumab + TACE vs lenvatinib + TACE for advanced HCC. Direct comparison of IO + anti-angiogenic + TACE (sintilimab + bev) vs lenvatinib + TACE.
NCT05823311 — Phase 3: Lenvatinib + tislelizumab + GPLET (gemcitabine + cisplatin + lenvatinib + tislelizumab) chemo-IO regimen.
NCT06089382 — Phase 3 (Adjuvant): Sintilimab + lenvatinib as adjuvant therapy after HCC resection — addresses the adjuvant gap (no FDA-approved HCC adjuvant therapy currently).
NCT05342194 — Phase 3 (1L Combo): Toripalimab + lenvatinib + gemcitabine-based chemotherapy as 1L treatment for advanced HCC.
NCT05608213 — Phase 3 (TACE-Refractory): Lenvatinib + I-125 seed brachytherapy vs lenvatinib alone for TACE-refractory HCC. Brachytherapy intensification of lenvatinib in TACE-refractory disease.
NCT05738616 — Phase 3 (Conversion): Lenvatinib + TACE + camrelizumab as conversion-resection regimen for advanced HCC.
NCT06201065 — Phase 3 (HAIC Backbone): FOLFOX-HAIC + lenvatinib + toripalimab vs FOLFOX-HAIC + lenvatinib for advanced HCC.
NCT07475026 — Phase 3 (Neoadjuvant): Neoadjuvant tislelizumab + lenvatinib in resectable HCC at high risk of recurrence.
NCT07537946 — Phase 3 (Local Consolidation): Local consolidation after sintilimab + lenvatinib for metastatic liver cancer.
NCT05718232 — Phase 3 (SEARCH): SBRT + lenvatinib + TACE for advanced primary HCC. Adds stereotactic radiotherapy to lenvatinib + TACE backbone.

Phase 2 — HCC Notable Combinations

NCT06034977 — Phase 2 (Platform Combo): ADI-PEG 20 + lenvatinib in unresectable HCC. Polaris Pharmaceuticals arginine-depletion + lenvatinib combination — novel metabolic + anti-angiogenic mechanism pairing.
NCT06984718 — Phase 2 (Head-to-Head): Cadonilimab (AK104, PD-1/CTLA-4 bispecific) + lenvatinib vs lenvatinib alone as 2L HCC. Tests whether adding a single bispecific IO to lenvatinib outperforms lenvatinib monotherapy in 2L HCC.
NCT07297654 — Phase 2 (Child-Pugh B): 1L lenvatinib in Child-Pugh B HCC patients unsuitable for curative treatment. Important real-world subset — Child-Pugh B patients are typically excluded from registration trials.
NCT06919848 — Phase 2: Oncolytic virus H101 + lenvatinib + toripalimab vs FOLFOX. Adds oncolytic virotherapy to lenvatinib + IO.
NCT07495579 — Phase 2 (REVIVE-HCC): Lenvatinib or regorafenib for advanced HCC after immunotherapy. Tests sequencing after IO progression.
NCT05185739 — Phase 2 (Perioperative): Perioperative pembrolizumab + lenvatinib in resectable HCC.

Phase 2/3 — RCC Earlier-Setting and IO-TKI Combinations

NCT05733715 — Phase 1 (Neoadjuvant): Neoadjuvant pembrolizumab + lenvatinib for renal cell carcinoma.
NCT06574412 — Phase 2 (Perioperative): Cardenilimab + lenvatinib in patients with perioperative resectable clear-cell RCC.
NCT07460206 — Phase 2 (Post-Pembro-Adjuvant): Pembrolizumab + lenvatinib in recurrent ccRCC patients failing pembrolizumab adjuvant. Addresses the emerging post-adjuvant-IO-failure population (KEYNOTE-564 era).
NCT07593040 — Phase 2 (Localized + HIF): Pembrolizumab + belzutifan with or without lenvatinib in localized RCC. Tests adding lenvatinib to the pembro + belzutifan HIF-2α combination.
NCT05319015 — Phase 2 (IVC Thrombus): Neoadjuvant lenvatinib + pembrolizumab for IVC tumor thrombus. Surgical-feasibility neoadjuvant strategy.

Endometrial, Cervical, and Other Gynecologic

NCT05112991 — Phase 2 (Endometrial): Envafolimab alone or with lenvatinib in advanced endometrial cancer.
NCT04865887 — Phase 2 (Cervical): Pembrolizumab + lenvatinib in advanced cervical cancer.
NCT05903833 — Phase 2 (Cervical Extension): Pembrolizumab + lenvatinib in recurrent, persistent, metastatic, or locally advanced cervical cancer.
NCT07368985 — Phase 2 (Locally Advanced Cervix): Pembrolizumab + lenvatinib in patients with high-risk locally advanced cervix cancer.
NCT04519151 — Phase 2 (Ovarian): Pembrolizumab + lenvatinib for platinum-sensitive recurrent ovarian cancer.

Breast Cancer Extensions

NCT05181033 — Phase 2 (ER+/HER2- Post-Endocrine): Lenvatinib + letrozole vs fulvestrant in metastatic ER+/HER2-negative breast cancer post endocrine progression.
NCT05286437 — Phase 2 (Endocrine-Resistant): Lenvatinib + pembrolizumab in endocrine-resistant breast cancer with letrozole.
NCT06110793 — Phase 1/2 (Triple Combo): Lenvatinib + pembrolizumab + fulvestrant in breast cancer.
NCT04427293 — Phase 1 (Preop TNBC): Preoperative lenvatinib + pembrolizumab in early-stage triple-negative breast cancer.

Cross-Cancer + Rare Indications

NCT05064280 — Phase 2 (Basket): Pembrolizumab + lenvatinib in TNBC, NSCLC, CRC, and other tumors.
NCT05746208 — Phase 2 (G3 NET): Lenvatinib + pembrolizumab in well-differentiated G3 neuroendocrine tumors. Cross-link with NET wizard work (sibling Task 410/411/412).
NCT07417501 — Phase 2 (11q13-Amp): Lenvatinib + PD-1 inhibitor for advanced solid tumors with 11q13 amplification. Biomarker-defined cohort (FGF19/CCND1 amplification).
NCT05617859 — Phase 2 (Sarcoma): Lenvatinib for advanced bone and soft tissue sarcoma.
NCT07619950 — Phase 2 (Bone Sarcoma): Everolimus + lenvatinib vs everolimus alone for bone sarcoma.

Showing a curated subset of recruiting lenvatinib interventional trials in the ClinTrialFinder corpus as of June 30, 2026 (approximately 100 recruiting interventional trials total). For the latest list: view all recruiting lenvatinib trials on ClinicalTrials.gov.

Mechanism: Oral Multikinase — VEGFR + FGFR + RET + KIT + PDGFR-alpha

Receptor coverage: VEGFR1/2/3 (classical anti-angiogenic axis — blocks tumor blood vessel growth), FGFR1/2/3/4 (the FGF/FGFR-mediated angiogenesis-escape pathway that limits pure VEGFR inhibitors; FGFR coverage is the distinctive lenvatinib feature among multikinase TKIs), PDGFR-alpha, KIT, and RET. The broad receptor profile is the basis for cross-cancer activity across both VEGFR-driven (HCC, RCC, DTC) and FGFR-driven (HCC subset, intrahepatic cholangiocarcinoma) tumor contexts.

Why FGFR matters in HCC: HCC tumors commonly upregulate FGF19 and FGFR4 signaling as a resistance mechanism to pure VEGFR inhibition. Lenvatinib's full FGFR1-4 coverage at clinically achievable concentrations may explain its higher ORR vs sorafenib in REFLECT (40.6% vs 12.4% by mRECIST) despite non-inferior OS — the FGFR blockade adds a second mechanism beyond classical anti-angiogenesis.

Why RET matters in thyroid cancer: differentiated thyroid cancer commonly harbors RET fusions or RET-driven signaling. Lenvatinib's RET coverage contributes to the SELECT Phase 3 PFS HR 0.21 in RAI-refractory DTC. Note: selective RET inhibitors (selpercatinib, pralsetinib) are now FDA-approved specifically for RET-fusion-positive thyroid cancer and may be preferred in molecularly-selected subsets; lenvatinib remains the broad-spectrum option for RAI-refractory DTC regardless of RET status.

How lenvatinib + pembrolizumab synergy works: VEGF/VEGFR inhibition normalizes the tumor vasculature, reduces hypoxia, increases effector T-cell infiltration, and decreases regulatory T-cell + myeloid-derived suppressor cell suppression in the tumor microenvironment. This creates a more favorable context for pembrolizumab to engage T-cell-mediated tumor killing. CLEAR (RCC) and KEYNOTE-775 (endometrial) validated this combination biology with Phase 3 OS benefit.

Sequencing and Comparison: Where Does Lenvima Fit?

Lenvima holds 5 FDA approvals across 4 cancer types. Sequencing decisions depend on indication, comorbidity profile, and patient eligibility for combination IO partners.

1L HCC sequencing: atezolizumab + bevacizumab preferred for eligible patients (IMbrave150 OS superior to sorafenib); lenvatinib for atezo + bev-ineligible patients (active autoimmune disease, untreated varices, hemorrhage history, bevacizumab contraindications); pembrolizumab + lenvatinib is being tested but not Phase 3-superior to sorafenib in HCC; durvalumab + tremelimumab (STRIDE regimen, HIMALAYA Phase 3) is another 1L IO-only option. 2L HCC post-atezo + bev: lenvatinib commonly used (no Phase 3 specifically); cabozantinib (CELESTIAL) and regorafenib (RESORCE) have formal 2L Phase 3 data from the pre-IO era; ramucirumab if AFP ≥400 ng/mL.
1L RCC sequencing: standard IO-TKI options include lenvatinib + pembrolizumab (CLEAR), cabozantinib + nivolumab (CheckMate-9ER), axitinib + pembrolizumab (KEYNOTE-426). For intermediate/poor-risk IMDC RCC, ipilimumab + nivolumab (CheckMate-214) is the standard IO + IO option. Choice typically depends on toxicity profile preference, infusion vs oral logistics, and IMDC risk stratification.
RAI-refractory DTC sequencing: lenvatinib (SELECT Phase 3) or sorafenib (DECISION Phase 3); cabozantinib (COSMIC-311 Phase 3, FDA Sep 2021 for radioiodine-refractory DTC progressing on or after lenvatinib or sorafenib) is the formal 2L option. For RET-fusion-positive DTC, selective RET inhibitors selpercatinib or pralsetinib are preferred over broad-spectrum multikinase TKIs. For BRAF V600E-mutant anaplastic thyroid cancer, dabrafenib + trametinib is FDA-approved (different histology).
Advanced endometrial cancer sequencing: pembrolizumab + lenvatinib (KEYNOTE-775 Phase 3) is the 2L all-comers standard after platinum chemotherapy progression. For MSI-H / dMMR endometrial, pembrolizumab monotherapy (KEYNOTE-158) or dostarlimab (GARNET) are alternative IO-only options. KEYNOTE-868 / NRG-GY018 (pembrolizumab + carboplatin/paclitaxel) and DUO-E (durvalumab + carboplatin/paclitaxel + olaparib) shifted IO-chemo into 1L advanced endometrial — pembrolizumab + lenvatinib's 2L role may evolve as 1L IO-chemo becomes more common.
Lenvatinib vs cabozantinib head-to-head: no formal Phase 3 head-to-head. Lenvatinib favored in HCC 1L and DTC (SELECT vs sorafenib robust). Cabozantinib favored in 2L HCC post-sorafenib (CELESTIAL Phase 3) and 2L DTC post-lenvatinib/sorafenib (COSMIC-311). In RCC, both are validated 1L IO-TKI partners (cabo + nivo CheckMate-9ER, lenva + pembro CLEAR) with similar efficacy magnitude.
Frame fairly: ask your oncologist about all 1L HCC options (atezo + bev preferred if eligible; lenvatinib if not), about IO-TKI combination choice in 1L RCC, about formal RET testing in DTC if RET-fusion-positive (selpercatinib or pralsetinib may be preferred), and about hypertension management plans before initiating lenvatinib (HTN must be controlled <150/90 mmHg before start; routine BP monitoring required).

Side Effects and Practical Considerations

⚠ Defining Lenvatinib Toxicity: Hypertension (Grade 3+ ~40%) + Multi-Organ Risk Profile

Hypertension is the defining lenvatinib toxicity — Grade 3 or higher in approximately 40% of patients across indications, the highest Grade 3+ HTN rate of any approved oncology multikinase inhibitor. Pre-existing hypertension must be controlled to less than 150/90 mmHg before initiation, blood pressure monitored weekly for the first 8 weeks then at least monthly, and antihypertensive regimens routinely require escalation (commonly amlodipine first-line, with ACE inhibitor or ARB added; beta-blockers if needed; multi-drug regimens common). Severe HTN crisis or hypertensive emergency is uncommon but reported — manage acutely + temporarily hold lenvatinib + escalate antihypertensives + resume at reduced dose once controlled.

Multi-organ risk profile from the FDA label: cardiac dysfunction (LV ejection fraction decreases — baseline echo + periodic monitoring in patients with cardiac risk factors), arterial thromboembolic events (MI, stroke), venous thromboembolic events (DVT, PE), hepatotoxicity (especially relevant in HCC where baseline hepatic impairment is common — Child-Pugh A or B7 generally accepted, Child-Pugh C contraindicated; monitor LFTs), renal failure and renal impairment (proteinuria monitoring with urine dipstick + 24-hour protein), GI perforation and fistula formation (rare but serious, especially with prior radiation), hemorrhagic events including severe pulmonary or intracranial hemorrhage (rare but reported), QT prolongation (baseline + periodic ECG), hypocalcemia (monitor and replete), reversible posterior leukoencephalopathy syndrome (RPLS, rare; presents with headache + altered mental status + seizures + visual changes), impairment of TSH suppression in DTC patients (monitor TSH closely + adjust levothyroxine).

Practical workflow: baseline labs (CBC, CMP, LFTs, TSH, urinalysis), baseline echo and ECG for high-risk patients, BP monitoring program established before initiation, antihypertensive optimization, patient education on warning signs (uncontrolled HTN, dyspnea, hemoptysis, sudden severe headache, chest pain, abdominal pain). Dose modifications are well-defined — HCC: 12 mg → 8 mg → 4 mg → discontinuation; DTC: 24 mg → 20 mg → 14 mg → 10 mg → 8 mg → 4 mg → discontinuation.

Other Common Adverse Events

Diarrhea — very common (~40-60% across indications); manage with loperamide, hydration, dose modifications.
Fatigue + asthenia — very common (~40-60%); multifactorial.
Decreased appetite + weight loss — common (~30-50%); nutritional support, dietitian referral useful.
Nausea + abdominal pain — common.
Palmar-plantar erythrodysesthesia (hand-foot syndrome) — common; topical urea-based emollients, supportive footwear, dose modifications.
Proteinuria — common; urine dipstick + 24-hour protein monitoring; dose hold or reduction for ≥ 2+ proteinuria or ≥ 2 g/24 hours.
Hypothyroidism — common (paradoxically — lenvatinib treats thyroid cancer but commonly induces hypothyroidism through capillary regression in the thyroid). TSH monitoring at baseline + every 4-8 weeks + early levothyroxine replacement when elevated. In DTC patients, ensure TSH suppression maintained for tumor-suppression purposes.
Stomatitis / mucositis — common; ice chips, oral care, dose modifications.
Headache — common (mild-to-moderate; severe sudden headache requires evaluation for RPLS or intracranial hemorrhage).

Long-Term Considerations

Patients on long-term lenvatinib (especially HCC and DTC monotherapy) require ongoing BP monitoring, periodic LFTs and thyroid function tests, urine protein monitoring, periodic cardiac assessment. The drug's anti-angiogenic mechanism means wound healing is impaired — plan for treatment holds around any surgery (typically hold 1-2 weeks before + 2 weeks after surgery depending on complexity). Patients undergoing dental procedures should inform the dentist and lenvatinib may need to be held. Discontinuation typically follows disease progression, intolerable adverse events, or hepatic decompensation in HCC patients.

Frequently Asked Questions

What is Lenvima (lenvatinib)?

Lenvima (USAN lenvatinib mesylate, development code E7080) is an oral once-daily multikinase inhibitor developed by Eisai. It blocks multiple tyrosine kinases simultaneously: VEGFR1, VEGFR2, VEGFR3 (classical anti-angiogenic), FGFR1, FGFR2, FGFR3, FGFR4 (the angiogenesis-escape pathway), plus PDGFR-alpha, KIT, and RET. This broad receptor profile is the basis for Lenvima's distinctive cross-cancer activity. Lenvima holds 5 distinct FDA approvals across 4 different cancer types: differentiated thyroid cancer (DTC, May 2015 SELECT Phase 3), advanced renal cell carcinoma in combination with everolimus (May 2016 Study 205 Phase 2), 1L unresectable hepatocellular carcinoma (HCC, August 2018 REFLECT Phase 3 non-inferiority vs sorafenib), advanced renal cell carcinoma in combination with pembrolizumab as 1L therapy (August 2021 CLEAR Phase 3), and advanced endometrial cancer in combination with pembrolizumab (September 2019 accelerated approval, July 2021 regular approval based on KEYNOTE-775 / Study 309 Phase 3). Eisai partnered with Merck globally in March 2018 on the pembrolizumab + lenvatinib combination program — driving the CLEAR and KEYNOTE-775 approvals.

Which patients qualify for Lenvima in HCC?

Lenvima is FDA-approved as 1L systemic therapy for adults with unresectable hepatocellular carcinoma, based on the REFLECT Phase 3 demonstrating non-inferior overall survival vs sorafenib (median OS 13.6 vs 12.3 months, OS HR 0.92, 95% CI 0.79-1.06). However, treatment guidelines now generally prefer atezolizumab + bevacizumab as the 1L HCC standard for eligible patients based on IMbrave150 demonstrating superior OS vs sorafenib (median OS 19.2 vs 13.4 months). Lenvima is the preferred 1L HCC alternative for patients ineligible for atezolizumab + bevacizumab — typically those with active autoimmune disease, untreated esophageal varices with high bleeding risk, recent or significant hemorrhage, severe portal hypertension, or other contraindications to checkpoint immunotherapy or bevacizumab. Lenvima also remains commonly used in 2L HCC after atezolizumab + bevacizumab progression. Key eligibility considerations: Child-Pugh class A or B7 (Child-Pugh C is contraindicated), ECOG performance status 0 or 1, adequate organ function, blood pressure controlled to less than 150/90 mmHg before initiation, no recent fistula or hemorrhagic event. The recommended dose is weight-based — 12 mg orally once daily for patients weighing 60 kg or more; 8 mg daily for less than 60 kg. See the HCC trials page for the full HCC trial landscape.

How does Lenvima differ from sorafenib, cabozantinib, and other multikinase inhibitors?

All four drugs (lenvatinib, sorafenib, cabozantinib, regorafenib) are oral multikinase inhibitors with overlapping VEGFR activity, but the receptor coverage and clinical profile differ meaningfully. Lenvatinib uniquely targets all four FGFR receptors (FGFR1-4) at clinically achievable concentrations, which is the rationale for its activity in FGFR-driven tumors (HCC, intrahepatic cholangiocarcinoma) and may explain superior tumor shrinkage rates vs sorafenib in REFLECT (40.6% ORR by mRECIST vs 12.4%). Sorafenib targets VEGFR2/3, PDGFR-beta, RAF kinase, KIT, and FLT3 — narrower spectrum, milder potency. Cabozantinib targets VEGFR1-3, MET, AXL, RET, KIT, and ROS1 — adds MET and AXL coverage relevant for HCC post-sorafenib failure (CELESTIAL Phase 3) and for thyroid medullary carcinoma. Regorafenib targets VEGFR1-3, TIE-2, FGFR1, PDGFR-beta, KIT, RET, RAF, and B-RAF — broadest classical TKI profile, used in 2L HCC after sorafenib (RESORCE Phase 3). The practical sequencing question in HCC: atezolizumab + bevacizumab 1L when feasible; lenvatinib 1L when atezo + bev contraindicated; cabozantinib (CELESTIAL) or regorafenib (RESORCE) as 2L+ options. In RCC, lenvatinib + pembrolizumab (CLEAR) is among the standard 1L IO-TKI options alongside axitinib + pembrolizumab (KEYNOTE-426), cabozantinib + nivolumab (CheckMate-9ER), and nivolumab + ipilimumab (CheckMate-214 for intermediate/poor risk).

What are the main side effects of Lenvima?

Lenvima's defining toxicity is hypertension — Grade 3 or higher in approximately 40% of patients across indications, the highest Grade 3+ hypertension rate of any approved multikinase inhibitor. Pre-existing hypertension must be controlled to less than 150/90 mmHg before initiation, and blood pressure monitoring is required weekly during the first 8 weeks and at least monthly thereafter. Antihypertensive regimens routinely require escalation. Other common adverse events: diarrhea, fatigue, decreased appetite, weight loss, nausea, abdominal pain, palmar-plantar erythrodysesthesia (hand-foot syndrome) requiring topical urea-based emollients and dose modifications, proteinuria (monitor urine dipstick and 24-hour protein), and hypothyroidism (paradoxically common despite lenvatinib's FDA approval for thyroid cancer — monitor TSH and initiate levothyroxine replacement early when elevated). The FDA label includes warnings for cardiac dysfunction, arterial and venous thromboembolic events, hepatotoxicity (especially in HCC), renal failure, GI perforation, hemorrhagic events, fistula formation, QT prolongation, hypocalcemia, reversible posterior leukoencephalopathy syndrome (RPLS), and impairment of TSH suppression in DTC patients. Dose modifications are well-defined — 12 mg / 8 mg / 4 mg daily for HCC, 24 mg / 20 mg / 14 mg / 10 mg / 8 mg / 4 mg for DTC. See the HCC trials page for the full HCC trial landscape and the RCC trials page for IO-TKI sequencing context.

What's the state of Lenvima research beyond its FDA labels?

The recruiting Lenvima trial pipeline is dominated by HCC combinations — approximately 70% of the recruiting trials are HCC, predominantly combinations with Chinese-developed PD-1 inhibitors (sintilimab, tislelizumab, pucotenlimab, toripalimab, camrelizumab, adebrelimab) plus locoregional therapies (transarterial chemoembolization TACE, hepatic arterial infusion chemotherapy HAIC, stereotactic body radiation therapy SBRT, I-125 brachytherapy). Headline HCC Phase 3 trials include NCT05608200 lenvatinib + sintilimab + TACE vs lenvatinib + TACE, NCT05985798 sintilimab + bevacizumab + TACE vs lenvatinib + TACE comparison, NCT05823311 lenvatinib + tislelizumab + GPLET chemo-IO regimen, NCT06089382 sintilimab + lenvatinib adjuvant after HCC resection, NCT05342194 toripalimab + lenvatinib + gemcitabine-based 1L chemo, NCT06201065 FOLFOX-HAIC + lenvatinib + toripalimab, and NCT07475026 neoadjuvant tislelizumab + lenvatinib in resectable HCC at high recurrence risk. Notable platform combinations: NCT06034977 ADI-PEG 20 + lenvatinib in unresectable HCC, and NCT06984718 cadonilimab (AK104) + lenvatinib vs lenvatinib alone as 2L HCC. Cross-cancer extensions of pembrolizumab + lenvatinib into TNBC + NSCLC + CRC basket (NCT05064280), platinum-sensitive ovarian (NCT04519151), endocrine-resistant breast (NCT05181033, NCT05286437, NCT06110793), preoperative early TNBC (NCT04427293), well-differentiated G3 neuroendocrine tumors (NCT05746208), 11q13-amplified solid tumors (NCT07417501), and bone and soft tissue sarcoma (NCT05617859, NCT07619950).

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