axitinib
Regulatory sources consulted
Approved indications
- First-line advanced renal-cell carcinoma with avelumab or pembrolizumab.
- Advanced renal-cell carcinoma in adults after failure of prior sunitinib or cytokine therapy.
Contraindications
Absolute
- CIMA: hypersensitivity to axitinib or excipients; the FDA label establishes no formal contraindications.
Clinical warnings
- Control blood pressure before and during treatment; treat hypertension and withhold or reduce for severe hypertension. Discontinue for hypertensive crisis. — OpenFDA, set_id 84137882-e000-47da-bd5b-fa76ab3c76f9
- Monitor arterial or venous thrombosis, hemorrhage, heart failure, gastrointestinal perforation or fistula, proteinuria, hepatotoxicity, and reversible posterior leukoencephalopathy syndrome. Do not use with untreated brain metastases or recent active gastrointestinal bleeding. — OpenFDA, set_id 84137882-e000-47da-bd5b-fa76ab3c76f9
Drug interactions
- HighStrong CYP3A4/5 inhibitors
Mechanism: They increase axitinib exposure.
Recommendation: Avoid; if essential, reduce by about half and readjust after stopping them.
OpenFDA, set_id 84137882-e000-47da-bd5b-fa76ab3c76f9
- HighStrong CYP3A4/5 inducers
Mechanism: They decrease axitinib exposure.
Recommendation: Avoid the combination and also avoid grapefruit or grapefruit juice.
OpenFDA, set_id 84137882-e000-47da-bd5b-fa76ab3c76f9
Adverse events
Common (≥1%)
diarrhea · hypertension · fatigue · nausea · decreased appetite · dysphonia · palmar-plantar erythrodysesthesia · hypothyroidism
Pregnancy and lactation
It may cause fetal harm. Use effective contraception during treatment and for 1 week afterward. Do not breastfeed during treatment; consult the partner-drug label when used in combination.
Recent literature (PubMed)
Immune checkpoint inhibitors in combination with tyrosine kinase inhibitors are standard treatments for advanced clear cell renal cell carcinoma (RCC). This phase III RENOTORCH study compared the efficacy and safety of toripalimab plus axitinib versus sunitinib for the first-line treatment of patients with intermediate-/poor-risk advanced RCC. Patients with intermediate-/poor-risk unresectable or metastatic RCC were randomized in a ratio of 1 : 1 to receive toripalimab (240 mg intravenously once every 3 weeks) plus axitinib (5 mg orally twice daily) or sunitinib [50 mg orally once daily for 4 weeks (6-week cycle) or 2 weeks (3-week cycle)]. The primary endpoint was progression-free survival (PFS) assessed by an independent review committee (IRC). The secondary endpoints were investigator-assessed PFS, overall response rate (ORR), overall survival (OS), and safety. A total of 421 patients were randomized to receive toripalimab plus axitinib (n = 210) or sunitinib (n = 211). With a median follow-up of 14.6 months, toripalimab plus axitinib significantly reduced the risk of disease progression or death by 35% compared with sunitinib as assessed by an IRC [hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.49-0.86; P = 0.0028]. The median PFS was 18.0 months in the toripalimab-axitinib group, whereas it was 9.8 months in the sunitinib group. The IRC-assessed ORR was significantly higher in the toripalimab-axitinib group compared with the sunitinib group (56.7% versus 30.8%; P < 0.0001). An OS trend favoring toripalimab plus axitinib was also observed (HR 0.61, 95% CI 0.40-0.92). Treatment-related grade ≥3 adverse events occurred in 61.5% of patients in the toripalimab-axitinib group and 58.6% of patients in the sunitinib group. In patients with previously untreated intermediate-/poor-risk advanced RCC, toripalimab plus axitinib provided significantly longer PFS and higher ORR than sunitinib and had a manageable safety profile TRIAL REGISTRATION: ClinicalTrials.gov N
We conducted a phase II trial evaluating the efficacy of VEGFR inhibitor axitinib and PD-L1 inhibitor avelumab in patients with recurrent/metastatic adenoid cystic carcinoma (R/M ACC). Eligible patients had R/M ACC with progression within 6 months before enrollment. Treatment consisted of axitinib and avelumab. The primary end point was objective response rate (ORR) per RECIST 1.1; secondary end points included progression-free survival (PFS), overall survival (OS), and toxicity. Simon's optimal two-stage design tested the null hypothesis of ORR ≤5% versus ORR ≥20% at 6 months; ≥4 responses in 29 patients would reject the null hypothesis. Forty patients enrolled from July 2019 to June 2021; 28 were evaluable for efficacy (six screen failures; six evaluable for safety only). The confirmed ORR was 18% (95% CI, 6.1 to 36.9); there was one unconfirmed partial response (PR). Two patients achieved PR after 6 months; thus, the ORR at 6 months was 14%. The median follow-up time for surviving patients was 22 months (95% CI, 16.6 to 39.1 months). The median PFS was 7.3 months (95% CI, 3.7 to 11.2 months), 6-month PFS rate was 57% (95% CI, 41 to 78), and median OS was 16.6 months (95% CI, 12.4 to not reached months). Most common treatment-related adverse events (TRAEs) included fatigue (62%), hypertension (32%), and diarrhea (32%). Ten (29%) patients had serious TRAEs, all grade 3; four patients (12%) discontinued avelumab, and nine patients (26%) underwent axitinib dose reduction. The study reached its primary end point with ≥4 PRs in 28 evaluable patients (confirmed ORR of 18%). The potential added benefit of avelumab to axitinib in ACC requires further investigation.
Intravitreal injections remain the standard for treating common retinal diseases including age-related macular degeneration (AMD), diabetic macular edema (DME) and diabetic retinopathy. However, frequent administration creates significant treatment burden due to limited drug half-life and the chronic nature of these conditions. This review summarizes emerging drug delivery techniques and therapies for retinal disease that have achieved FDA approval within the past five years or have advanced to Phase 3 development, including intravitreal sustained-release platforms and alternative delivery routes (suprachoroidal, subretinal, topical, and subcutaneous). Specific innovations discussed include the ranibizumab port delivery system, EYP-1901 (Duravyu, vorolanib implant), KSI-301 (tarcocimab tedromer), KSI-501, OTX-TKI (Axpaxli, axitinib implant), 4D-150, revakinagene taroretcel-lwey (Encelto, NT-501, encapsulated cell therapy), Xipere (triamcinolone acetonide injectable suspension), AU-011 (belzupacap sarotalocan targeted delivery), ABBV-RGX-314, elamipretide, and OCS-01 (high concentration dexamethasone). Promising innovations include sustained-release intravitreal implants, topical and subcutaneous delivery systems, and targeted methods like suprachoroidal and subretinal injections, each with unique advantages and limitations. Challenges include overcoming the blood-retinal barrier, surgical complications with implantable devices, and ensuring patient adherence. Advances in smart delivery systems, drug formulations, and predictive models, alongside interdisciplinary collaboration, will be crucial in achieving personalized, effective, and sustainable retinal therapies.
Physiological vascular endothelial cell division and angiogenesis occur during embryonic development, wound healing, in the endometrium during the menstrual cycle, and during placental development. Otherwise, vascular endothelial cells divide less than once per decade. Neoplasms are limited in size (∼ 1.0 mm) owing to a deficiency of oxygen and metabolic fuels. To grow larger, new blood vessels form from pre-existing vasculature by angiogenesis (capillary sprouting). During this process, mature endothelial cells replicate and become incorporated into new capillaries resulting in tumor growth. Angiogenesis results in part from the increased production of vascular endothelial growth factors (VEGFs). The human VEGF family consists of VEGF-A/B/C/D and placental growth factor (PlGF). The VEGF family of receptors consists of three protein-tyrosine kinases (VEGFR1/2/3) and two nonprotein kinase receptors (neuropilin-1 and neuropilin-2). Semaphorins 3A-F/4A-G/5 A/B/6A-G/7 A are regulatory ligands that interact with their neuropilin and plexin receptors (PlxA1-A4/B1-B3/C1/D1) and regulate angiogenesis. Angiopoietin-1/2/4 interact with their Tie1/2 receptor protein-tyrosine kinases to modulate vasculogenesis and angiogenesis. Ephrin ligands (EfnA1/A2/A3/A4/A5/B1/B2/B3) and Ephrin receptors (EphA1/A2/A3/A4/A5/A6/A7/A8/A10/B1/B2/B3/B4/B6/) also contribute to angiogenesis. Platelet-derived growth factors, fibroblast growth factors, hepatocyte growth factor (c-Met), stem cell growth factor (Kit) receptor protein-tyrosine kinases, PKB/Akt, Src, and MAP kinases also participate in angiogenesis. Owing to its importance in tumor progression, the inhibition of angiogenic signaling represents an attractive cancer treatment. Ponatinib, regorafenib, and vandetanib are FDA-approved VEGFR, Tie2, and Ephrin receptor blockers used in the treatment of various malignancies. Other disorders characterized by aberrant angiogenesis include diabetic retinopathies and neovascular age-related macular