Cabozantinib for the treatment of solid tumors: a systematic review

Abstract

Background: Cabozantinib is approved, in various settings, for the treatment of renal cell carcinoma, medullary thyroid cancer, and hepatocellular carcinoma, and it has been investigated for the treatment of other cancers. With the available evidence and the real-world performance of cabozantinib compared with clinical trial data, we performed a systematic review of cabozantinib monotherapy as treatment for solid tumors in adults. Methods: This study was designed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses and registered with PROSPERO (CRD42020144680). We searched for clinical and observational studies of cabozantinib monotherapy for solid tumors using Embase, MEDLINE, and Cochrane databases (October 2020), and screened relevant congress abstracts. Eligible studies reported clinical or safety outcomes, or biomarker data. Small studies ( n < 25) and studies of cabozantinib combination therapies were excluded. Quality was assessed using National Institute for Health and Care Excellence methodology, and study characteristics were described qualitatively. Results: Of 2888 citations, 114 were included (52 randomized studies, 29 observational studies, 32 nonrandomized phase I or II studies or pilot trials, and 1 analysis of data from a randomized study and a nonrandomized study). Beyond approved indications, other tumors studied were castration-resistant prostate cancer, urothelial carcinoma, Ewing sarcoma, osteosarcoma, uveal melanoma, non-small-cell lung cancer, Merkel cell carcinoma, glioblastoma, pheochromocytomas and paragangliomas, cholangiocarcinoma, gastrointestinal stromal tumor, colorectal cancer, salivary gland cancer, carcinoid and pancreatic neuroendocrine tumors, and breast, endometrial and ovarian cancers. The most common adverse events were hypertension, diarrhea, and fatigue. Conclusion: The identified evidence demonstrates the positive efficacy/effectiveness of cabozantinib monotherapy in various solid tumor types, with safety findings being consistent with those observed with other VEGFR-targeting tyrosine kinase inhibitors. When available, real-world findings were consistent with the data reported from clinical trials. A limitation of this review is the high proportion of abstracts; however, this allowed us to capture the most up-to-date findings.

Cabozantinib-Loaded PLGA Nanoparticles: A Potential Adjuvant Strategy for Surgically Resected High-Risk Non-Metastatic Renal Cell Carcinoma

“…Various targets of CZ are associated with immunosuppression, thus allowing it to directly immunomodulate the tumor microenvironment, increase cytotoxic T cell activation/infiltration, and induce susceptibility of tumor cells to cytotoxic T cell-mediated tumor cell killing, differentiating itself from other VEGF-targeting TKIs [ 26 , 37 , 39 , 41 , 43 , 44 , 67 , 74 ]. In particular, TAM kinases such as AXL and MET promote immunosuppressive phenotypes in tumor-associated immunosuppressive cells (including regulatory T cells, myeloid-derived suppressor cells, and tumor-activated macrophages) [ 37 ], which in turn contribute to the resistance against immune checkpoint inhibitors [ 37 , 41 ].…”

“…RCC management has advanced significantly with the advent of newer generation TKIs, such as cabozantinib (CZ), that are effective in the first-line setting for intermediate- or poor-risk metastatic RCC, with significant clinical benefits in the progression-free survival and overall response rate [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ]. CZ is an oral, potent multi-target TKI that targets the VEGF receptor (VEGFR)-2 and several other receptor tyrosine kinases (RTKs), including the hepatocyte growth factor receptor (MET), the TAM (TYRO-3, AXL, and MER) family of receptor kinases, the ROS proto-oncogene 1, the c-kit proto-oncogene product, the Fms-related receptor tyrosine kinase 3, the tropomyosin receptor kinase B, the angiopoietin-1 receptor, and the RET proto-oncogene [ 34 , 35 , 39 , 41 , 42 , 44 ]. Compared to other pure anti-angiogenic TKIs, the concomitant inhibition of multiple clinically relevant RTKs with a greater potency provided by CZ interferes with tumor progression, metastasis, angiogenesis, and therapeutic resistance to VEGF inhibition through dual multi-facet effects on the tumor cells and their microenvironment [ 34 , 35 , 39 , 41 , 42 , 44 ].…”

“…CZ is an oral, potent multi-target TKI that targets the VEGF receptor (VEGFR)-2 and several other receptor tyrosine kinases (RTKs), including the hepatocyte growth factor receptor (MET), the TAM (TYRO-3, AXL, and MER) family of receptor kinases, the ROS proto-oncogene 1, the c-kit proto-oncogene product, the Fms-related receptor tyrosine kinase 3, the tropomyosin receptor kinase B, the angiopoietin-1 receptor, and the RET proto-oncogene [ 34 , 35 , 39 , 41 , 42 , 44 ]. Compared to other pure anti-angiogenic TKIs, the concomitant inhibition of multiple clinically relevant RTKs with a greater potency provided by CZ interferes with tumor progression, metastasis, angiogenesis, and therapeutic resistance to VEGF inhibition through dual multi-facet effects on the tumor cells and their microenvironment [ 34 , 35 , 39 , 41 , 42 , 44 ]. In particular, CZ has a unique anti-tumor immunomodulatory profile because several targets of CZ, including VEGFR2, MET, and the TAM kinases, play crucial roles in mediating the immunosuppressive tumor microenvironment in metastatic RCC.…”

“…Generally, the recommended starting dose of tablets (Cabometyx) for patients with metastatic RCC is 60 mg once daily, and treatment is continued until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs [ 26 , 34 , 35 , 38 , 40 , 44 , 45 , 46 , 47 ]. However, despite its successful anticancer efficacy in clinical trials and real-world clinical settings, CZ is associated with a clinically relevant toxicity profile and a high frequency of dose reduction, interruption, or treatment withdrawal leading to sub-optimal dose-induced therapeutic failures [ 26 , 34 , 35 , 38 , 40 , 44 , 45 , 46 , 47 ]. Furthermore, CZ exhibits poor aqueous solubility and low oral bioavailability, leading to insufficient CZ delivery to tumors below the threshold concentration [ 26 , 44 , 48 ].…”

“…However, despite its successful anticancer efficacy in clinical trials and real-world clinical settings, CZ is associated with a clinically relevant toxicity profile and a high frequency of dose reduction, interruption, or treatment withdrawal leading to sub-optimal dose-induced therapeutic failures [ 26 , 34 , 35 , 38 , 40 , 44 , 45 , 46 , 47 ]. Furthermore, CZ exhibits poor aqueous solubility and low oral bioavailability, leading to insufficient CZ delivery to tumors below the threshold concentration [ 26 , 44 , 48 ]. More importantly, chronic long-term exposure to several oral TKIs has been observed to be associated with a decrease in the plasmatic drug concentration over time and, therefore, a reduced efficacy and therapeutic failures of TKIs (‘tachyphylaxis’).…”