Cabozantinib in metastatic renal cell carcinoma: latest findings and clinical potential

Abstract

Since the advent of immunotherapy revolutionized the treatment of metastatic renal cell carcinoma (mRCC), the attention of oncologists has been unavoidably shifted from tyrosine kinase inhibitors (TKIs) to immune checkpoint blockade, with the associated risk of listing cabozantinib as just one of many available TKIs. On the contrary, we think that cabozantinib represents a very good option for mRCC treatment, with outstanding outcomes in terms of response rate, progression-free survival, overall survival and quick time to treatment response. Its safety profile is acceptable and its discontinuation rate, due to toxicity, is similar to those of other TKIs. It is still not clear if the effectiveness of this drug is justified by its wide spectrum of multikinase activity, extended to the MET and AXL kinases, or by the simple maintenance of a ‘vascular endothelial growth factor receptor pressure’ after another previous TKI. Early-phase studies are currently ongoing to investigate the potential activity and safety of cabozantinib in association with immunotherapy, albeit with the risk of an overly toxic combination. Thus, future opportunities to improve the clinical use of this drug will probably be represented by a smart treatment sequence.

Metastatic Renal Cell Carcinoma Rapidly Progressive to Sunitinib: What to Do Next?

“…Interestingly, cabozantinib efficacy seems to be independent of MET expression and by its typical "VEGF inhibition-related" toxicity profile. These previous data, together with our current findings, suggest that maintaining "VEGF pressure" can still slow disease progression irrespective of the primary sensitivity to TKI [21]. Finally, we provided informative observations on pathological characterization: our population included a relatively high proportion of tumors with sarcomatoid features (18%) compared with historical cohorts [22,23], underlining the interest for different therapeutic strategies in these poorprognosis subtypes, which may benefit from conventional chemotherapy [24] and possibly from the use of CKIs [25].…”

A network meta-analysis of short-term efficacy of different single-drug targeted therapies in the treatment of renal cell carcinoma

“…TKI including Axitinib, Sorafenib, Sunitinib, Pazopanib, and Tivozanib inhibit VEGF signaling by targeting the intracellular domain of the VEGFR; however, mTOR–raptor signaling is a potential target for antitumor therapy and mTOR inhibitors are currently under investigation for the treatment of various human cancers [ 44 ]. Cabozantinib represents a very good option for mRCC treatment, with outstanding outcomes in terms of response rate, PFS, OS, and quick time to treatment response [ 45 ]. Everolimus is an orally active mTOR inhibitor, and VEGF is a potent proangiogenic protein that plays an important role in tumor angiogenesis [ 10 ] and acts by binding to the VEGFR on endothelial cells [ 46 ].…”

A Review of Papillary Renal Cell Carcinoma and MET Inhibitors

“…Cabozantinib is another TKI that targets multiple receptors, including c-MET, VEGF, RET, KIT, AXL, TIE2, and FLT3 [43]. Data from phase I study from Choueiri et al demonstrated safety and tolerability in RCC [44].…”