Incidence and risk of hand-foot skin reaction with cabozantinib, a novel multikinase inhibitor: a meta-analysis

Abstract

Summary Background Cabozantinib is approved in the treatment of progessive, metastatic medullary thyroid cancer (MTC). It is a small molecule inhibitor, which targets multiple receptors including vascular endothelial growth factor receptor, tyrosine kinase with Ig and epidermal growth factor homology domains-2 and the proto-oncogenes MET (mesenchymal-epithelial transition factor) and RET (rearranged during transfection). The drug is currently in phase I/II/III clinical trials for a number of other solid tumours and haematological malignancies. The adverse event (AE) profile is similar to that of other newer angiogenesis inhibitors. Hand–foot skin reaction (HFSR) is an important dose-limiting dermatological adverse event of this class of drugs. Aim To ascertain the incidence and risk of HFSR in patients with cancer during treatment with cabozantinib. Methods Electronic databases (PubMed, Web of Science) and the American Society for Clinical Oncology website were queried from inception to July 2014. Only phase II/III studies investigating cabozantinib for the treatment of cancer were shortlisted. The incidence, relative risk (RR) and 95% CI were calculated using random- or fixed-effects models, depending on the heterogeneity of included studies. Results We included 831 patients treated with cabozantinib for various solid malignancies in the analysis. The overall incidence was 35.3% (95% CI 27.9–43.6%) for all-grade and 9.5% (95% CI 7.6–11.7%) for high-grade HFSR. The RR of all-grade and high-grade HFSR with cabozantinib, compared with controls, was increased for both all-grade (27.3; 95% CI 6.9–108.3; P < 0.001) and high-grade, 28.1; 95% CI 1.7–457; P < 0.02) HFSR, respectively. Conclusions The incidence and risk of developing HFSR with cabozantinib are high. Timely recognition of this dose-limiting AE is critical to direct supportive care efforts including patient counselling, and to institute preventative and/or treatment interventions.

Multikinase Inhibitor-Induced Hand–Foot Skin Reaction: A Review of Clinical Presentation, Pathogenesis, and Management

“…Several MKIs are found to have multitargeting effects because of the structural homolog among adenosine triphosphate (ATP)-binding sites of kinases [13]. Sorafenib, sunitinib, pazopanib, cediranib, regorafenib, axitinib, vandetanib, cabozantinib, masitinib, and telatinib are small-molecule, anti-angiogenic inhibitors of the tyrosine kinase with multi-targeting inhibition [14][15][16][17][18][19][20][21][22][23][24][25]. Table 1 summarizes and lists in order of frequency (high to low) the types of anti-angiogenic MKIs, their therapeutic indications and targets, and the incidence of all-grade and high-grade (grade 3) HFSRs [14][15][16][17][18][20][21][22][23].…”

“…Within 1-6 weeks of initiating MKI therapy, patients may experience prodromal symptoms of palmar-plantar dysesthesia, which are tingling, burning, or painful sensations in the palms and soles, as well as decreased tolerance to contact with objects [11,14,39]. This is followed by three clinical phases [16]. First, the inflammatory phase is marked by the appearance of well-defined, symmetrical erythema, and tense bullae on the palms and soles (Fig.…”

“…This has been validated for many agents in this group, including sorafenib, sunitinib, axitinib, and cabozantinib [16,[46][47][48][49]. Higher initial dose, initial dose per body weight, and initial dose per body surface area all result in a significant incidence of high-grade HFSR [50].…”

Design and characterization of MP0250, a tri-specific anti-HGF/anti-VEGF DARPin® drug candidate

“…[10][11][12] The drawback of broad specificity drugs (e.g., cabozantinib) and drugs with off-target toxicity (e.g., tivantinib) 13,14 is a high incidence of adverse events. 15,16 Interestingly, the anti-HGF mAb rilotumumab, which exhibits partial HGF inhibition, 17 did not demonstrate efficacy as a single agent in Phase 2 trials in prostate cancer 18,19 and in Phase 3 trials in gastric cancer combined with chemotherapy. 20 Similarly, onartuzumab, 21,22 an anti-cMet antibody, failed to show benefit when tested in combination with the EGFR inhibitor erlotinib in a Phase 3 non-small-cell lung cancer trial, 23 which might be due to inappropriate patient selection.…”

Management of Adverse Events Associated with Cabozantinib Therapy in Renal Cell Carcinoma

“…Adverse events (AEs) associated with cabozantinib include diarrhea, fatigue, hypertension, dermatological manifestations such as hand-foot syndrome (HFS), weight loss and decreased appetite, stomatitis, and nausea [21][22][23][24][25]. These AEs can have a negative impact on patients' health-related quality of life (HRQoL) and may require drug dose reductions or interruptions as a way to manage them [23,25,26].…”