Management Of Tyrosine Kinase Inhibitor–Induced Hand–Foot Skin Reaction: Viewpoints from the Medical Oncologist, Dermatologist, and Oncology Nurse
We are living in an era of “molecularly targeted therapy.” This targeted approach has developed as advances in science have led to a more detailed understanding of the inner workings of the cell, both in health and in illness. Once a molecular pathway has been implicated in the development and progression of cancer, modulators can be developed to intervene in this
Sorafenib and sunitinib specifically recognize and inhibit c-KIT, VEGFR, PDGFR-β, and Flt3 receptor tyrosine kinases. Sorafenib also inhibits RAF, a serine/threonine kinase involved in the RAF/MEK/ERK kinase pathway
c-KIT = stem-cell growth factor receptor (a cytokine receptor expressed on the surface of hematopoietic stem cells as well as other cell types); ERK = extracellular signal–regulated kinase; Flt3 = FMS-like tyrosine kinase 3 (a cytokine receptor expressed on the surface of hematopoietic progenitor cells); Flt3L = FMS-like tyrosine kinase 3 ligand (Flt3 ligand); MEK = (MAPK/ERK) kinase; PDGF-ΒΒ = platelet-derived growth factor BB; PDGFR-β = platelet-derived growth factor receptor beta; RAF = a gene that encodes for a protein kinase (Raf1) that functions in the mitogen-activated protein kinase/extracellular signal–regulated kinase (MAPK/ERK) signal-transduction pathway as part of a protein kinase cascade; RAS = a superfamily of genes that encode small GTPases involved in cellular signal transduction; SCF = stem-cell factor; VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor
Adapted with permission from Lacouture et al3
Sorafenib was approved for the treatment of advanced renal cell carcinoma (RCC) in 2005 and for unresectable hepatocellular carcinoma (HCC) in 2007. The efficacy of sorafenib in 903 patients with advanced RCC was demonstrated in the phase III Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET), the largest phase III trial ever conducted in the second-line setting in patients with advanced RCC. Sorafenib significantly enhanced median progression-free survival (PFS) compared with placebo (24 vs 12 weeks),9 which led to early termination of the study and crossover from placebo to active drug. A preplanned analysis, which did not include patients who received placebo (who had crossed over to active treatment), ultimately demonstrated that sorafenib significantly prolonged overall survival (OS).10 Furthermore, 84% of sorafenib-treated patients experienced a clinical benefit, defined as objective response or disease stabilization.9 These results have been confirmed in larger, “real-world” patient populations in expanded-access programs conducted in North America (n = 2504)11 and the European Union (n = 118).12
Definitive data supporting the efficacy of sorafenib in HCC were provided by the randomized, double-blind, placebo-controlled Sorafenib CCC Assessment Randomized Protocol (SHARP) trial, the largest phase III trial ever conducted in patients with advanced HCC (n = 599) and the first phase III study to demonstrate a significant survival advantage with a systemic treatment in advanced HCC. In this trial, patients treated with sorafenib experienced a 44% increase in median OS (10.7 vs 7.9 months, hazard ratio [HR] = 0.69, 95% confidence interval [CI] 0.55–0.87, P < 0.001) and a 73% prolongation in median time to radiographic progression (5.5 vs 2.8 months, P < 0.001) compared with patients who received placebo.13 These results were confirmed in a separate phase III, randomized, double-blind, placebo-controlled study conducted in 226 patients from the Asia-Pacific region with advanced HCC.14 In this trial also, sorafenib significantly prolonged median OS (6.5 vs 4.2 months, HR = 0.68, 95% CI 0.50–0.93, P = 0.014) and time to progression (TTP) (2.8 vs 1.4 months, HR = 0.57, 95% CI 0.42–0.79, P = 0.0005) compared with placebo.
Sunitinib received approval in 2006 for use in patients with gastrointestinal stromal tumor (GIST) whose disease is refractory to imatinib (Gleevec®; Novartis Pharmaceuticals, East Hanover, NJ) or who are intolerant to the drug and in those with advanced RCC. Approval of sunitinib for the treatment of GIST was based on data from a randomized, placebo-controlled, phase III trial of 312 patients with imatinib-refractory GIST.15 In that study, sunitinib treatment increased median PFS (24.1 vs 6.0 weeks, HR = 0.33, 95% CI 0.24–0.47, P < 0.0001) and median TTP (27.3 vs 6.4 weeks, HR = 0.33, 95% CI 0.23–0.47, P < 0.0001) compared with placebo. The trial was unblinded early when a planned interim analysis revealed significantly longer TTP with sunitinib than with placebo. A subsequent analysis showed that median OS with sunitinib was about twice that with placebo (73.9 vs 35.7 weeks, P < 0.001).16 In an ongoing, worldwide treatment-use program to provide expanded access to sunitinib for patients with advanced GIST intolerant of or resistant to imatinib,17 sunitinib treatment resulted in a median estimated TTP of 41 weeks and a median estimated OS of 75 weeks in the population analyzed (n = 1,117).
A separate phase III randomized controlled trial was conducted in 750 patients with advanced RCC and no history of systemic therapy for RCC.[18] and [19] The active comparator in this trial was interferon-alfa (IFN-α). Compared with IFN-α, sunitinib significantly increased median PFS (11 vs 5 months, HR = 0.539, 95% CI 0.451–0.643, P < 0.001) and was associated with a greater objective response rate (47% vs 12%, P < 0.001). Median OS was greater in the sunitinib group (26.4 vs 21.8 months), but the difference was not significant (P = 0.051). Data from expanded-access programs in patients with RCC and GIST support the phase III trial data for sunitinib.20 Efficacy data for sorafenib and sunitinib are summarized in Table 1.[9], [10], [11], [12], [13], [14], [15], [17], [18] and [20]
