Pathway Sorafenib Pharmacodynamics

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Description

Sorafenib (NEXAVAR®, BAY43-9006) is an oral anti-cancer drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced renal cell carcinoma (RCC), unresectable or metastatic hepatocellular carcinoma (HCC), and locally recurrent or metastatic, progressive and differentiated thyroid carcinoma (DTC) refractory to radioactive iodine treatment [Article:21374666]. It is also being evaluated in acute myeloid leukemia (AML) and other solid tumors in adults and children. Sorafenib inhibits tumor cell proliferation and angiogenesis via targeting numerous serine/threonine and tyrosine kinases (RAF1, BRAF, VEGFR 1, 2, 3, PDGFR, KIT, FLT3, FGFR1, and RET) in multiple oncogenic signaling pathways [Articles:15466206, 16507829, 17016424, 17470685]. The most common adverse effects associated with sorafenib include hand-foot skin reaction (HFSR), diarrhea, hypertension, rash, fatigue, abdominal pain and nausea [Articles:21898496, 24283303, 27443985, 27106231]. Serious adverse effects (eg. liver failure, myocardial infarction) are rare but may arise in some cases. Adverse events may lead to compromised efficacy due to dose reduction or treatment interruptions. There is high interpatient variability in cumulative drug exposure and responses following sorafenib treatment [Articles:17016424, 17470685, 25641331, 25976912]. In this review, we discuss the clinical pharmacology of sorafenib and highlight genetic variations that may contribute to the diverse pharmacological responses to sorafenib. Better understanding of the factors contributing to the high variability of response to sorafenib should improve the efficacy and safety of the drug, and help select patients who will benefit most from sorafenib therapy.

Pharmacodynamics Sorafenib was initially identified as a Raf-1 kinase inhibitor [Articles:14692719, 15466206]. Further in vitro and in vivo studies demonstrated that it also targets multiple receptor tyrosine kinases in the cell membranes (eg. VEGFR 1, 2, and 3, PDGFR, stem cell factor receptor (KIT), FMS-related tyrosine kinase 3 receptor (FLT3), fibroblast growth factor receptor 1 (FGFR1), and RET proto-oncogene (RET)) as well as downstream intracellular serine/threonine kinases (eg. RAF1, wild-type BRAF and mutant BRAF carrying V600E) [Articles:15466206, 16507829, 17016424, 17470685]. Blocking these kinases and their downstream signaling molecules in multiple oncogenetic pathways leads to potent inhibition of both tumor cell proliferation, apoptosis, as well as tumor angiogenesis (Figure 2).

Preclinical studies have demonstrated that sorafenib inhibits tumor growth in a wide spectrum of human cancers (melanoma, renal, colon, pancreatic, hepatocellular, thyroid, ovarian, and non-small cell lung carcinomas (NSCLCs)) and in some cases induces tumor regression [Article:18852116]. In Dec 2005, Sorafenib was approved for the treatment of advanced renal cell carcinoma (RCC) by the FDA after favorable progression-free survival (PFS) results (5.5 months for sorafenib vs. 2.8 months for placebo) were obtained in the pivotal double-blind, placebo-controlled Phase III TARGET trial (Treatment Approaches in Renal Cancer Global Evaluation Trial) [Article:17215530]. Shortly after that in 2007, sorafenib was approved for the treatment of advanced unresectable hepatocellular carcinoma (HCC) after it demonstrated significant survival benefits in two global phase III clinical trials (the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) trial and the Asia Pacific trial) [Articles:18650514, 19095497]. In 2013, sorafenib was also approved by the FDA to be the first-line treatment option in advanced, radioiodine-refractory differentiated thyroid carcinoma (DTC) [Article:25053887]. The Phase III study conducted in radioiodine-refractory DTC showed that sorafenib significantly prolongs progression-free survival compared to placebo, 10.8 versus 5.8 months, respectively [Article:24768112]. Though it prolongs overall survival (OS) or PFS in these trials, sorafenib’s efficacy is modest with short survival prolongation periods of a few months. Following the approval of sorafenib, there have been various tyrosine kinase inhibitors (TKIs) investigated in phase II and III trials as first-line and second-line therapies to improve treatment outcomes of these advanced diseases. For advanced HCC, none of the TKIs have demonstrated superiority versus sorafenib in the front line setting or improved survival advantages over sorafenib used alone or in combination [Articles:24081937, 23980084, 23980090, 25547503]. Sorafenib remains the only approved therapy for HCC and is one of the most commonly used kinase inhibitors for the treatment of solid tumors.

Sorafenib has a low response rate, but was demonstrated to improve progression-free and overall survival. However, small numbers of patients in individual trials have demonstrated significant reductions in tumor burden. Biomarkers that can predict sorafenib efficacy, especially these burden reduction effects, would be helpful to identify the group of patients that are likely to benefit most from the treatment. Numerous clinical studies have been published trying to identify biomarkers that may predict prognosis or efficacy for sorafenib [Articles:20651059, 22374331, 22547010, 24703956, 26476711, 26420960, 27220960]. However, no predictive biomarker has yet been found or clinically validated. The candidate biomarkers that have been examined include molecular targets of sorafenib, ligands to those target receptors, as well as molecules that have been implicated in the pathogenesis of HCC. The clinical outcomes involved in biomarker analysis are PFS, OS and toxicities related to sorafenib treatment. The most convincing evidence evaluating plasma biomarkers to predict prognosis and response to sorafenib came from large randomized controlled trials. In the phase III randomized controlled SHARP trial involving 602 patients with HCC, Llovet et al found that plasma biomarkers (angiopoietin 2 (Ang2), VEGFA, HGF and IGF2) were predictors of prognosis in patients with HCC; however, none of the plasma biomarkers tested reached statistical significance to predict response to sorafenib, only high s-c-KIT or low HGF showed trends towards enhanced survival [Article:22374331]. A recent exploratory biomarker study in 494 patients with advanced HCC treated with sorafenib with or without erlotinib in the phase III SEARCH (Sorafenib and Erlotinib, a Randomized Trial Protocol for the Treatment of Patients With Hepatocellular Carcinoma) trial showed that high baseline plasma levels of HGF and VEGFA correlated significantly with shorter overall survival (OS), and high KIT concentration with longer OS. Additionally, high VEGF-C correlated with better time to progression (TTP) [Article:27220960]. However, since the SEARCH trial did not include a non-sorafenib (placebo alone) arm, it is not possible to determine if any of these markers tested would be predictive of treatment benefit from sorafenib, was prognostic, or spurious. Similar findings were reported from analysis of patients with differentiated thyroid cancer (DTC) in the phase III DECISION trial (http://meetinglibrary.asco.org/content/169956-176). The authors reported that elevated baseline serum thyroglubulin (Tg), VEGFA, VEGFC, TGF-ß1, and low E-cadherin were correlated with poor prognosis in DTC. However, none of the biomarkers tested were able to predict benefit from sorafenib. In summary, despite the large number of plasma and tissue biomarkers that have been examined in various trials and clinical studies, unfortunately no predictive biomarkers of responsiveness to sorafenib have been validated for clinical use.

Clinical pharmacodynamics biomarkers such as treatment adverse effects have also been examined. Hypertension and HSFR are two of the common side effects associated with sorafenib in cancer patients, and the occurrence of these events have been associated with more favorable clinical outcomes [Articles:19228742, 20630084, 23636006, 27882800]. These adverse events are also commonly seen with other anti-angiogenic therapies (eg. pazopanib, sunitinib, lenvatinib etc.) and are considered a class-specific toxicity [Articles:24988441, 24637941, 26123049, 25482593, 25471178]. The mechanism behind sorafenib-induced toxicities is not clear and may involve simultaneous disruptions of multiple signaling pathways including VEGF, PDGF, RAF1, BRAF, KIT, and FLT3 in normal organs [Articles:18210295, 18779536, 19923864].

Authors: Li Gong, Marilyn M. Giacomini, Craig P. Giacomini.
Citation:
Gong Li, Giacomini Marilyn M, Giacomini Craig, Maitland Michael L, Altman Russ B, Klein Teri E . "PharmGKB summary: sorafenib pathways" Pharmacogenetics and genomics (2017).
History:
Therapeutic Categories:
  • Anticancer agents

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