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The Oncologist, Vol. 12, No. 4, 426-437, April 2007; doi:10.1634/theoncologist.12-4-426
© 2007 AlphaMed Press

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 Safety, Pharmacokinetics, and Preliminary Antitumor Activity of Sorafenib: ...
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Clinical Pharmacology

Safety, Pharmacokinetics, and Preliminary Antitumor Activity of Sorafenib: A Review of Four Phase I Trials in Patients with Advanced Refractory Solid Tumors

Dirk Strumberga, Jeffrey W. Clarkb, Ahmad Awadac, Malcolm J. Moored, Heike Richlya, Alain Hendliszc, Hal W. Hirtee, Joseph P. Ederf, Heinz-Josef Lenzg, Brian Schwartzh

aDepartment of Hematology and Medical Oncology, Marienhospital Herne, University Medical School of Bochum, Herne, Germany; bMassachusetts General Hospital Cancer Center, Boston, Massachusetts, USA; cJules Bordet Institute, Brussels, Belgium; dPrincess Margaret Hospital, Toronto, Ontario, Canada; eJuravinski Cancer Center, Hamilton, Ontario, Canada; fDana-Farber Cancer Institute, Boston, Massachusetts, USA; gUniversity of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California, USA; hBayer Pharmaceuticals Corporation, West Haven, Connecticut, USA

Key Words. Sorafenib • BAY 43-9006 • Phase I clinical trials • Review

Correspondence: Correspondence: Dirk Strumberg, M.D., Department of Hematology and Medical Oncology, Marienhospital Herne, University Medical School of Bochum, Hölkeskampring 40, D-44621 Herne, Germany. Telephone: 49-2323-499-5252; Fax: 49-2323-499-1578; e-mail: dirk.strumberg{at}marienhospital-herne.de

Received June 19, 2006; accepted for publication January 10, 2007.


   LEARNING OBJECTIVES
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 Learning Objectives
Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Disclosure of Potential...
 References
 
After completing this course, the reader will be able to:

  1. Describe the mechanisms of action of sorafenib.
  2. Discuss the safety and toxicity data from phase I trials of sorafenib.
  3. Evaluate phase I and II trials of sorafenib with activity data.
  4. Discuss future areas for research in the development of this drug.

Access and take the CME test online and receive 1 AMA PRA Category 1 CreditTM at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 Disclosure of Potential...
 References
 
Sorafenib is an oral multikinase inhibitor that inhibits Raf serine/threonine kinases and receptor tyrosine kinases involved in tumor growth and angiogenesis. It has demonstrated preclinical and clinical activity in several tumor types. Sorafenib 400 mg twice daily (bid) has been approved in several countries worldwide for the treatment of renal cell carcinoma. This review summarizes key safety, pharmacokinetic, and efficacy data from four phase I, single-agent, dose-escalation studies with sorafenib in patients with advanced refractory solid tumors (n = 173). These trials followed different treatment regimens (7 days on/7 days off, n = 19; 21 days on/7 days off, n = 44; 28 days on/7 days off, n = 41; or continuous dosing, n = 69) to establish the optimum dosing schedule. Sorafenib was generally well tolerated; most adverse events were mild to moderate in severity up to the defined maximum-tolerated dose of 400 mg twice daily (bid). The most frequently reported drug-related adverse events at any grade included fatigue (40%), anorexia (35%), diarrhea (34%), rash/desquamation (27%), and hand–foot skin reaction (25%). Sorafenib demonstrated preliminary antitumor activity, particularly among patients with renal cell carcinoma or hepatocellular carcinoma: overall, two of 137 evaluable patients achieved partial responses and 38 (28%) had stable disease. Although there was high interpatient variability in plasma pharmacokinetics across these studies, this was not associated with an increased incidence or severity of toxicity. Preliminary studies suggest that phosphorylated extracellular signal–related kinase in tumor cells or peripheral blood lymphocytes may be a useful biomarker for measuring and, ultimately, predicting the effects of sorafenib. Based on these findings, continuous daily 400 mg bid sorafenib was chosen as the optimal regimen for phase II/III studies. Trials are ongoing in renal cell carcinoma, hepatocellular carcinoma, melanoma, and non-small cell lung cancer.

Disclosure of potential conflicts of interest is found at the end of this article.


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 Disclosure of Potential...
 References
 
The ubiquitous Raf–mitogen-activated protein kinase/extracellular signal–related kinase kinase (MEK)–extracellular signal–related kinase (ERK) signaling pathway has a major role in the regulation of cell proliferation, survival, and differentiation [1]. Dysregulated signaling via Raf is associated with the development of solid tumors [1–3]. Thus, Raf–MEK–ERK is an appropriate pathway to target for therapeutic intervention [4]. Because advanced solid tumors or metastatic solid tumors are often refractory to standard cytotoxic treatments and associated with a poor prognosis and low 5-year survival rates (e.g., 0%–20% for metastatic renal cell carcinoma [RCC]) [5], there is a need for the development of well tolerated and effective targeted therapies that can stabilize or slow their progression [6].

Oncogenic ras mutations, leading to aberrant signaling through Raf, occur in approximately 30% of human cancers, including many solid tumors [7]. K-ras mutations occur frequently in non-small-cell lung cancer (NSCLC) [7], colorectal cancer (CRC) [8], and pancreatic carcinomas [9], whereas H-ras mutations are common in bladder, kidney, and thyroid carcinomas [7]. N-ras mutations are found in melanoma, hepatocellular carcinoma (HCC), and hematologic malignancies [7]. Overactivation of receptor tyrosine kinases (RTKs), such as vascular endothelial growth factor receptor (VEGFR)-2/-3, platelet-derived growth factor receptor (PDGFR)-ß, and epidermal growth factor receptor (EGFR), as a result of either activating mutations or overexpression of their growth factor ligands, can result in aberrant signaling through Raf, dysregulated cell growth, and cancer [1, 2, 10]. Aberrant signaling through VEGFR-2 is associated with neoangiogenesis [11] and melanoma progression [12], whereas overexpression of VEGFR-3 occurs in vascular skin tumors and invasive breast carcinoma microvasculature [13]. Oncogenic mutations that lead to aberrant activation of PDGFR-ß occur in myeloid leukemias and gastrointestinal stromal tumors (GISTs) [14]. Mutations in Flt-3 have been reported in acute myelogenous leukemia (AML) [15], while c-Kit mutations occur in GIST [16], chromophobe RCC [17], AML [18], and uveal melanomas [19]. Furthermore, activating b-raf V600E (formerly designated V599E [20]) mutations are common in melanoma (60%–90%) [21–24], papillary thyroid carcinomas (36%) [25], CRC (9%) [26], and, to a lesser extent, pancreatic carcinomas [27], gastric carcinomas [28], and NSCLC [23]. V600E mutations have also been reported in a relatively high proportion (82%) of nevi [22]. Data suggest that mutational activation of the Raf–MEK–ERK pathway is a critical step in the initiation of melanocytic neoplasia, but alone is insufficient for melanoma tumorigenesis [22].

Sorafenib is an oral multikinase inhibitor that was originally developed because of its inhibitory effects on the serine/threonine kinase Raf and several RTKs that induce cell proliferation and/or angiogenesis. The ability of sorafenib to inhibit Raf-1 and additional Raf isoforms (e.g., V600E mutant b-raf) and RTKs (e.g., VEGFR-1/-2/-3) was demonstrated by in vitro biochemical assays (Table 1) [29, 30]. Recent in vitro studies have shown that sorafenib potently inhibited oncogenic rearranged during transfection (RET) kinase activity and growth of RET-transfected fibroblast cells and human thyroid cancer cells harboring RET/papillary thyroid carcinoma (PTC) and RET/multiple endocrine neoplasia (MEN) type 2 oncogenes (Table 1) [31].

Furthermore, sorafenib reduced phosphorylated (p)ERK levels in tumor cell lines in which the Raf–MEK–ERK pathway was upregulated by oncogenic ras and/or raf mutations, including colon and pancreatic tumor cells (both K-ras), melanoma tumor cells (b-raf V600E), and breast tumor cells (K-ras and b-raf G463V) [29]. Sorafenib also demonstrated proapoptotic effects by enhancing proteasomal degradation of the antiapoptotic myeloid cell leukemia-1 (Mcl-1) protein in several cancer cell lines, including lung cancer, RCC, colon cancer, and breast cancer [32].

In vivo, sorafenib has demonstrated preclinical activity in several advanced solid tumor models [29]. In tumor xenografts, sorafenib inhibited growth of human tumors with oncogenic b-raf or K-ras mutations (e.g., colon cancer, pancreatic cancer, and NSCLC), or increased signaling through Raf due to upstream RTK overexpression [29, 33, 34]. In a number of xenograft models, sorafenib appeared to act in an antiproliferative manner by inhibiting signaling through Raf, as evidenced by reduced tumor pERK levels. Sorafenib has also demonstrated antiangiogenic effects in animal models, which could be mediated by inhibition of endothelial cell signaling at the level of VEGFR-2, PDGFR-ß, and/or Raf [29]. Further in vivo studies in several tumor xenograft models, including HCC [35], RCC [36], and melanoma [37], are ongoing to determine the mechanisms of action responsible for sorafenib's antitumor and antiangiogenic effects. Recent findings have shown that sorafenib inhibited tumor growth and angiogenesis (reduced microvessel area), and induced apoptosis (downregulated Mcl-1), through Raf–MEK–ERK-dependent or -independent pathways, depending on the type of tumor being investigated [35, 36].

Sorafenib has been investigated as monotherapy in four phase I trials, each following a dose-escalation procedure and a different treatment schedule: 7 days on/7 days off [38], 21 days on/7 days off [39], 28 days on/7 days off [40], and continuous dosing [41]. These studies were performed to evaluate the safety, pharmacokinetics, preliminary antitumor activity, and biomarkers of sorafenib, and to determine the optimum dosing schedule to achieve effective tumor inhibition, with an acceptable level of toxicities, in patients with advanced refractory solid tumors.

This review highlights the key findings of these phase I trials, focusing on sorafenib doses of 200–600 mg twice daily (bid)—close to the determined maximum tolerated dose (MTD) of 400 mg bid subsequently recommended for evaluation in phase II/III trials.


   PATIENTS AND METHODS
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 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 Disclosure of Potential...
 References
 
Trial Design and Treatment Plan
Full descriptions of the inclusion and exclusion criteria, schedules, and safety, pharmacokinetic, and pharmacodynamic endpoints for each of the four phase I trials have been described previously [38–41]. Briefly, these trials were open-label, non–placebo-controlled, dose-escalation studies with sorafenib performed at sites in the U.S. [38], Belgium [39], Canada [40], and Germany [41]. These trials were performed to evaluate different bid dosing schedules: 7 days on/7 days off [38], 21 days on/7 days off [39], 28 days on/7 days off [40], and continuous [41]. Patients eligible for enrollment were ≥16 years of age with advanced, incurable, metastatic or recurrent solid tumors, refractory to available therapy. Each patient had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0–2, life expectancy of ≥12 weeks, clinically evaluable disease, and adequate bone marrow, hepatic, and renal function.

A range of dose levels was investigated in these studies. Sorafenib was supplied as 50-mg tablets. Patients received sorafenib at doses ranging from 50 mg once daily (every 4 or 5 days, or every other day) to 800 mg bid, including 100 mg once daily, 100 mg bid, 200 mg bid, 400 mg bid, and 600 mg bid. The starting dose of 50 mg was considered to be within the therapeutic range without being excessively toxic, based on preclinical studies in dogs and assuming that oral bioavailability of sorafenib is similar in humans and in dogs. Three patients were initially enrolled into each dosing group, and subsequent groups were treated according to a standardized dose-escalation schema to determine the MTD (Fig. 1). In the absence of dose-limiting toxicities (DLTs) within the first treatment cycle, the next three patients were enrolled. If any patient developed a DLT, three additional patients were enrolled at that dose. The incidence, severity, and relationship to study drug of adverse events were assessed at the end of each cycle, and graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC), version 2.0 [42]. Following completion of treatment, a toxicity assessment was made 30 days after discontinuation of study drug. Dose escalation proceeded until the MTD was reached. The MTD in these trials was defined as the dose level below that at which at least two of six patients experienced a DLT during the first treatment cycle, which was defined as grade ≥4 hematologic toxicity for 5 days; grade ≥3 nonhematologic toxicity, febrile neutropenia, or grade 4 neutropenia lasting at least 4 days; or grade ≥3 thrombocytopenia [42]. In each trial, sorafenib treatment continued until the occurrence of unacceptable toxicity, withdrawn consent, tumor progression, or death.

Best tumor response was evaluated according to the Response Evaluation Criteria In Solid Tumors (RECIST) [43]. Complete response was defined as the disappearance of all clinical and radiologic evidence of both target and nontarget tumors; partial response was defined as a ≥30% decrease in the sum of the longest diameter (LD) of target lesions; stable disease was defined as a tumor that had between a <30% decrease and <20% increase in the sum of the LD; disease progression was defined as a ≥20% increase in the sum of the LD. Unequivocal progression of a nonmeasured lesion could be accepted as evidence of disease progression. Complete or partial responses required a confirmatory scan ≥4 weeks later. For an assessment of stable disease, documentation of stable disease was also required at least once ≥4 weeks from baseline. The duration of response was defined as the time period from the initial measurement of complete or partial response to the first date that disease progression or recurrent disease was objectively documented. Duration of stable disease was measured from the start of therapy until the criteria for progression were met. The same method of assessment and the same techniques were used to identify, characterize, and report each lesion at baseline and during follow-up.

Pharmacokinetic analyses were performed at Bayer HealthCare Pharmaceuticals, West Haven, CT (7 days on/7 days off and 28 days on/7 days off); Institut Bordet, Brussels, Belgium (21 days on/7 days off); and Bayer HealthCare, Pharma Research Center, Wuppertal, Germany (continuous dosing). Samples for pharmacokinetic analyses were taken at regular intervals up to 168 hours after dosing on the last day of treatment during cycle 1.


   RESULTS
Top
 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 Disclosure of Potential...
 References
 
The majority of the 173 participants (age range, 18–79 years) had received prior chemotherapy (96%), surgery (94%), and/or radiotherapy (36%) (Table 2). The majority of patients were male (56%), and the most common primary cancer sites included colon (66 patients, 38%) and the upper gastrointestinal tract (15 patients, 9%).

Safety and Tolerability
Sorafenib was generally well tolerated in these phase I trials, particularly at doses ≤400 mg bid. Although the majority of patients experienced at least one adverse event, these toxicities were mostly mild to moderate in severity, and easily manageable. The most frequently reported drug-related adverse events at any grade included fatigue (40%), anorexia (35%), diarrhea (34%), rash/desquamation (27%), and hand–foot skin reaction (HFSR) (25%) (Table 3). The most frequent drug-related adverse events of grade ≥3 in severity were HFSR (8%), fatigue (6%), and diarrhea (4%). Adverse events were mainly grade 2 or lower (89%) in severity and were resolved by reducing the dose and/or discontinuing sorafenib. Most adverse events at the 400 mg bid dose level were grade 2 or lower in severity in the three noncontinuous trials. However, in the continuous-dosing study, grade 3 alopecia occurred at this dose in two patients, while skin toxicity was reported in nine of 14 patients at 600 mg bid [41]. Grade 3 or 4 drug-related myelosuppression (i.e., neutropenia or thrombocytopenia) or biochemical abnormalities (e.g., elevated lipase) were observed infrequently. Severe hematologic, cardiovascular, hepatic, and renal toxicities were not reported after sorafenib administration in these trials. Across the four phase I trials, treatment-emergent hypertension at any grade was observed in 5%–11% (grade 3 or 4, 0%–5%) of patients.

Dose reductions or interruptions were reported in a total of 31 patients across the four phase I trials. In the 21 days on/7 days off trial, nine of 12 (75%) patients had their starting dose of 600 mg bid reduced to 400 mg bid and continued to receive this lower dose until the end of therapy [39]. Of these nine patients, six (67%) experienced DLTs before their dose was reduced to 400 mg bid. Two of the three patients originally assigned to 800 mg bid received a dose reduction; one patient to 600 mg bid, and one patient to 600 mg bid (four cycles) and then to 400 mg bid (five cycles) as a result of toxicity (i.e., 10 cycles in total were received by this patient) [39]. In the 28 days on/7 days off trial, a total of six patients (15%) had dose reductions because of toxicity (four patients had HFSR, one patient had changes in bilirubin, and one patient had constipation and abdominal pain) [40]. Throughout the four studies, many patients had dose reductions or discontinued because of unacceptable toxicity at the highest doses of sorafenib (600 and 800 mg bid).

The median number of treatment cycles ranged from one to five, across the three non–continuous phase I trials, and the maximum number of cycles received by any patient was 30 (100 mg bid group, 7 days on/7 days off). In these three trials, patients received a median of either three or four treatment cycles (range, 1–14) at the MTD of 400 mg bid. There was no clear dose-dependent decrease in the number of cycles that patients received, up to 600 mg bid. In the continuous-dosing trial, the mean durations of treatment were similar in patients receiving the 200 and 400 mg bid doses (264 and 230 days, respectively) [41]. However, patients receiving the 600 and 800 mg bid doses had shorter treatment durations (89 and 88 days, respectively) than with the lower doses.

DLTs, MTD
The majority of DLTs occurred at the highest doses of sorafenib (i.e., ≥600 mg bid). Six patients of a total of 13 reported DLTs at the 800 mg bid dose: three in the 7 days on/7 days off trial (grade 3 rash/desquamation, n = 2; grade 3 hypertension and grade 2 rash, n = 1) and three in the continuous trial (grade 3 diarrhea, n = 2; grade 3 fatigue, n = 1). Seven patients of a total of 39 reported DLTs on the 600 mg bid dose: three in the 28 days on/7 days off trial (all HFSR) and four in the continuous-dosing trial (all skin toxicity). Only one patient experienced a DLT at the 400 mg bid dose level (in the 21 days on/7 days off trial [37]: grade 3 fatigue, anorexia, vomiting, nausea, and pain). Three DLTs (grade 3 fatigue, diarrhea, and pancreatitis) were experienced at the lower doses of sorafenib (i.e., 100 and 200 mg bid), and these occurred in the trials in which patients received sorafenib for the longest duration (i.e., the 28 days on/7 days off and continuous trials).

The MTD was defined as 400 mg bid continuously in three of the four trials, as this dose was not associated with significant toxicity; 600 mg bid was determined to be the MTD in the 7 days on/7 days off trial [38].

Pharmacokinetics
Multiple dosing with oral sorafenib was associated with high interpatient pharmacokinetic variability, and plasma concentration–time profiles of sorafenib increased less than proportionally with increasing dose [38, 40, 41] (Table 4). However, this interpatient pharmacokinetic variability was not related to the incidence or severity of drug-related adverse events. Substantial accumulation in plasma following multiple bid administrations was observed in the continuous dosing study [41]. Steady-state concentrations of sorafenib were reached after 7 days of dosing, with no further substantial accumulation observed after this time [39]. Although the time to maximum concentration (tmax) was variable, accumulation of sorafenib in the plasma after multiple bid dosing was observed in each of the three noncontinuous trials (Table 5). At the overall MTD (400 mg bid) in the three noncontinuous trials, the mean maximum concentration (Cmax) and area under the concentration–time curve (AUC) values were substantially greater on the last day (i.e., pharmacokinetic sampling performed on the final day of dosing in cycle 1 [at steady state] in each phase I trial, i.e., day 7, 21, or 28) compared with day 1 (Table 4). Cmax was in the range of 2.3–3.0 mg/l on day 1 and 5.4–10.0 mg/l on the last day of dosing in cycle 1 for each trial. AUC0–12 was in the range of 18.0–24.0 mg·h/l on day 1 and 47.8–76.5 mg·h/l on the last day of dosing in cycle 1 for each trial, at 400 mg bid. Sorafenib has a relatively long elimination half-life (t1/2), which was in the range of 20.0–27.4 hours at the 400 mg bid dose across the three noncontinuous studies. In the continuous dosing study, Cmax and AUC values were also variable after multiple dosing with sorafenib [41]. The mean Cmax was lowest (2.31 mg/l) at the 100 mg bid dose, and the mean AUC0–12 was lowest (16.1 mg·h/l) at the 200 mg bid dose. The maximum Cmax (9.81 mg/l) and AUC0–12 (79.0 mg·h/l) values, which were obtained at the 600 mg bid dose, were similar to the corresponding values at the 400 mg bid dose level. Importantly, the intake of food prior to dosing had no major effect on the pharmacokinetics of sorafenib, except for a slight prolongation of the tmax in the continuous dosing trial [41].

Tumor Response
Sorafenib demonstrated preliminary evidence of antitumor activity, although it acted primarily by inducing disease stabilization. Although more patients receiving sorafenib doses ≥200 mg bid appeared to experience antitumor activity, there was no clear dose–response relationship in the four trials. A total of 137 patients were analyzed for tumor response by RECIST unidimensional measurement [43]. Of the patients evaluable for response, only two patients across the four phase I studies had an objective partial response. In the 21 days on/7 days off trial, one patient with RCC had a sustained partial response with a starting dose of 600 mg bid sorafenib, lasting 104 days; in the continuous trial, a patient with HCC who received a 400 mg bid dose had a partial response lasting >6 months. The most frequently observed response was disease stabilization, which occurred in 28% of patients (38/137) evaluated for tumor response. It is important to note that not all enrolled patients were evaluable for tumor response across the four studies. In the 21 days on/7 days off trial, tumor response was not done or missing, or unevaluable, in a total of 12 patients. In the continuous trial, antitumor activity was measured only for patients treated continuously with sorafenib at doses ≥100 mg bid.

In the continuous trial, five patients (11%) had sustained stable disease lasting >12 months [41]. One heavily pretreated patient with RCC, who had failed three prior standard treatment regimens, had sustained stable disease lasting approximately 2 years. Furthermore, two CRC patients had stable disease for >1 year, and 50% of the HCC patients showed stable disease for at least 6 months.

In the 21 days on/7 days off trial, two patients had stable disease for >12 months (600 mg bid starting dose), and six patients had stable disease for 6–12 months [39]. An additional 19 patients (43%) survived at least 6 months, and a further three patients (7%) survived >12 months after the initiation of sorafenib treatment. In the 7 days on/7 days off trial, a patient with metastatic RCC, who started treatment with 100 mg bid sorafenib, showed stable disease and was subsequently entered into an extension phase; this patient remained on therapy for approximately 2 years [38].

Although there appeared to be a greater likelihood of antitumor activity with doses of ≥200 mg bid in the 21 days on/7 days off and continuous dosing trials, no clear dose–response relationship was observed.

The median time to disease progression varied from 42 days (7 days on/7 days off trial) to 83 days (continuous trial) in the four phase I trials.

Biomarkers
Sorafenib-induced inhibition of pERK following activation with phorbol myristate acetate (PMA) was investigated in patients' peripheral blood lymphocytes (PBLs) [41]. Isolated PBLs were stained with a phospho-specific antibody for ERK-1 and ERK-2, a fluorescein isothiocyanate–goat-anti-rabbit antibody, and an anti-CD7 antibody.

In the continuous-dosing trial, PMA-induced phosphorylation of ERK in PBLs from six patients was almost totally inhibited by 400 mg bid sorafenib on day 21 [41]. These preliminary findings suggest that the antitumor activity of sorafenib at the MTD may correlate with decreased nuclear pERK levels, and that the MTD is sufficient to inhibit pERK in PBLs. One patient in the 7 days on/7 days off trial with metastatic melanoma (involving the right thigh, liver, and lung), who received a 600 mg bid dose and showed a minor response, was evaluated for pERK [38]. A comparison of melanoma biopsies taken from this patient on day 1 of cycle 1 and day 7 of cycle 2 showed that the percentage of cell nuclei staining positively for pERK decreased with sorafenib treatment. Positron emission tomography (PET) scans of the same tumor performed at baseline and on day 22 revealed a reduced uptake of [18F]2-fluoro-2-deoxy-d-glucose (FDG) with sorafenib treatment, suggesting that sorafenib inhibited tumor activity. Subsequent scans at day 43 and day 64 showed stable disease.


   DISCUSSION
Top
 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
Disclosure of Potential...
 References
 
Overall, sorafenib was safe and well tolerated at doses up to 400 mg bid in four dose-escalation phase I trials [38–41]. Sorafenib demonstrated preliminary anti-tumor activity in these trials, primarily by inducing disease stabilization in patients with a variety of advanced refractory tumors, consistent with results obtained in preclinical studies [44]. Limited biomarker analyses from one institution suggest that, at the MTD, sorafenib plasma concentrations are sufficient to inhibit signaling through the Raf–MEK–ERK pathway in PBLs.

Results from these four phase I trials show that most patients receiving sorafenib treatment experienced drug-related adverse events, including fatigue, diarrhea, and skin toxicities. However, these were mainly mild to moderate in severity, and easily manageable by down-titration or cessation of treatment. The MTD in these trials was defined as the highest dose of sorafenib achievable with an acceptable level of toxicity, and was to be recommended for use in further studies. Because DLTs, including skin toxicities, diarrhea, and fatigue, occurred mainly at the higher doses (600 and 800 mg bid) across the four trials, but were relatively infrequent at lower doses (100 and 200 mg bid), the overall MTD was determined to be 400 mg bid. However, in contrast to the other three trials, in the 7 days on/7 days off study [38], the MTD was determined as 600 mg bid. This higher MTD may reflect the shorter duration of treatment in this trial relative to the other trials, which allowed patients to tolerate higher doses of sorafenib. The observation that the DLTs observed at the lowest doses of sorafenib only occurred in the trials with the longest treatment durations (28 days on/7 days off and continuous dosing) is consistent with this suggestion. However, these findings need to be confirmed in further trials. At the MTD of 400 mg bid, the continuous-dosing schedule was not associated with DLTs or significant grade 3 or 4 toxicities [41]. Therefore, continuous bid dosing, rather than a noncontinuous regimen, was chosen as the optimum dosing schedule to be used in further phase II and III trials. Results from a preclinical study in a human colon (DLD-1) carcinoma xenograft model also support a continuous dosing regimen: continuous sorafenib induced threefold greater tumor growth delays than a single 10-day dosing course [45]. Treatment-emergent hypertension at any grade was observed in ≤11% of patients across the four phase I trials, which was slightly lower than that reported in the recent phase III TARGETs trial (Treatment Approaches in Renal Cancer Global Evaluation Trials) [46]. A total of 17% (4% grade 3 or 4) of patients with RCC receiving sorafenib at a dose of 400 mg bid had treatment-emergent hypertension, versus 2% (<1% grade 3 or 4) of patients receiving placebo in the phase III trial. However, sorafenib-related hypertension rarely required intervention and was easily manageable.

The favorable toxicity profile suggests that sorafenib has the potential to be combined with other anticancer therapies, including those that are associated with higher toxicity, which may improve efficacy over the single agents alone. Sorafenib has also demonstrated good tolerability and promising antitumor activity in phase I/II combination studies, including combinations with oxaliplatin [47], 5-fluorouracil and leucovorin [48], paclitaxel plus carboplatin [49], gemcitabine [50], doxorubicin [51], docetaxel [52], and irinotecan [53].

Although sorafenib exhibited high interpatient pharmacokinetic variability following multiple dosing in the four phase I monotherapy trials, there was no evidence to suggest that the observed increases in mean plasma exposure (Cmax and AUC) resulted in increased overall toxicity. There was no apparent relationship between mean plasma exposure and antitumor activity. Sorafenib accumulated in the plasma after 7 days of multiple dosing in the four studies. Other studies have shown that there was no further increase in Cmax or AUC beyond 7 days of multiple dosing [54]. However, further trials are required to clarify whether there is a relationship between exposure and toxicity/efficacy.

Sorafenib monotherapy demonstrated preliminary antitumor activity in these phase I studies in patients with several advanced refractory solid tumor types, including RCC, HCC, and CRC. Sorafenib was mostly associated with durable disease stabilization, while two patients (one each with RCC and HCC) had partial responses. Aberrant activation of the Raf–MEK–ERK signaling pathway has been associated with RCC and HCC tumors [55, 56]. However, in these highly vascularized tumors, overexpression of angiogenic growth factors, such as VEGF, and their receptors, which signal through Raf, are also implicated in their progression [57–59]. Therefore, there is a rationale for using sorafenib in these tumor types, although it would be difficult to determine whether inhibition of Raf, VEGFR, and/or PDGFR is responsible for its antitumor effect. It is important to note that prolonged (>6 months) disease stabilizations were reported in a total of eight patients (18%, including four with CRC and two with HCC) who were treated continuously with sorafenib [41]. In addition, five of these patients (11%) had stable disease for >1 year. Phase II studies have confirmed that a continuous 400 mg bid sorafenib dosing schedule has disease-stabilizing effects in patients with advanced refractory RCC and HCC [60, 61]. Furthermore, results from the phase III TARGETs trial have shown that sorafenib significantly prolonged progression-free survival versus placebo, and was well tolerated in patients with advanced, treatment-refractory RCC [46]. Although the extent of tumor shrinkage did not meet the requirements to be considered a partial response according to RECIST, shrinkage (ranging from <1% to 100% change from baseline) was observed in 76% of patients treated with sorafenib, compared with only 25% receiving placebo [46].

The Raf–MEK–ERK signaling cascade has an important role in tumor pathogenesis, and several novel anticancer therapies that target this ubiquitous pathway are in clinical development [2]. The challenges for clinical investigators evaluating novel targeted agents are how to: establish the optimum dose threshold that delivers maximum therapeutic effect, monitor treatment progress, and predict outcomes. The identification and validation of molecular biomarkers will help clinicians to overcome these challenges. For sorafenib, which inhibits Raf-1, wild-type B-Raf, and b-raf V600E, the level of ERK phosphorylation may be useful as a biomarker of response. However, biochemical assays have also demonstrated that sorafenib inhibits multiple kinases involved in signal transduction processes, including VEGFR-2, VEGFR-3, Flt-3, and c-Kit [29]. These additional targets could also provide biomarkers of sorafenib response. In preclinical studies, ERK phosphorylation was inhibited by sorafenib in a number of tumor cell lines and xenograft models [29]. pERK either within the tumor or in PBLs is emerging as an appropriate molecular biomarker for sorafenib. In 2002, a biomarker assay was established using fluorescence-activated cell sorting for the detection of PMA-induced activated ERK-1/2 in PBLs (CD7+ T cells) derived from patients with solid tumors treated with sorafenib [62, 63]. Using this assay, inhibition of the Raf kinase pathway, as evidenced by a decrease in pERK in PBLs, was shown to be pronounced at tolerable doses of sorafenib, including the MTD of 400 mg bid and the higher 600 mg bid dose [62, 63]. Therefore, PBL pERK is a potential surrogate marker for the effects of mitogen-activated protein kinase inhibitors in cancer patients [64]. pERK was investigated further as a potential biomarker in clinical trials. Preliminary biomarker evaluations of a patient with metastatic melanoma, who had a minor response to sorafenib, demonstrated that decreased nuclear pERK levels within the tumor may be predictive of anti-tumor activity [38]. A significant correlation was also observed between baseline tumor-cell pERK levels and time to progression (TTP) in a phase II study with HCC patients, further supporting a role for pERK as a biomarker of sorafenib response [65]. HCC patients whose tumors expressed higher baseline pERK levels had a longer TTP following treatment with the sorafenib MTD of 400 mg bid [65]. Additional biomarkers of sorafenib response are also being evaluated, and will hopefully benefit future development of the drug. Activating b-raf mutations result in overstimulation of the Raf–MEK–ERK pathway and may drive proliferation of tumor cells [66] where they occur with a high frequency, such as in melanoma cells [67]. Oncogenic b-raf mutations and VEGFR-2 expression are currently being evaluated in phase I–III trials as potential sorafenib biomarkers.

Technological advances have also provided novel ways to accurately monitor changes in tumor volume, activity, and vascularity with treatment. FDG–positron emission tomography (PET) is one such technique capable of monitoring early-stage tumor growth, by detecting the metabolic activity of malignant cells before any morphologic signs are evident with radiologic examination [68]. PET scans of a melanoma patient showed a reduction in FDG uptake (i.e., reduced metabolism) by the tumor relative to baseline, suggesting that sorafenib decreased tumor activity [38]. FDG-PET may also be useful for disease staging, in addition to providing an early indication of outcome with sorafenib.

In summary, sorafenib demonstrated good safety and tolerability up to the MTD of 400 mg bid in these four phase I trials. Furthermore, sorafenib induced preliminary antitumor activity, mainly associated with disease stabilization, particularly in patients with RCC and HCC. Ongoing phase II and III studies are further evaluating sorafenib and its potential biomarkers in a variety of tumors, including RCC [60, 46], HCC [61], and melanoma [49].


   DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
Top
 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Disclosure of Potential...
References
 
D.S. has acted as a consultant for, performed contract work for, and served as a board member for Bayer AG and Tamko Pharm. A.A. and A.H. received financial support to perform one of the phase I trials of sorafenib. B.S. was formerly employed by Bayer and was the clinical leader responsible for the development of sorafenib. His current affiliation is Ziopharm Oncology.


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  		Table 1. Sorafenib inhibits the components of the Raf–MEK–ERK signaling pathway and RTKs

 


Figure 1
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  		Figure 1. Dosing schedule for phase I sorafenib trials. Abbreviations: DLT, dose-limiting toxicity; MTD, maximum tolerated dose.

 


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  		Table 2. Demographic and clinical characteristics of patients participating in the sorafenib phase I program

 


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  		Table 3. Summary of drug-related adverse events occurring in >10% of patients according to NCI-CTC, version 2, across the phase I program

 


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  		Table 4. Plasma pharmacokinetic parameters measured after dosing with sorafenib 100, 200, 400, and 600 mg twice daily (bid) in the three non–continuous dosing trials

 


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  		Table 5. Summary of plasma pharmacokinetic parameters measured after dosing with sorafenib 400 mg twice daily in the three non–continuous dosing trials

 

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 Learning Objectives
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 Patients and Methods
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 Discussion
 Disclosure of Potential...
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